Keywords: Gene drive mechanisms
Compound effector genes suppress malaria parasite infections in gene-drive population modification strains of the African malaria mosquitoes, Anopheles gambiae and Anopheles coluzzii
35494Rebeca Carballar-Lejarazú, Yuemei Dong, Thai Binh Pham, et al., G3 Genes|Genomes|Genetics, 2026-03-09 10:43:52.
Malaria remains a major global health burden and is caused by protozoan parasites in the genus Plasmodium. Parasites are transmitted to humans during blood feeding by anopheline mosquitoes, and members of the Anopheles gambiae species complex are important vectors in sub-Saharan Africa. Gene-drive technologies offer promising options for disease control by enabling the spread of genetic traits through mosquito populations that block parasite transmission. We report here the development and characterization of four population modification gene-drive strains in Anopheles gambiae s.s. and An. coluzzii carrying compound effector genes. We sought to enhance the effectiveness of existing gene-drive strains to block Plasmodium transmission, thereby reducing vector competence and minimizing the opportunities for selection of resistant parasites. Two compound effector gene modules, TP24 and TP43, were introduced using Cas9 endonuclease and dual guide RNAs into TP13-based gene-drive strains to produce the An. gambiae AgTP24 and AgTP43 strains. The gene-drive cassettes were then introgressed into An. coluzzii to produce AcTP24 and AcTP43. Gene-drive dynamics, gene conversion, and inheritance were high in all strains, with 95% to 100% inheritance of the gene-drive constructs. Life table analyses showed mixed impacts on fitness dependent on the species and copy number (hemi- or homozygosity) of the gene-drive systems. The compound effector molecule gene complexes significantly reduced both parasite prevalence and infection intensities in An. gambiae and An. coluzzii following challenge assays with the human malaria parasite, P. falciparum. These findings highlight the potential of compound effector strategies in gene-drive systems to achieve durable malaria transmission control.
Stochastic dynamics at the back of a gene drive eradication wave
35468Léna Kläy, Léo Girardin, Florence Débarre, Vincent Calvez, Theoretical Population Biology, 168:44-64. 2026-02-24 14:22:40.
Gene drive alleles bias their own inheritance to offspring. They can fix in a wild-type population in spite of a fitness cost, and even lead to the eradication of the target population if the fitness cost is high. However, this outcome may be prevented or delayed if areas previously cleared by the drive are recolonised by wild-type individuals. Here, we investigate the conditions under which these stochastic wild-type recolonisation events are likely and when they are unlikely to occur in one spatial dimension. More precisely, we examine the conditions ensuring that the last individual carrying a wild-type allele is surrounded by a large enough number of drive homozygous individuals, resulting in a very low chance of wild-type recolonisation. To do so, we make a deterministic approximation of the distribution of drive alleles within the wave, and we split the distribution of wild-type alleles into a deterministic part and a stochastic part. Our analytical and numerical results suggest that the probability of wild-type recolonisation events increases with lower fitness of drive individuals and with smaller local carrying capacity. Numerical simulations show that these results extend to two spatial dimensions. The role of the migration rate however, is less clear but has a lower impact. We further demonstrate that, in the event of wild-type recolonisation, the probability of subsequent drive reinvasion decreases with smaller values of the intrinsic growth rate of the population. Overall, our study paves the way for further analysis of wild-type recolonisation at the back of eradication travelling waves.
Mapping Gene Drive Dynamics onto Mendelian Models
35414Zihang Wen, Monica Wan, Gili Greenbaum, Oana Carja, bioRxiv, 2026-01-30 16:46:40.
CRISPR-based gene drives bias their own transmission and can spread even when deleterious, giving rise to evolutionary dynamics that can be substantially more complex than those governed by standard Mendelian inheritance. Identifying conditions under which gene-drive dynamics can be faithfully approximated by Mendelian models would therefore enable the extensive theoretical toolkit of classical population genetics to be applied to gene-drive systems. Here, we develop a general mapping framework that translates gene-drive models into dynamically equivalent Mendelian models, allowing their behavior to be analyzed using classical theory. By deriving both haploid and diploid effective-parameter mappings, we identify Mendelian models that closely reproduce allele-frequency trajectories of gene drives across a wide range of conversion rates, fitness costs, and dominance effects. We delineate the regions of the parameter space where a one-parameter haploid approximation provides an accurate first-order representation, and where incorporating dominance in a diploid mapping substantially improves fidelity and recovers internal equilibria and threshold behavior. Analytic approximations yield efficient mappings across most of the drive parameter space, while a trajectory-based grid search further improves accuracy near nonlinear regime boundaries. To demonstrate the utility of this framework, we apply it to predicting gene swamping in a two-deme migration-selection model and show that the mapped Mendelian system accurately forecasts transitions between fixation and loss under three relevant release scenarios: environmental variation in fitness, engineered fitness asymmetries, and environment-dependent conversion. Together, these results establish a theoretical bridge between non-Mendelian gene drives and classical population genetic models, providing an interpretable and computationally efficient foundation for predicting gene-drive outcomes and guiding the design of gene drive systems and deployment strategies.
Parental-effect gene-drive elements under partial selfing, or why do Caenorhabditis genomes have hyperdivergent regions?
33170Matthew V Rockman, Genetics, 2024-10-31 08:57:53.
Self-fertile Caenorhabditis nematodes carry a surprising number of Medea elements, alleles that act in heterozygous mothers and cause death or developmental delay in offspring that don’t inherit them. At some loci, both alleles in a cross operate as independent Medeas, affecting all the homozygous progeny of a selfing heterozygote. The genomic coincidence of Medea elements and ancient, deeply coalescing haplotypes, which pepper the otherwise homogeneous genomes of these animals, raises questions about how these apparent gene-drive elements persist for long periods of time. Here I investigate how mating system affects the evolution of Medeas, and their paternal-effect counterparts, peels. Despite an intuition that antagonistic alleles should induce balancing selection by killing homozygotes, models show that, under partial selfing, antagonistic elements experience positive frequency dependence: the common allele drives the rare one extinct, even if the rare one is more penetrant. Analytical results for the threshold frequency required for one allele to invade a population show that a very weakly penetrant allele, one whose effects would escape laboratory detection, could nevertheless prevent a much more penetrant allele from invading under high rates of selfing. Ubiquitous weak antagonistic Medeas and peels could then act as localized barriers to gene flow between populations, generating genomic islands of deep coalescence. Analysis of gene expression data, however, suggest that this cannot be the whole story. A complementary explanation is that ordinary ecological balancing selection generates ancient haplotypes on which Medeas can evolve, while high homozygosity in these selfers minimizes the role of gene drive in their evolution.
A viral gene drive could offer a new approach to fighting herpes
32519Meghan Rosen, ScienceNews, 2024-10-15 08:28:16.
The words “herpes” and “spread” in the same sentence don’t typically spell good news. Unless, that is, you’re talking about a busybody new virus. That virus includes designer DNA called a gene drive that spreads from one herpes simplex virus to another. And it may be a first step toward an entirely new way of treating the infection, researchers report September 17 in Nature Communications. For now, the team has shown simply that their gene drive DNA sequence can copy/paste itself into the genomes of other herpes viruses during an infection in mice. But the idea is to one day create a gene drive virus that shuts down herpes simplex infections in people, says Keith Jerome, a virologist at the Fred Hutchinson Cancer Center in Seattle. Jerome ultimately wants to say to patients: “You don’t ever have to worry about this virus again. It’s never going to cause disease. You’re never going to infect another person. It just doesn’t matter to your life anymore.” Though some may consider herpes more annoyance than agony, “these viruses have a tremendous effect on people’s health,” Jerome says. They can cause a huge range of symptoms — some people don’t even know they’re infected while others sprout oozing sores around the genitals or mouth. Current therapies include antivirals, but they just tamp the virus down, they don’t eradicate it. One challenge is that herpes can lie dormant in people’s nerve cells for months or years and then roar awake again, spawning fresh blisters. Infection lasts a lifetime. A therapy that disables the slumbering virus could potentially cure the infection. But how to do it? Marius Walter, a Fred Hutch virologist, remembers reading an article that claimed designing gene drives in viruses was impossible. “That got me thinking,” he says.
Experimental demonstration of tethered gene drive systems for confined population modification or suppression
17153M. Metzloff, E. Yang, S. Dhole, A. G. Clark, P. W. Messer and J. Champer, bioRxiv, 2021.05.29.446308. 2021-05-30 10:50:23.
Tethered drive systems, in which a locally confined gene drive provides the CRISPR nuclease needed for a homing drive, could provide a solution to this problem, offering the power of a homing drive and confinement of the supporting drive. Here, we demonstrate the engineering of a tethered drive system in Drosophila, using a TARE drive to support modification and suppression homing drives. Each drive was able to bias inheritance in its favor, and the TARE drive was shown to spread only when released above a threshold frequency in experimental cage populations. After the TARE drive had established in the population, it facilitated the spread of a subsequently released split homing modification drive (to all individuals in the cage) and of a homing suppression drive (to its equilibrium frequency). Our results show that the tethered drive strategy is a viable and easily engineered option for providing confinement of homing drives to target populations. Competing Interest StatementThe authors have declared no competing interest.
Split versions of Cleave and Rescue selfish genetic elements for measured self limiting gene drive
16426G. Oberhofer, T. Ivy and B. A. Hay, PLoS genetics, 17:e1009385. 2021-02-18 20:00:28.
Self-sustaining Cleave and Rescue (ClvR) elements include a DNA sequence-modifying enzyme such as Cas9/gRNAs that disrupts endogenous versions of an essential gene, a tightly linked recoded version of the essential gene resistant to cleavage (the Rescue), and a Cargo. ClvR spreads by creating loss-of-function (LOF) conditions in which those without ClvR die because they lack functional copies of the essential gene. We use modeling to show that when the Rescue-Cargo and one or both components required for LOF allele creation (Cas9 and gRNA) reside at different locations (split ClvR), drive of Rescue-Cargo is self-limiting due to a progressive decrease in Cas9 frequency, and thus opportunities for creation of LOF alleles, as spread occurs. Importantly, drive strength and duration can be extended in a measured manner-which is still self-limiting-by moving the two components close enough to each other that they experience some degree of linkage. With linkage, Cas9 transiently experiences drive by hitchhiking with Rescue-Cargo until linkage disequilibrium between the two disappears, a function of recombination frequency and number of generations, creating a novel point of control. We implement split ClvR in Drosophila, with key elements on different chromosomes. Cargo/Rescue/gRNAs spreads to high frequency in a Cas9-dependent manner, while the frequency of Cas9 decreases.
Suppression gene drive in continuous space can result in unstable persistence of both drive and wild-type alleles
15938J. Champer, I. K. Kim, S. E. Champer, A. G. Clark and P. W. Messer, Mol Ecol, 2021-01-07 19:32:54.
Using spatially explicit simulations, we show that the release of a suppression drive can result in what we term "chasing" dynamics, in which wild-type individuals recolonize areas where the drive locally eliminated the population. Despite the drive subsequently reconquering these areas, complete population suppression often fails to occur or is substantially delayed. This increases the likelihood that the drive is lost or that resistance evolves. We analyze how chasing dynamics are influenced by the type of drive, its efficiency, fitness costs, and ecological factors such as the maximal growth rate of the population and levels of dispersal and inbreeding. We find that chasing is more common for lower efficiency drives when dispersal is low and that some drive mechanisms are substantially more prone to chasing behavior than others. Our results demonstrate that the population dynamics of suppression gene drives are determined by a complex interplay of genetic and ecological factors, highlighting the need for realistic spatial modeling to predict the outcome of drive releases in natural populations.
Gene Drives across engineered fitness valleys: Modeling a design to prevent drive spillover.
14880F. J. H. de Haas and S. Otto, bioRxiv, 2020.10.29.360404. 2020-10-29 15:44:22.
We model a proposed drive system that transitions in time from a low threshold drive system (homing-based gene drive) to a high threshold drive system (underdominance) using daisy chain technology. This combination leads to a spatially restricted drive strategy while maintaining an attainable release threshold.
MGDrivE 2: A simulation framework for gene drive systems incorporating seasonality and epidemiological dynamics
14733S. L. Wu, J. B. Bennett, H. M. Sanchez C, A. J. Dolgert, T. M. Leon and J. M. Marshall, bioRxiv, 2020.10.16.343376. 2020-10-17 15:42:27.
We present MGDrivE 2 (Mosquito Gene Drive Explorer 2): an extension of and development from the MGDrivE 1 simulation framework that investigates the population dynamics of a variety of gene drive architectures and their spread through spatially-explicit mosquito populations.
The potential for a CRISPR gene drive to eradicate or suppress globally invasive social wasps
13486P. J. Lester, M. Bulgarella, J. W. Baty, P. K. Dearden, J. Guhlin and J. M. Kean, Scientific Reports, 10:12398. 2020-07-24 17:41:41.
P. J. Lester, M. Bulgarella, J. W. Baty, P. K. Dearden, J. Guhlin and J. M. Kean (2020). Scientific Reports. doi: 10.1038/s41598-020-69259-6 Gene drives have potential for widespread and cost-efficient pest control, but are highly controversial. We examined a potential gene drive targeting spermatogenesis to control the invasive common wasp (Vespula vulgaris) in New Zealand.
Analysis of a Strong Suppressor of Segregation Distorter inDrosophila melanogaster
14264R. G. Temin, Genetics, 215:1085-1105. 2020-06-19 14:59:33.
These studies highlight the polygenic nature of distortion and its dependence on a constellation of positive and negative modifiers, provide insight into the stability of Mendelian transmission in natural populations even when a drive system arises, and pave the way for molecular characterization ofSu(SD)whose identity should reveal new information about the mechanism of distortion.
Malaria mosquitoes eliminated in lab by creating all male populations
11609H. Dunning, Imperial College London, 2020-05-11 16:07:00.
A team led by Imperial College London spread a genetic modification that distorts the sex ratio through a population of caged Anopheles gambiae mosquitoes using ‘gene drive’ technology.
Genetic variation not an obstacle to gene drive strategy to control mosquitoes
11230University of California Davis, ScienceDaily, 2020-04-16 15:42:49.
New research from entomologists at UC Davis clears a potential obstacle to using CRISPR-Cas9 "gene drive" technology to control mosquito-borne diseases such as malaria, dengue fever, yellow fever and Zika.
Experimental manipulation of selfish genetic elements links genes to microbial community function
11218S. D. Quistad, G. Doulcier and P. B. Rainey, Philosophical Transactions of the Royal Society B-Biological Sciences, 375:12. 2020-03-23 15:17:13.
Microbial communities underpin the Earth's biological and geochemical processes, but their complexity hampers understanding. Motivated by the challenge of diversity and the need to forge ways of capturing dynamical behaviour connecting genes to function, biologically independent experimental communities comprising hundreds of microbial genera were established from garden compost and propagated on nitrogen-limited minimal medium with cellulose (paper) as sole carbon source. After 1 year of bi-weekly transfer, communities retained hundreds of genera. To connect genes to function, we used a simple experimental manipulation that involved the periodic collection of selfish genetic elements (SGEs) from separate communities, followed by pooling and redistribution across communities. The treatment was predicted to promote amplification and dissemination of SGEs and thus horizontal gene transfer. Confirmation came from comparative metagenomics, which showed the substantive movement of ecologically significant genes whose dynamic across space and time could be followed. Enrichment of genes implicated in nitrogen metabolism, and particularly ammonification, prompted biochemical assays that revealed a measurable impact on community function. Our simple experimental strategy offers a conceptually new approach for unravelling dynamical processes affecting microbial community function. This article is part of the theme issue 'Conceptual challenges in microbial community ecology'.
Anti-CRISPR protein applications: natural brakes for CRISPR-Cas technologies
11201Marino, N. D., Pinilla-Redondo, R. , Csorgo, B., Bondy-Denomy, J., Nature Methods, 2020-03-16 13:52:42.
Clustered, regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) genes, a diverse family of prokaryotic adaptive immune systems, have emerged as a biotechnological tool and therapeutic. The discovery of protein inhibitors of CRISPR-Cas systems, called anti-CRISPR (Acr) proteins, enables the development of more controllable and precise CRISPR-Cas tools. Here we discuss applications of Acr proteins for post-translational control of CRISPR-Cas systems in prokaryotic and mammalian cells, organisms and ecosystems. This Review highlights recent discoveries and applications of anti-CRISPR (Acr) proteins that enable the regulation of CRISPR-Cas technology.
The Buzz About Genetically Modified Mosquitoes – a podcast
7932The Scientist Creative Services Team, The Scientist, podcast. 2020-02-26 18:17:44.
Mosquito-borne diseases afflict a large portion of the world. In this month’s episode, we consider genetic methods to eradicate diseases such as Zika fever, Dengue fever, and malaria. We spoke with Omar Akbari, professor of Cell and Developmental Biology at the University of California, San Diego, to learn more.
Vector genetics, insecticide resistance and gene drives: an agent-based modeling approach to evaluate malaria transmission and elimination
7941P. Selvaraj, E. A. Wenger, D. Bridenbecker, N. Windbichler, J. R. Russell, J. Gerardin, C. A. Bever and M. Nikolov, bioRxiv, 2020.01.27.920421. 2020-02-06 20:32:18.
Vector control has been a key component in the fight against malaria for decades, and chemical insecticides are critical to the success of vector control programs worldwide. However, increasing resistance to insecticides threatens to undermine these efforts. Understanding the evolution and propagation of resistance is thus imperative to mitigating loss of intervention effectiveness. Additionally, accelerated research and development of new tools that can be deployed alongside existing vector control strategies is key to eradicating malaria in the near future. Methods such as gene drives that aim to genetically modify large mosquito populations in the wild to either render them refractory to malaria or impair their reproduction may prove invaluable tools. Mathematical models of gene flow in populations can offer invaluable insight into the behavior and potential impact of gene drives as well as the spread of insecticide resistance in the wild. Here, we present the first multi-locus, agent-based model of vector genetics that accounts for mutations and many-to-many mappings of genotypes to phenotypes to investigate gene flow and the propagation of gene drives in Anopheline populations. This model is embedded within a large scale individual-based model of malaria transmission representative of a high burden, high transmission setting characteristic of the Sahel. Results are presented for the selection of insecticide-resistant vectors and the spread of resistance through repeated deployment of insecticide treated nets (ITNs), in addition to scenarios where gene drives act in concert with existing vector control tools such as ITNs. The roles of seasonality, spatial distribution of vector habitat and feed sites, and existing vector control in propagating alleles that confer phenotypic traits via gene drives that result in reduced transmission are explored. The ability to model a spectrum of vector species with different genotypes and phenotypes in the context of malaria transmission allows us to test deployment strategies for existing interventions that reduce the deleterious effects of resistance and allows exploration of the impact of new tools being proposed or developed.Author summary Vector control interventions are essential to the success of global malaria control and elimination efforts but increasing insecticide resistance worldwide threatens to derail these efforts. Releasing genetically modified mosquitoes that use gene drives to pass on desired genes and their associated phenotypic traits to the entire population within a few generations has been proposed to address resistance and other issues such as transmission heterogeneity that can sustain malaria transmission indefinitely. While the ethics and safety of these methods are being debated, mathematical models offer an efficient way of predicting the behavior and estimating the efficacy of these interventions if deployed to specific regions facing challenges to reaching elimination. We have developed a detailed mathematical model of vector genetics where specific genomes code for physical attributes that influence transmission and are affected by the surrounding environment. This is the first model to incorporate an individual-based multi locus genetic model into a detailed individual-based model of malaria transmission. This model opens the door to investigate a number of subtle but important questions such as the effects of small numbers of mosquitoes in a region sustaining malaria transmission during the low transmission season, and the success of gene drives in regions where extant vector control interventions could kill off gene drive mosquitoes before establishment. Here, we investigate the reduced efficacy of current vector control measures in the presence of insecticide resistance and evaluate the likelihood of achieving local malaria elimination using gene drive mosquitoes released into a high transmission setting alongside other vector control measures.
A transcomplementing gene drive provides a flexible platform for laboratory investigation and potential field deployment
6668V. López Del Amo, A. L. Bishop, H. M. Sánchez C, J. B. Bennett, X. Feng, J. M. Marshall, E. Bier and V. M. Gantz, Nature Communications, 11:352. 2020-01-17 18:00:23.
CRISPR-based gene drives can spread through wild populations by biasing their own transmission above the 50% value predicted by Mendelian inheritance. These technologies offer population-engineering solutions for combating vector-borne diseases, managing crop pests, and supporting ecosystem conservation efforts. Current technologies raise safety concerns for unintended gene propagation. Herein, we address such concerns by splitting the drive components, Cas9 and gRNAs, into separate alleles to form a trans-complementing split–gene-drive (tGD) and demonstrate its ability to promote super-Mendelian inheritance of the separate transgenes. This dual-component configuration allows for combinatorial transgene optimization and increases safety by restricting escape concerns to experimentation windows. We employ the tGD and a small–molecule-controlled version to investigate the biology of component inheritance and resistant allele formation, and to study the effects of maternal inheritance and impaired homology on efficiency. Lastly, mathematical modeling of tGD spread within populations reveals potential advantages for improving current gene-drive technologies for field population modification.
Mathematical modeling of self-contained CRISPR gene drive reversal systems
6023M. G. Heffel and G. C. Finnigan, Scientific Reports, 9:20050. 2019-12-27 20:31:43.
There is a critical need for further research into methods to control biological populations. Numerous challenges to agriculture, ecological systems, and human health could be mitigated by the targeted reduction and management of key species (e.g. pests, parasites, and vectors for pathogens). The discovery and adaptation of the CRISPR/Cas editing platform co-opted from bacteria has provided a mechanism for a means to alter an entire population. A CRISPR-based gene drive system can allow for the forced propagation of a genetic element that bypasses Mendelian inheritance which can be used to bias sex determination, install exogenous information, or remove endogenous DNA within an entire species. Laboratory studies have demonstrated the potency by which gene drives can operate within insects and other organisms. However, continued research and eventual application face serious opposition regarding issues of policy, biosafety, effectiveness, and reversal. Previous mathematical work has suggested the use of modified gene drive designs that are limited in spread such as daisy chain or underdominance drives. However, no system has yet been proposed that allows for an inducible reversal mechanism without requiring the introduction of additional individuals. Here, we study gene drive effectiveness, fitness, and inducible drive systems that could respond to external stimuli expanding from a previous frequency-based population model. We find that programmed modification during gene drive propagation could serve as a potent safeguard to either slow or completely reverse drive systems and allow for a return to the original wild-type population.
Experimental population modification of the malaria vector mosquito, Anopheles stephensi
6182T. B. Pham, C. H. Phong, J. B. Bennett, K. Hwang, N. Jasinskiene, K. Parker, D. Stillinger, J. M. Marshall, R. Carballar-Lejarazú and A. A. James, PLOS Genetics, 15:e1008440. 2019-12-19 19:05:32.
The experimental introduction of manipulated genes into insect species has a long history in basic genetics. Recent advances in genome editing technologies have spurred considerable effort to exploit these methodologies to provide genetic solutions to some of the worst medical and agricultural problems caused by insects. Insect population suppression and population modification approaches have been proposed to control transmission of vector-borne diseases, including malaria. We used small cage trials to explore the efficacy of non-drive and gene-drive releases to deliver anti-malarial effector genes to a vector mosquito, Anopheles stephensi. We show that both approaches can work to introduce genes to high percentages, but as expected, the gene-drive approaches were more efficient in that they needed only a single release with a much lower number of released insects. The gene-drive females in our studies exhibited a significant load that resulted in some cage populations going to extinction. Furthermore, the accumulation of drive-resistant target genes prevented full introduction of the transgenes in those cages that did not go extinct. While none of the strains evaluated here are proposed for open release, these laboratory cage trials reveal features that can be used to improve next-generation gene-drive strains for population modification.
Gene drive: progress and prospects
5795Wedell, N., T. A. R. Price and A. K. Lindholm, Proceedings of the Royal Society B: Biological Sciences, 286:20192709. 2019-12-19 14:25:02.
Gene drive is a naturally occurring phenomenon in which selfish genetic elements manipulate gametogenesis and reproduction to increase their own transmission to the next generation. Currently, there is great excitement about the potential of harnessing such systems to control major pest and vector populations. If synthetic gene drive systems can be constructed and applied to key species, they may be able to rapidly spread either modifying or eliminating the targeted populations. This approach has been lauded as a revolutionary and efficient mechanism to control insect-borne diseases and crop pests. Driving endosymbionts have already been deployed to combat the transmission of dengue and Zika virus in mosquitoes. However, there are a variety of barriers to successfully implementing gene drive techniques in wild populations. There is a risk that targeted organisms will rapidly evolve an ability to suppress the synthetic drive system, rendering it ineffective. There are also potential risks of synthetic gene drivers invading nontarget species or populations. This Special Feature covers the current state of affairs regarding both natural and synthetic gene drive systems with the aim to identify knowledge gaps. By understanding how natural drive systems spread through populations, we may be able to better predict the outcomes of synthetic drive release.
The potential for a released autosomal X-shredder becoming a driving-Y chromosome and invasively suppressing wild populations of malaria mosquitoes
5648Alcalay, Y., S. Fuchs, R. Galizi, F. Bernardini, R. E. Haghighat-Khah, D. B. Rusch, J. R. Adrion, M. W. Hahn, P. Tortosa and P. A. Papathanos, bioRxiv, 2019:860551. 2019-12-17 17:51:02.
Synthetic sex-ratio distorters based on X-chromosome shredding are predicted to be more efficient than sterile males for population suppression of malaria mosquitoes using genetic control. X chromosome shredding operates through the targeted elimination of X-chromosome-bearing gametes during male spermatogenesis, resulting in males that have a high fraction of male offspring. Strains harboring autosomal constructs containing a modified endonuclease I-PpoI have now been developed in the malaria mosquito Anopheles gambiae, resulting in strong sex-ratio distortion towards males. Data are being gathered for these strains for submission of regulatory dossiers for contained use and subsequent field release in West Africa. Since autosomal X shredders are transmitted in a Mendelian fashion and can be selected against their frequency in the population is expected to decline once releases are halted. However, any unintended transfer of the X-shredder to the Y-chromosome could theoretically change these dynamics: This could lead to 100% transmission of the newly Y-linked X-shredder to the predominant male-biased offspring and its insulation from negative selection in females, resulting in its potential spread in the population and ultimately to suppression. Here, we analyze plausible mechanisms whereby an autosomal X-shredder could become linked to the Y-chromosome after release and provide data regarding its potential for activity should it become linked to the Y-chromosome. Our results strongly suggest that Y-chromosome linkage through remobilization of the transposon used for the initial genetic transformation is unlikely, and that, in the unexpected event that the X-shredder becomes linked to the Y-chromosome, expression and activity of the X-shredder would likely be inhibited by meiotic sex chromosome inactivation. We conclude that a functioning X-shredding based Y-drive resulting from a naturally induced transposition or translocation of the transgene onto the Y-chromosome is unlikely.
Disrupting female flight in the vector Aedes aegypti
5624O'Leary, S. and Z. N. Adelman, bioRxiv, 862300:862300. 2019-12-17 16:35:43.
Aedes aegypti is a vector of dengue, chikungunya, and Zika viruses. Current vector control strategies such as community engagement, source reduction, and insecticides have not been sufficient to prevent viral outbreaks. Thus, interest in novel strategies involving genetic engineering is growing. Female mosquitoes rely on flight to mate with males and obtain a bloodmeal from a host. We hypothesized that knockout of genes specifically expressed in female mosquitoes associated with the indirect flight muscles would result in a flightless female mosquito. With the CRISPR-Cas9 system, we performed embryonic microinjections of Cas9 protein and guide RNAs specific to genes hypothesized to control flight in mosquitoes, and have obtained genetic knockouts in several genes specifically expressed in the flight-muscle, including those specific to female flight muscle. Analysis of the phenotype of these female-specific gene knockout mutants resulted in flightless females and flying males. While further assessment is required, this work lays the groundwork for a mechanism of population control that is female-specific for the Ae. aegypti vector.
Identification and characterisation of a Masculinizer homolog in the diamondback moth Plutella xylostella
5607Harvey-Samuel, T., V. C. Norman, R. Carter, E. Lovett and L. Alphey, Insect Molecular Biology, 2019:2019. 2019-12-17 16:09:12.
Recently, a novel sex-determination system was identified in the silkworm (Bombyx mori) in which a piRNA encoded on the female-specific W chromosome silences a Z-linked gene (Masculinizer) which would otherwise initiate male sex-determination and dosage compensation. Masculinizer provides various opportunities for developing improved genetic pest management tools. A pest lepidopteran in which a genetic pest management system has been developed, but which would benefit greatly from such improved designs, is the diamondback moth, Plutella xylostella. However, Masculinizer has not yet been identified in this species. Here, focusing on the previously described ?masculinizing? domain of B. mori Masculinizer, we identify P. xylostella Masculinizer (PxyMasc). We show that PxyMasc is Z-linked, regulates sex-specific alternative splicing of doublesex and is necessary for male survival. Similar results in B. mori suggest this survival effect is possibly through failure to initiate male dosage compensation. The highly conserved function and location of this gene between these two distantly related lepidopterans suggests a deep role for Masculinizer in the sex-determination systems of the Lepidoptera.
Genetic Control of Mosquitoes
5588Alphey, L., Annual Review of Entomology, 59:205-224. 2019-12-16 19:01:55.
Genetics can potentially provide new, species-specific, environmentally friendly methods for mosquito control. Genetic control strategies aim either to suppress target populations or to introduce a harm-reducing novel trait. Different approaches differ considerably in their properties, especially between self-limiting strategies, where the modification has limited persistence, and self-sustaining strategies, which are intended to persist indefinitely in the target population and may invade other populations. Several methods with different molecular biology are under development and the first field trials have been completed successfully.
Effects of a male meiotic driver on male and female transcriptomes in the house mouse
6639A. Lindholm, A. Sutter, S. Kunzel, D. Tautz and H. Rehrauer, Proceedings of the Royal Society B-Biological Sciences, 286:1-8. 2019-11-13 20:18:05.
Not all genetic loci follow Mendel's rules, and the evolutionary consequences of this are not yet fully known. Genomic conflict involving multiple loci is a likely outcome, as restoration of Mendelian inheritance patterns will be selected for, and sexual conflict may also arise when sexes are differentially affected. Here, we investigate effects of the t haplotype, an autosomal male meiotic driver in house mice, on genome-wide gene expression patterns in males and females. We analysed gonads, liver and brain in adult same-sex sibling pairs differing in genotype, allowing us to identify t-associated differences in gene regulation. In testes, only 40% of differentially expressed genes mapped to the approximately 708 annotated genes comprising the t haplotype. Thus, much of the activity of the t haplotype occurs in trans, and as upregulation. Sperm maturation functions were enriched among both cis and trans acting t haplotype genes. Within the t haplotype, we observed more downregulation and differential exon usage. In ovaries, liver and brain, the majority of expression differences mapped to the t haplotype, and were largely independent of the differences seen in the testis. Overall, we found widespread transcriptional effects of this male meiotic driver in the house mouse genome.
The impact of local population genetic background on the spread of the selfish element Medea-1 in red flour beetles
6379S. A. Cash, M. A. Robert, M. D. Lorenzen and F. Gould, Ecology and Evolution, 12:1-12. 2019-11-10 16:06:41.
Selfish genetic elements have been found in the genomes of many species, yet our understanding of their evolutionary dynamics is only partially understood. A number of distinct selfish Medea elements are naturally present in many populations of the red flour beetle (Tribolium castaneum). Although these Medea elements are predicted by models to increase in frequency within populations because any offspring of a Medea-bearing mother that do not inherit at least one Medea allele will die, experiments demonstrating an increase in a naturally occurring Medea element are lacking. Our survey of the specific Medea element, M-1, in the United States showed that it had a patchy geographic distribution. From the survey, it could not be determined if this distribution was caused by a slow process of M-1 colonization of discrete populations or if some populations lacked M-1 because they had genetic factors conferring resistance to the Medea mechanism. We show that populations with naturally low to intermediate M-1 frequencies likely represent transient states during the process of Medea spread. Furthermore, we find no evidence that genetic factors are excluding M-1 from US populations where the element is not presently found. We also show how a known suppressor of Medea can impair the increase of M-1 in populations and discuss the implications of our findings for pest-management applications of Medea elements.
The distribution and spread of naturally occurring Medea selfish genetic elements in the United States
6383S. A. Cash, M. D. Lorenzen and F. Gould, Ecology and Evolution, 9:14407–14416.. 2019-11-09 16:17:38.
Selfish genetic elements (SGEs) are DNA sequences that are transmitted to viable offspring in greater than Mendelian frequencies. Medea SGEs occur naturally in some populations of red flour beetle (Tribolium castaneum) and are expected to increase in frequency within populations and spread among populations. The large-scale U.S. distributions of Medea-4 (M4) had been mapped based on samples from 1993 to 1995. We sampled beetles in 2011?2014 and show that the distribution of M4 in the United States is dynamic and has shifted southward. By using a genetic marker of Medea-1 (M1), we found five unique geographic clusters with high and low M1 frequencies in a pattern not predicted by microsatellite-based analysis of population structure. Our results indicate the absence of rigid barriers to Medea spread in the United States, so assessment of what factors have limited its current distribution requires further investigation. There is great interest in using synthetic SGEs, including synthetic Medea, to alter or suppress pest populations, but there is concern about unpredicted spread of these SGEs and potential for populations to become resistant to them. The finding of patchy distributions of Medea elements suggests that released synthetic SGEs cannot always be expected to spread uniformly, especially in target species with limited dispersal.
Threshold-Dependent Gene Drives in the Wild: Spread, Controllability, and Ecological Uncertainty
6946G. A. Backus and J. A. Delborne, BioScience, 69:900-907. 2019-09-18 16:02:59.
Gene drive technology could allow the intentional spread of a desired gene throughout an entire wild population in relatively few generations. However, there are major concerns that gene drives could either fail to spread or spread without restraint beyond the targeted population. One potential solution is to use more localized threshold-dependent drives, which only spread when they are released in a population above a critical frequency. However, under certain conditions, small changes in gene drive fitness could lead to divergent outcomes in spreading behavior. In the face of ecological uncertainty, the inability to estimate gene drive fitness in a real-world context could prove problematic because gene drives designed to be localized could spread to fixation in neighboring populations if ecological conditions unexpectedly favor the gene drive. This perspective offers guidance to developers and managers because navigating gene drive spread and controllability could be risky without detailed knowledge of ecological contexts.
A natural gene drive system influences bovine tuberculosis susceptibility in African buffalo: Possible implications for disease management
6038P. van Hooft, W. M. Getz, B. J. Greyling and A. D. S. Bastos, PLoS One, 14:e0221168. 2019-09-04 20:57:09.
Bovine tuberculosis (BTB) is endemic to the African buffalo (Syncerus caffer) of Hluhluwe-iMfolozi Park (HiP) and Kruger National Park, South Africa. In HiP, the disease has been actively managed since 1999 through a test-and-cull procedure targeting BTB-positive buffalo. Prior studies in Kruger showed associations between microsatellite alleles, BTB and body condition. A sex chromosomal meiotic drive, a form of natural gene drive, was hypothesized to be ultimately responsible. These associations indicate high-frequency occurrence of two types of male-deleterious alleles (or multiple-allele haplotypes). One type negatively affects body condition and BTB resistance in both sexes. The other type has sexually antagonistic effects: negative in males but positive in females. Here, we investigate whether a similar gene drive system is present in HiP buffalo, using 17 autosomal microsatellites and microsatellite-derived Y-chromosomal haplotypes from 401 individuals, culled in 2002–2004. We show that the association between autosomal microsatellite alleles and BTB susceptibility detected in Kruger, is also present in HiP. Further, Y-haplotype frequency dynamics indicated that a sex chromosomal meiotic drive also occurred in HiP. BTB was associated with negative selection of male-deleterious alleles in HiP, unlike positive selection in Kruger. Birth sex ratios were female-biased. We attribute negative selection and female-biased sex ratios in HiP to the absence of a Y-chromosomal sex-ratio distorter. This distorter has been hypothesized to contribute to positive selection of male-deleterious alleles and male-biased birth sex ratios in Kruger. As previously shown in Kruger, microsatellite alleles were only associated with male-deleterious effects in individuals born after wet pre-birth years; a phenomenon attributed to epigenetic modification. We identified two additional allele types: male-specific deleterious and beneficial alleles, with no discernible effect on females. Finally, we discuss how our findings may be used for breeding disease-free buffalo and implementing BTB test-and-cull programs.
Assessment of a split homing based gene drive for efficient knockout of multiple genes
5915Kandul, N. P., J. Liu, A. Buchman, V. M. Gantz, E. Bier and O. S. Akbari, bioRxiv, 2019:706929. 2019-07-18 16:34:25.
Homing based gene drives (HGD) possess the potential to spread linked cargo genes into natural populations and are poised to revolutionize population control of animals. Given that host-encoded genes have been identified that are important for pathogen transmission, targeting these genes using guide RNAs as cargo genes linked to drives may provide a robust method to prevent transmission. However, effectiveness of the inclusion of additional guide RNAs that target separate host encoded genes has not been thoroughly explored. To test this approach, here we generated a split-HGD in Drosophila melanogaster that encoded a drive linked effector consisting of a second gRNA engineered to target a separate host encoded gene, which we term a gRNA-mediated effector (GME). This design enabled us to assess homing and knockout efficiencies of two target genes simultaneously, and also explore the timing and tissue specificity of Cas9 expression on cleavage/homing rates. We demonstrate that inclusion of a GME can result in high efficiency of disruption of its target gene during super-Mendelian propagation of split-HGD. However, maternal deposition and embryonic expression of Cas9 resulted in the generation of drive resistant alleles which can accumulate and limit the spread of such a drive. Alternative design principles are discussed that could mitigate the accumulation of resistance alleles while incorporating a GME.
Self-destructing mosquitoes and sterilized rodents: the promise of gene drives
6645M. Scudellari, Nature, 571:160-162. 2019-07-09 20:27:18.
Altering the genomes of entire animal populations could help to defeat disease and control pests, but researchers worry about the consequences of unleashing this new technology.
Interpopulation spread of a parasitic B chromosome is unlikely through males in the grasshopper Eyprepocnemis plorans
6166M. I. Manrique-Poyato, J. Cabrero, M. D. López-León, F. Perfectti, R. Gómez and J. P. M. Camacho, Heredity, 124:197-206. 2019-07-08 18:29:07.
The near-neutral model of B chromosome evolution predicts that population invasion is quite fast. To test this prediction, in 1994, we introduced males of the grasshopper Eyprepocnemis plorans from a B-carrying population into a B-lacking population and monitored the evolution of B-chromosome frequency up to 2013. We observed fluctuating very low B frequency across years but, remarkably, the B chromosome introduced (the B2 variant) was found up to 1996 only, whereas the B1 variant was present from 1996 onwards, presumably introduced by fishermen using E. plorans males as bait. Effective introgression of genetic material from the donor population was evidenced by the presence of a satellite DNA on autosome 9 (up to 1999) and the presence of one individual in 2006 showing an ISSR marker profile being highly similar to that found in the donor population. This indicated that the males introduced by us effectively mated with resident females, but donor genes rapidly decreased in frequency after this non-recurrent migration event. Taken together, our results indicated: (i) that the non-recurrent migration event had a slight, transient genetic effect on the recipient population, which was diluted in only a few generations; and (ii) that even with recurrent migration (forced by fishermen) the B chromosome failed to increase in frequency. Bearing in mind that B chromosomes in this species drive through females only, we hypothesize that B chromosomes most likely failed invasion in both migration events because the migrating sex shows no B-drive.
A century of bias in genetics and evolution
6691L. D. Hurst, Heredity, 123:33-44. 2019-06-12 17:55:20.
Mendel proposed that the heritable material is particulate and that transmission of alleles is unbiased. An assumption of unbiased transmission was necessary to show how variation can be preserved in the absence of selection, so overturning an early objection to Darwinism. In the second half of the twentieth century, it was widely recognised that even strongly deleterious alleles can invade if they have strongly biased transmission (i.e. strong segregation distortion). The spread of alleles with distorted segregation can explain many curiosities. More recently, the selectionist-neutralist duopoly was broken by the realisation that biased gene conversion can explain phenomena such as mammalian isochore structures. An initial focus on unbiased transmission in 1919, has thus given way to an interest in biased transmission in 2019. A focus on very weak bias is now possible owing to technological advances, although technical biases may put a limit on resolving power. To understand the relevance of weak bias we could profit from having the concept of the effectively Mendelian allele, a companion to the effectively neutral allele. Understanding the implications of unbiased and biased transmission may, I suggest, be a good way to teach evolution so as to avoid psychological biases.
Daisy-chain gene drives
5497MIT Media Lab, 2019-04-03 18:36:17.
Who should decide whether, when, and how to alter the environment? These are hard questions, especially when the decisions will impact people in many different communities or nations. Daisy drive systems may help by empowering local communities to make decisions concerning their local environments without imposing them on anyone else.
On the road to a gene drive in mammals
3902Conklin, BR, Nature, 566:43-45. 2019-01-20 00:00:00.
A method for making a version of a gene more likely to be inherited than normal, generating what is called a gene drive, might be used to control insect populations. It has now been reported to work in mammals, too.
Variability in the durability of CRISPR-Cas immunity
3899Chabas, HN, A.; Meaden, S.; Westra, E. R.; Tremblay, D. M.; Pradier, L.; Lion, S.; Moineau, S.; Gandon, S., Philosophical Transactions of the Royal Society B-Biological Sciences, 374:1-9. 2019-01-17 00:00:00.
The durability of host resistance is challenged by the ability of pathogens to escape the defence of their hosts. Understanding the variability in the durability of host resistance is of paramount importance for designing more effective control strategies against infectious diseases. Here, we study the durability of various clustered regularly interspaced short palindromic repeats-Cas (CRISPR-Cas) alleles of the bacteria Streptococcus thermophilus against lytic phages. We found substantial variability in durability among different resistant bacteria. Since the escape of the phage is driven by a mutation in the phage sequence targeted by CRISPR-Cas, we explored the fitness costs associated with these escape mutations. We found that, on average, escape mutations decrease the fitness of the phage. Yet, the magnitude of this fitness cost does not predict the durability of CRISPR-Cas immunity. We contend that this variability in the durability of resistance may be because of variations in phage mutation rate or in the proportion of lethal mutations across the phage genome. These results have important implications on the coevolutionary dynamics between bacteria and phages and for the optimal deployment of resistance strategies against pathogens and pests. Understanding the durability of CRISPR-Cas immunity may also help develop more effective gene-drive strategies based on CRISPR-Cas9 technology. This article is part of a discussion meeting issue 'The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems'.
Predicting the spatial dynamics of Wolbachia infections in Aedes aegypti arbovirus vector populations in heterogeneous landscapes
3917Hancock, PAR, S. A.; Koenraadt, C. J. M.; Scott, T. W.; Hoffmann, A. A.; Godfray, H. C. J., Journal of Applied Ecology, 56:1674-1686. 2019-01-15 00:00:00.
A promising strategy for reducing the transmission of dengue and other arboviral human diseases by Aedes aegypti mosquito vector populations involves field introductions of the endosymbiotic bacteria Wolbachia. Wolbachia infections inhibit viral transmission by the mosquito, and can spread between mosquito hosts to reach high frequencies in the vector population. Wolbachia spreads by maternal transmission, and spread dynamics can be variable and highly dependent on natural mosquito population dynamics, population structure and fitness components. We develop a mathematical model of an A. aegypti metapopulation that incorporates empirically validated relationships describing density-dependent mosquito fitness components. We assume that density dependent relationships differ across subpopulations, and construct heterogeneous landscapes for which model-predicted patterns of variation in mosquito abundance and demography approximate those observed in field populations. We then simulate Wolbachia release strategies similar to that used in field trials. We show that our model can produce rates of spatial spread of Wolbachia similar to those observed following field releases. We then investigate how different types of spatio-temporal variation in mosquito habitat, as well as different fitness costs incurred by Wolbachia on the mosquito host, influence predicted spread rates. We find that fitness costs reduce spread rates more strongly when the habitat landscape varies temporally due to stochastic and seasonal processes. Synthesis and applications: Our empirically based modelling approach represents effects of environmental heterogeneity on the spatial spread of Wolbachia. The models can assist in interpreting observed spread patterns following field releases and in designing suitable release strategies for targeting spatially heterogeneous vector populations.
Design, execution, and analysis of CRISPR-Cas9-based deletions and genetic interaction networks in the fungal pathogen Candida albicans
3916Halder, VP, C. B. M.; Chavez, A.; Shapiro, R. S., Nature Protocols, 14:955-975. 2019-01-14 00:00:00.
The study of fungal pathogens is of immediate importance, yet progress is hindered by the technical challenges of genetic manipulation. For Candida species, their inability to maintain plasmids, unusual codon usage, and inefficient homologous recombination are among the obstacles limiting efficient genetic manipulation. New advances in genomic biotechnologies -particularly CRISPR-based tools-have revolutionized genome editing for many fungal species. Here, we present a protocol for CRISPR-Cas9-based manipulation in Candida albicans using a modified gene-drive-based strategy that takes similar to 1 month to complete. We detail the generation of Candida-optimized Cas9-based plasmids for gene deletion, an efficient transformation protocol using C. albicans haploids, and an optimized mating strategy to generate homozygous single- and double-gene diploid mutants. We further describe protocols for quantifying cell growth and analysis pipelines to calculate fitness and genetic interaction scores for genetic mutants. This protocol overcomes previous limitations associated with genetic manipulation in C. albicans and advances researchers' ability to perform genetic analysis in this pathogen; the protocol also has broad applicability to other mating-competent microorganisms.
CRISPR-Clear: A fieldable detection procedure for potential CRISPR-Cas9 gene drive based bioweapons.
3931Nieuwenweg, ACvG, Martijn M.; Horsting, Angelina; Hegge, Jorrit W; Velders, Aldrik; Saggiomo, Vittorio, ChemRxiv, 2019:1-11. 2019-01-09 00:00:00.
Rapid progression in genetic modification research has made gene editing increasingly cheaper and easier to use. CRISPR-Cas9 for example, allows for the specific alteration of the genome of an organism with relative simplicity and low costs. This raised a worrying question; can genetic modification techniques be used to create novel bioweapons? A specific scenario is the initiation of a synthetic gene drive for malicious purposes. A synthetic gene drive can be used to quickly spread a mutation through an entire population. This mutation could alter vectors in such a way that they will spread human diseases or eradicate essential organisms. Since a gene drive spreads efficiently through a population, timely detection is essential. Thus, a quick and field deployable screening method is needed to counteract the malicious use of gene drives.; ; Here, we show a battery-operated, sensitive screening method, named CRISPR-Clear, for the detection of gene drive modified organisms. CRISPR-Clear is based on the combination of three components: 1) A DNA amplification technique known as loop-mediated isothermal amplification (LAMP) for detecting the presence of a gene drive; b) a portable battery-operated Arduino device which heats up the sample to allow DNA amplification, and c) a naked-eye visualization of the results.; ; We designed and tested six LAMP primers targeting a Cas9 endonuclease-based gene drive, assembled a battery-operated Arduino device and tested the naked-eye visualization method. In addition, we were able to detect the presence of the Cas9 gene, extracted from a transformed bacteria, providing a proof-of-concept of the CRISPR-Clear device.
Integral gene drives for population replacement
3930Nash, AU, Giulia Mignini; Beaghton, Andrea K.; Hoermann, Astrid; Papathanos, Philippos Aris; Christophides, George K.; Windbichler, Nikolai, Biology Open, 8:bio037762. 2019-01-08 00:00:00.
A first generation of CRISPR-based gene drives has now been tested in the laboratory in a number of organisms, including malaria vector mosquitoes. Challenges for their use in the area-wide genetic control of vector-borne disease have been identified, including the development of target site resistance, their long-term efficacy in the field, their molecular complexity, and practical and legal limitations for field testing of both gene drive and coupled anti-pathogen traits. We have evaluated theoretically the concept of integral gene drive (IGD) as an alternative paradigm for population replacement. IGDs incorporate a minimal set of molecular components, including drive and anti-pathogen effector elements directly embedded within endogenous genes – an arrangement that in theory allows targeting functionally conserved coding sequences without disrupting their function. Autonomous and non-autonomous IGD strains could be generated, optimized, regulated and imported independently. We performed quantitative modeling comparing IGDs with classical replacement drives and show that selection for the function of the hijacked host gene can significantly reduce the establishment of resistant alleles in the population, while drive occurring at multiple genomic loci prolongs the duration of transmission blockage in the face of pre-existing target site variation. IGD thus has potential as a more durable and flexible population replacement strategy.
Large-cage assessment of a transgenic sex-ratio distortion strain on populations of an African malaria vector
3910Facchinelli, LN, A.; Collins, C.; Menichelli, M.; Persampieri, T.; Bucci, A.; Spaccapelo, R.; Crisanti, A.; Benedict, M., Parasites & Vectors, 12:70. 2019-01-08 00:00:00.
Novel transgenic mosquito control methods require progressively more realistic evaluation. The goal of this study was to determine the effect of a transgene that causes a male-bias sex ratio on Anopheles gambiae target populations in large insectary cages. Life history characteristics of Anopheles gambiae wild type and Ag(PMB)1 (aka (gfp)124L-2) transgenic mosquitoes, whose progeny are 95% male, were measured in order to parameterize predictive population models. Ag(PMB)1 males were then introduced at two ratios into large insectary cages containing target wild type populations with stable age distributions and densities. The predicted proportion of females and those observed in the large cages were compared. A related model was then used to predict effects of male releases on wild mosquitoes in a west African village. The frequency of transgenic mosquitoes in target populations reached an average of 0.44 +/- 0.02 and 0.56 +/- 0.02 after 6 weeks in the 1:1 and in the 3:1 release ratio treatments (transgenic male:wild male) respectively. Transgenic males caused sex-ratio distortion of 73% and 80% males in the 1:1 and 3:1 treatments, respectively. The number of eggs laid in the transgenic treatments declined as the experiment progressed, with a steeper decline in the 3:1 than in the 1:1 releases. The results of the experiment are partially consistent with predictions of the model; effect size and variability did not conform to the model in two out of three trials, effect size was over-estimated by the model and variability was greater than anticipated, possibly because of sampling effects in restocking. The model estimating the effects of hypothetical releases on the mosquito population of a West African village demonstrated that releases could significantly reduce the number of females in the wild population. The interval of releases is not expected to have a strong effect. The biological data produced to parameterize the model, the model itself, and the results of the experiments are components of a system to evaluate and predict the performance of transgenic mosquitoes. Together these suggest that the Ag(PMB)1 strain has the potential to be useful for reversible population suppression while this novel field develops.
Modeling the mutation and reversal of engineered underdominance gene drives
3909Edgington, MPA, Luke S., Journal of Theoretical Biology, 479:14-21. 2019-01-07 00:00:00.
A range of gene drive systems have been proposed that are predicted to increase their frequency and that of associated desirable genetic material even if they confer a fitness cost on individuals carrying them. Engineered underdominance (UD) is such a system and, in one version, is based on the introduction of two independently segregating transgenic constructs each carrying a lethal gene, a suppressor for the lethal at the other locus and a desirable genetic “cargo”. Under this system individuals carrying at least one copy of each construct (or no copies of either) are viable whilst those that possess just one of the transgenic constructs are non-viable. Previous theoretical work has explored various properties of these systems, concluding that they should persist indefinitely in absence of resistance or mutation. Here we study a population genetics model of UD gene drive that relaxes past assumptions by allowing for loss-of-function mutations in each introduced gene. We demonstrate that mutations are likely to cause UD systems to break down, eventually resulting in the elimination of introduced transgenes. We then go on to investigate the potential of releasing “free suppressor” carrying individuals as a new method for reversing UD gene drives and compare this to the release of wild-types; the only previously proposed reversal strategy for UD. This reveals that while free suppressor carrying individuals may represent an inexpensive reversal strategy due to extremely small release requirements, they are not able to return a fully wild-type population as rapidly as the release of wild-types.
Controlling invasive rodents via synthetic gene drive and the role of polyandry
3927Manser, AC, S. J.; Sutter, A.; Blondel, D. V.; Serr, M.; Godwin, J.; Price, T. A. R., Proceedings of the Royal Society B-Biological Sciences, 286:9. 2019-01-05 00:00:00.
House mice are a major ecosystem pest, particularly threatening island ecosystems as a non-native invasive species. Rapid advances in synthetic biology offer new avenues to control pest species for biodiversity conservation. Recently, a synthetic sperm-killing gene drive construct called t-Sry has been proposed as a means to eradicate target mouse populations owing to a lack of females. A factor that has received little attention in the discussion surrounding such drive applications is polyandry. Previous research has demonstrated that sperm-killing drivers are extremely damaging to a male's sperm competitive ability. Here, we examine the importance of this effect on the t-Sry system using a theoretical model. We find that polyandry substantially hampers the spread of t-Sry such that release efforts have to be increased three-to sixfold for successful eradication. We discuss the implications of our finding for potential pest control programmes, the risk of drive spread beyond the target population, and the emergence of drive resistance. Our work highlights that a solid understanding of the forces that determine drive dynamics in a natural setting is key for successful drive application, and that exploring the natural diversity of gene drives may inform effective gene drive design.
Gene conversion generates evolutionary novelty that fuels genetic conflicts
3905Daugherty, MDZ, Sarah E., Current Opinion in Genetics & Development, 58-59:49-54. 2019-01-03 00:00:00.
Genetic conflicts arise when the evolutionary interests of two genetic elements are not aligned. Conflicts between genomes (e.g. pathogen versus host) or within the same genome (e.g. internal parasitic DNA sequences versus the rest of the host genome) can both foster ‘molecular arms races’, in which genes on both sides of the conflict rapidly evolve due to bouts of adaptation and counter-adaptation. Importantly, a source of genetic novelty is needed to fuel these arms races. In this review, we highlight gene conversion as a major force in generating the novel alleles on which selection can act. Using examples from both intergenomic and intragenomic conflicts, we feature the mechanisms by which gene conversion facilitates the rapid evolution of genes in conflict.
Evaluating the Probability of CRISPR-based Gene Drive Contaminating Another Species
3904Courtier-Orgogozo, VD, Antoine; Gouyon, Pierre-Henri; Boëte, Christophe, bioRxiv, 776609:27. 2019-01-02 00:00:00.
The probability D that a given CRISPR-based gene drive element contaminates another, non-target species can be estimated by the following Drive Risk Assessment Quantitative Estimate (DRAQUE) Equation: D = (hyb+transf).express.cut.flank.immune.nonextinct withhyb = probability of hybridization between the target species and a non-target speciestransf = probability of horizontal transfer of a piece of DNA containing the gene drive cassette from the target species to a non-target species (with no hybridization)express = probability that the Cas9 and guide RNA genes are expressedcut = probability that the CRISPR-guide RNA recognizes and cuts at a DNA site in the new hostflank = probability that the gene drive cassette inserts at the cut siteimmune = probability that the immune system does not reject Cas9-expressing cellsnonextinct = probability of invasion of the drive within the population We discuss and estimate each of the seven parameters of the equation, with particular emphasis on possible transfers within insects, and between rodents and humans. We conclude from current data that the probability of a gene drive cassette to contaminate another species is not insignificant. We propose strategies to reduce this risk and call for more work on estimating all the parameters of the formula.CRISPRClustered Regularly Interspaced Short Palindromic RepeatsDRAQUEDrive Risk Assessment Quantitative EstimateHGThorizontal gene transferHTThorizontal transfer of transposable elementTEtransposable element
CRISPR Gene Drive (Complete guide 2019)
5507Every Cell A Universe, 2018-11-18 18:59:09.
Crispr gene drive - malaria cure and a new way to look at conservation.
Population modification of Anopheline species to control malaria transmission
6694R. Carballar-Lejarazú and A. A. James, Pathogens and Global Health, 111:424-435. 2018-02-01 17:58:10.
Vector control strategies based on population modification of Anopheline mosquitoes may have a significant role in the malaria eradication agenda. They could consolidate elimination gains by providing barriers to the reintroduction of parasites and competent vectors, and allow resources to be allocated to new control sites while maintaining treated areas free of malaria. Synthetic biological approaches are being used to generate transgenic mosquitoes for population modification. Proofs-of-principle exist for mosquito transgenesis, the construction of anti-parasite effector genes and gene-drive systems for rapidly introgressing beneficial genes into wild populations. Key challenges now are to develop field-ready strains of mosquitoes that incorporate features that maximize safety and efficacy, and specify pathways from discovery to development. We propose three pathways and a framework for target product profiles that maximize safety and efficacy while meeting the demands of the complexity of malaria transmission, and the regulatory and social diversity of potential end-users and stakeholders.
Engineered Reciprocal Chromosome Translocations Drive High Threshold, Reversible Population Replacement in Drosophila
3961Buchman, ABI, Tobin; Marshall, John M.; Akbari, Omar S.; Hay, Bruce A., ACS Synthetic Biology, 7:1359-1370. 2018-01-19 00:00:00.
Replacement of wild insect populations with transgene-bearing individuals unable to transmit disease or survive under specific environmental conditions using gene drive provides a self-perpetuating method of disease prevention. Mechanisms that require the gene drive element and linked cargo to exceed a high threshold frequency in order for spread to occur are attractive because they offer several points of control: they bring about local, but not global population replacement; and transgenes can be eliminated by reintroducing wildtypes into the population so as to drive the frequency of transgenes below the threshold frequency required for drive. Reciprocal chromosome translocations were proposed as a tool for bringing about high threshold population replacement in 1940 and 1968. However, translocations able to achieve this goal have only been reported once, in the spider mite Tetranychus urticae, a haplo-diploid species in which there is strong selection in haploid males for fit homozygotes. We report the creation of engineered translocation-bearing strains of Drosophila melanogaster, generated through targeted chromosomal breakage and homologous recombination. These strains drive high threshold population replacement in laboratory populations. While it remains to be shown that engineered translocations can bring about population replacement in wild populations, these observations suggest that further exploration of engineered translocations as a tool for controlled population replacement is warranted.
Engineered integrative and conjugative elements for efficient and inducible DNA transfer to undomesticated bacteria
3960Brophy, JANT, Alexander J.; Adams, Bryn L.; Renberg, Rebecca L.; Stratis-Cullum, Dimitra N.; Grossman, Alan D.; Voigt, Christopher A., Nature Microbiology, 3:1043-1053. 2018-01-18 00:00:00.
Engineering microorganisms to promote human or plant health will require manipulation of robust bacteria that are capable of surviving in harsh, competitive environments. Genetic engineering of undomesticated bacteria can be limited by an inability to transfer DNA into the cell. Here we developed an approach based on the integrative and conjugative element from Bacillus subtilis (ICEBs1) to overcome this problem. A donor strain (XPORT) was built to transfer miniaturized integrative and conjugative elements (mini-ICEBs1) to undomesticated bacteria. The strain was engineered to enable inducible control over conjugation, to integrate delivered DNA into the chromosome of the recipient, to restrict spread of heterologous DNA through separation of the type IV secretion system from the transferred DNA, and to enable simple isolation of engineered bacteria through a d-alanine auxotrophy. Efficient DNA transfer (10–1 to 10–7 conjugation events per donor) is demonstrated using 35 Gram-positive strains isolated from humans (skin and gut) and soil. Mini-ICEBs1 was used to rapidly characterize the performance of an isopropyl-?-d-thiogalactoside (IPTG)-inducible reporter across dozens of strains and to transfer nitrogen fixation to four Bacillus species. Finally, XPORT was introduced to soil to demonstrate DNA transfer under non-ideal conditions.
Evaluating active genetic options for the control of Sea Lampreys (Petromyzon marinus) in the Laurentian Great Lakes
4020Thresher, REJ, Michael; Drake, D. Andrew, Canadian Journal of Fisheries and Aquatic Sciences, 76:1186-1202. 2018-01-18 00:00:00.
For more than two decades the Great Lakes Fishery Commission has sought tactics to complement, and potentially replace, the use of barriers and lampricides to control Sea Lamprey in the Great Lakes, but thus far without success. This paper examines the potential of modern genetic technology to suppress these invasive populations. We identified six recombinant options that appeared to be moderately to highly feasible, most of which were judged by an expert panel as extremely low or low risk, and for which R&D was broadly supported by stakeholders. The two options judged to overall best combine high efficacy and low risks were a Mendelian “sex ratio drive” and genetically modifying a prey species as to kill or sterilize Sea Lamprey that fed on it. Core issues regarding use of genetic biocontrol in the Great Lakes include technical problems associated with maintaining a Sea Lamprey brood line, information gaps for most options, the extent of broader public support, and the extent and nature of national and international consultation required in making decisions about control options.
Evolutionary genetics of cytoplasmic incompatibility genes cifA and cifB in prophage WO of Wolbachia
5929Lindsey, A. R. I., D. W. Rice, S. R. Bordenstein, A. W. Brooks, S. R. Bordenstein and I. L. G. Newton, Genome Biology and Evolution, 10:434-451. 2018-01-17 17:04:14.
The bacterial endosymbiont Wolbachia manipulates arthropod reproduction to facilitate its maternal spread through host populations. The most common manipulation is cytoplasmic incompatibility (CI): Wolbachia-infected males produce modified sperm that cause embryonic mortality, unless rescued by embryos harboring the same Wolbachia. The genes underlying CI, cifA and cifB, were recently identified in the eukaryotic association module of Wolbachia’s prophage WO. Here, we use transcriptomic and genomic approaches to address three important evolutionary facets of the cif genes. First, we assess whether or not cifA and cifB comprise a classic toxin–antitoxin operon in wMel and show that the two genes exhibit striking, transcriptional differences across host development. They can produce a bicistronic message despite a predicted hairpin termination element in their intergenic region. Second, cifA and cifB strongly coevolve across the diversity of phage WO. Third, we provide new domain and functional predictions across homologs within Wolbachia, and show that amino acid sequences vary substantially across the genus. Finally, we investigate conservation of cifA and cifB and find frequent degradation and loss of the genes in strains that no longer induce CI. Taken together, we demonstrate that cifA and cifB exhibit complex transcriptional regulation in wMel, provide functional annotations that broaden the potential mechanisms of CI induction, and report recurrent erosion of cifA and cifB in non-CI strains, thus expanding our understanding of the most widespread form of reproductive parasitism.
Genetic villains: Killer meiotic drivers
3959Bravo Núñez, MAN, Nicole L.; Zanders, Sarah E., Trends in Genetics, 34:424-433. 2018-01-17 00:00:00.
Unbiased allele transmission into progeny is a fundamental genetic concept canonized as Mendel’s Law of Segregation. Not all alleles, however, abide by the law. Killer meiotic drivers are ultra-selfish DNA sequences that are transmitted into more than half (sometimes all) of the meiotic products generated by a heterozygote. As their name implies, these loci gain a transmission advantage in heterozygotes by destroying otherwise viable meiotic products that do not inherit the driver. We review and classify killer meiotic drive genes across a wide spectrum of eukaryotes. We discuss how analyses of these ultra-selfish genes can lead to greater insight into the mechanisms of gametogenesis and the causes of infertility.
Origin, composition, and structure of the supernumerary B chromosome of Drosophila melanogaster
3978Hanlon, SLM, Danny E.; Eche, Salam; Hawley, R. Scott, Genetics, 210:1197. 2018-01-16 00:00:00.
The number of chromosomes carried by an individual species is one of its defining characteristics. Some species, however, can also carry supernumerary chromosomes referred to as B chromosomes. B chromosomes were recently identified in a laboratory stock of Drosophila melanogaster—an established model organism with a wealth of genetic and genomic resources—enabling us to subject them to extensive molecular analysis. We isolated the B chromosomes by pulsed-field gel electrophoresis and determined their composition through next-generation sequencing. Although these B chromosomes carry no known euchromatic sequence, they are rich in transposable elements and long arrays of short nucleotide repeats, the most abundant being the uncharacterized AAGAT satellite repeat. Fluorescent in situ hybridization on metaphase chromosome spreads revealed this repeat is located on chromosome 4, strongly suggesting the origin of the B chromosomes is chromosome 4. Cytological and quantitative comparisons of signal intensity between chromosome 4 and the B chromosomes supports the hypothesis that the structure of the B chromosome is an isochromosome. We also report the identification of a new B chromosome variant in a related laboratory stock. This B chromosome has a similar repeat signature as the original but is smaller and much less prevalent. We examined additional stocks with similar genotypes and did not find B chromosomes, but did find these stocks lacked the AAGAT satellite repeat. Our molecular characterization of D. melanogaster B chromosomes is the first step toward understanding how supernumerary chromosomes arise from essential chromosomes and what may be necessary for their stable inheritance.
Carrying a selfish genetic element predicts increased migration propensity in free-living wild house mice
4012Runge, J-NL, Anna K., Proceedings of the Royal Society B: Biological Sciences, 285:20181333. 2018-01-10 00:00:00.
Life is built on cooperation between genes, which makes it vulnerable to parasitism. Selfish genetic elements that exploit this cooperation can achieve large fitness gains by increasing their transmission relative to the rest of the genome. This leads to counter-adaptations that generate unique selection pressures on the selfish genetic element. This arms race is similar to host–parasite coevolution, as some multi-host parasites alter the host’s behaviour to increase the chance of transmission to the next host. Here, we ask if, similarly to these parasites, a selfish genetic element in house mice, the t haplotype, also manipulates host behaviour, specifically the host’s migration propensity. Variants of the t that manipulate migration propensity could increase in fitness in a meta-population. We show that juvenile mice carrying the t haplotype were more likely to emigrate from and were more often found as migrants within a long-term free-living house mouse population. This result may have applied relevance as the t has been proposed as a basis for artificial gene drive systems for use in population control.
Unexpected patterns of segregation distortion at a selfish supergene in the fire ant Solenopsis invicta
4010Ross, KGS, DeWayne, BMC Genetics, 19:101. 2018-01-08 00:00:00.
The Sb supergene in the fire ant Solenopsis invicta determines the form of colony social organization, with colonies whose inhabitants bear the element containing multiple reproductive queens and colonies lacking it containing only a single queen. Several features of this supergene — including suppressed recombination, presence of deleterious mutations, association with a large centromere, and “green-beard” behavior — suggest that it may be a selfish genetic element that engages in transmission ratio distortion (TRD), defined as significant departures in progeny allele frequencies from Mendelian inheritance ratios. We tested this possibility by surveying segregation ratios in embryo progenies of 101 queens of the “polygyne” social form (3512 embryos) using three supergene-linked markers and twelve markers outside the supergene.
Veni, vidi, vici: the success of wtf meiotic drivers in fission yeast
3990López Hernández, JFZ, Sarah E., Yeast, 35:447-453. 2018-01-08 00:00:00.
Meiotic drivers are selfish DNA loci that can bias their own transmission into gametes. Owing to their transmission advantages, meiotic drivers can spread in populations even if the drivers or linked variants decrease organismal fitness. Meiotic drive was first formally described in the 1950s and is thought to be a powerful force shaping eukaryotic genomes. Classic genetic analyses have detected the action of meiotic drivers in plants, filamentous fungi, insects and vertebrates. Several of these drive systems have limited experimental tractability and relatively little is known about the molecular mechanisms of meiotic drive. Recently, however, meiotic drivers were discovered in a yeast species. The Schizosaccharomyces pombe wtf gene family contains several active meiotic drive genes. This review summarizes what is known about the wtf family and highlights its potential as a highly tractable experimental model for molecular and evolutionary characterization of meiotic drive.
Development of a multi-locus CRISPR gene drive system in budding yeast
4029Yan, YF, Gregory C., Scientific reports, 8:17277-17277. 2018-01-07 00:00:00.
The discovery of CRISPR/Cas gene editing has allowed for major advances in many biomedical disciplines and basic research. One arrangement of this biotechnology, a nuclease-based gene drive, can rapidly deliver a genetic element through a given population and studies in fungi and metazoans have demonstrated the success of such a system. This methodology has the potential to control biological populations and contribute to eradication of insect-borne diseases, agricultural pests, and invasive species. However, there remain challenges in the design, optimization, and implementation of gene drives including concerns regarding biosafety, containment, and control/inhibition. Given the numerous gene drive arrangements possible, there is a growing need for more advanced designs. In this study, we use budding yeast to develop an artificial multi-locus gene drive system. Our minimal setup requires only a single copy of S. pyogenes Cas9 and three guide RNAs to propagate three gene drives. We demonstrate how this system could be used for targeted allele replacement of native genes and to suppress NHEJ repair systems by modifying DNA Ligase IV. A multi-locus gene drive configuration provides an expanded suite of options for complex attributes including pathway redundancy, combatting evolved resistance, and safeguards for control, inhibition, or reversal of drive action.
Population dynamics of underdominance gene drive systems in continuous space
3969Champer, JZ, Joanna; Champer, Sam; Liu, Jingxian; Messer, Philipp W., bioRxiv, 449355:1-23. 2018-01-07 00:00:00.
Underdominance gene drive systems promise a mechanism for rapidly spreading payload alleles through a local population while otherwise remaining confined, unable to spread into neighboring populations due to their frequency-dependent dynamics. Such systems could provide a new tool in the fight against vector-borne diseases by disseminating transgenic payloads through vector populations. If local confinement can indeed be achieved, the decision-making process for the release of such constructs would likely be considerably simpler compared to other gene drive mechanisms such as CRISPR homing drives. So far, the confinement ability of underdominance systems has only been demonstrated in models of panmictic populations linked by migration. How such systems would behave in realistic populations where individuals move over continuous space remains largely unknown. Here, we study several underdominance systems in continuous-space population models and show that their dynamics are drastically altered from those in panmictic populations. Specifically, we find that all underdominance systems we studied can fail to persist in such environments, even after successful local establishment. At the same time, we find that a two-locus two-toxin-antitoxin system can still successfully invade neighboring populations in many scenarios even under weak migration. This suggests that the parameter space for underdominance systems to both establish in a given region and remain confined to that region would likely be highly limited. Overall, these results indicate that spatial context must be considered when assessing strategies for the deployment of underdominance systems.
Tuning CRISPR-Cas9 gene grives in Saccharomyces cerevisiae
4009Roggenkamp, EG, Rachael M.; Schrock, Madison N.; Turnquist, Emily; Halloran, Megan; Finnigan, Gregory C., G3-Genes Genomes Genetics, 8:999. 2018-01-07 00:00:00.
Control of biological populations is an ongoing challenge in many fields, including agriculture, biodiversity, ecological preservation, pest control, and the spread of disease. In some cases, such as insects that harbor human pathogens (e.g., malaria), elimination or reduction of a small number of species would have a dramatic impact across the globe. Given the recent discovery and development of the CRISPR-Cas9 gene editing technology, a unique arrangement of this system, a nuclease-based “gene drive,” allows for the super-Mendelian spread and forced propagation of a genetic element through a population. Recent studies have demonstrated the ability of a gene drive to rapidly spread within and nearly eliminate insect populations in a laboratory setting. While there are still ongoing technical challenges to design of a more optimal gene drive to be used in wild populations, there are still serious ecological and ethical concerns surrounding the nature of this powerful biological agent. Here, we use budding yeast as a safe and fully contained model system to explore mechanisms that might allow for programmed regulation of gene drive activity. We describe four conserved features of all CRISPR-based drives and demonstrate the ability of each drive component—Cas9 protein level, sgRNA identity, Cas9 nucleocytoplasmic shuttling, and novel Cas9-Cas9 tandem fusions—to modulate drive activity within a population.
Reducing resistance allele formation in CRISPR gene drive
3968Champer, JL, Jingxian; Oh, Suh Yeon; Reeves, Riona; Luthra, Anisha; Oakes, Nathan; Clark, Andrew G.; Messer, Philipp W., Proceedings of the National Academy of Sciences of the United States of America, 115:5522-5527. 2018-01-06 00:00:00.
A functioning gene drive mechanism could fundamentally change our strategies for the control of vector-borne diseases, such as malaria, dengue, and Zika. CRISPR homing gene drive promises such a mechanism, which could be used to rapidly spread genetic modifications among the mosquitoes that transmit these diseases. However, recent studies have shown that current drives would likely be unable to spread in insect populations due to the high rate at which resistance will evolve. In this study, we provide an experimental demonstration that guide RNA multiplexing can successfully reduce resistance rates but also find that such an approach would still need to be combined with additional strategies to create drives that are efficient enough for use in wild populations.CRISPR homing gene drives can convert heterozygous cells with one copy of the drive allele into homozygotes, thereby enabling super-Mendelian inheritance. Such a mechanism could be used, for example, to rapidly disseminate a genetic payload in a population, promising effective strategies for the control of vector-borne diseases. However, all CRISPR homing gene drives studied in insects thus far have produced significant quantities of resistance alleles that would limit their spread. In this study, we provide an experimental demonstration that multiplexing of guide RNAs can both significantly increase the drive conversion efficiency and reduce germline resistance rates of a CRISPR homing gene drive in Drosophila melanogaster. We further show that an autosomal drive can achieve drive conversion in the male germline, with no subsequent formation of resistance alleles in embryos through paternal carryover of Cas9. Finally, we find that the nanos promoter significantly lowers somatic Cas9 expression compared with the vasa promoter, suggesting that nanos provides a superior choice in drive strategies where gene disruption in somatic cells could have fitness costs. Comparison of drive parameters among the different constructs developed in this study and a previous study suggests that, while drive conversion and germline resistance rates are similar between different genomic targets, embryo resistance rates can vary significantly. Taken together, our results mark an important step toward developing effective gene drives capable of functioning in natural populations and provide several possible avenues for further control of resistance rates.
RPM-Drive: A robust, safe, and reversible gene drive system that remains functional after 200+ generations
4008Reed, FAA-M, Todd G.; Costantini, Maria S.; Láruson, Áki J.; Sutton, Jolene T., arXiv, 1806.05304:1-19. 2018-01-06 00:00:00.
Despite the advent of several novel, synthetic gene drive mechanisms and their potential to one-day control a number of devastating diseases, among other applications, practical use of these systems remains contentious and risky. In particular, there is little in the way of empirical evidence of the long-term robustness of these synthetic systems against mutational breakdown. Rather, most existing systems are either known or predicted to be susceptible to rapid inactivation, though methodological designs continue to be refined. Here we evaluate a currently existing synthetic, underdominance-based gene drive system 200+ generations after it was first established in a laboratory colony of Drosophila melanogaster. Not only do we find that the system is still functioning as designed, we also show evidence that disruptions to the genetic construct are highly likely to be removed by natural selection, contributing to the system's robust, long-term stability. This stability appears to be a result of a fundamental relationship between ribosomal proteins (a novel target of the system) and natural cellular defenses that protect against cancer development. As far as we are aware, this is the longest continually functioning synthetic gene drive system thus verified, making it highly appropriate for additional research into its eventual suitability for field trials. Due to inherent properties of this gene drive, it is also likely to be adaptable for use in many different species. The insect lines established and used to test this system have been deposited at a Drosophila stock center, and are available to labs for further, independent testing.
A CRISPR–Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes
3987Kyrou, KH, Andrew M.; Galizi, Roberto; Kranjc, Nace; Burt, Austin; Beaghton, Andrea K.; Nolan, Tony; Crisanti, Andrea, Nature Biotechnology, 36:1062–1066. 2018-01-05 00:00:00.
In the human malaria vector Anopheles gambiae, the gene doublesex (Agdsx) encodes two alternatively spliced transcripts, dsx-female (AgdsxF) and dsx-male (AgdsxM), that control differentiation of the two sexes. The female transcript, unlike the male, contains an exon (exon 5) whose sequence is highly conserved in all Anopheles mosquitoes so far analyzed. We found that CRISPR–Cas9-targeted disruption of the intron 4–exon 5 boundary aimed at blocking the formation of functional AgdsxF did not affect male development or fertility, whereas females homozygous for the disrupted allele showed an intersex phenotype and complete sterility. A CRISPR–Cas9 gene drive construct targeting this same sequence spread rapidly in caged mosquitoes, reaching 100% prevalence within 7–11 generations while progressively reducing egg production to the point of total population collapse. Owing to functional constraint of the target sequence, no selection of alleles resistant to the gene drive occurred in these laboratory experiments. Cas9-resistant variants arose in each generation at the target site but did not block the spread of the drive.
Correction to ‘Dodging silver bullets: good CRISPR gene-drive design is critical for eradicating exotic vertebrates’
4007Prowse, TAAC, Phillip; Ross, Joshua V.; Pfitzner, Chandran; Wittmann, Talia; Thomas, Paul, Proceedings of the Royal Society B: Biological Sciences, 285:1-2. 2018-01-05 00:00:00.
Proc. R. Soc. B 284, 20170799. (Published Online 9 August 2017). (doi:10.1098/rspb.2017.0799)We recently found an error in our calculation of the probability of a wild-type allele moving from s to j susceptible sites (), and acquiring the gene drive (), during gene-drive homing, under the assumption that multiplexed gRNAs are expressed simultaneously. In the R code provided (function GeneDriveSimRec, appendix S1), these probabilities are calculated recursively and the multiplier was missing (from line 11), where j is the number of cut target sites along an inter-site NHEJ-mediated deletion at which NHEJ …
Rationally-engineered reproductive barriers using CRISPR & CRISPRa: an evaluation of the synthetic species concept in Drosophila melanogaster
4027Waters, AJC, Paolo; Gaboriau, David C. A.; Papathanos, Philippos Aris; Windbichler, Nikolai, Scientific Reports, 8:13125. 2018-01-05 00:00:00.
The ability to erect rationally-engineered reproductive barriers in animal or plant species promises to enable a number of biotechnological applications such as the creation of genetic firewalls, the containment of gene drives or novel population replacement and suppression strategies for genetic control. However, to date no experimental data exist that explores this concept in a multicellular organism. Here we examine the requirements for building artificial reproductive barriers in the metazoan model Drosophila melanogaster by combining CRISPR-based genome editing and transcriptional transactivation (CRISPRa) of the same loci. We directed 13 single guide RNAs (sgRNAs) to the promoters of 7 evolutionary conserved genes and used 11 drivers to conduct a misactivation screen. We identify dominant-lethal activators of the eve locus and find that they disrupt development by strongly activating eve outside its native spatio-temporal context. We employ the same set of sgRNAs to isolate, by genome editing, protective INDELs that render these loci resistant to transactivation without interfering with target gene function. When these sets of genetic components are combined we find that complete synthetic lethality, a prerequisite for most applications, is achievable using this approach. However, our results suggest a steep trade-off between the level and scope of dCas9 expression, the degree of genetic isolation achievable and the resulting impact on fly fitness. The genetic engineering strategy we present here allows the creation of single or multiple reproductive barriers and could be applied to other multicellular organisms such as disease vectors or transgenic organisms of economic importance.
Redkmer: An assembly-free pipeline for the identification of abundant and specific X-chromosome target sequences for X-shredding by CRISPR endonucleases
4006Papathanos, PAW, Nikolai, CRISPR Journal, 1:88-98. 2018-01-04 00:00:00.
CRISPR-based synthetic sex ratio distorters, which operate by shredding the X-chromosome during male meiosis, are promising tools for the area-wide control of harmful insect pest or disease vector species. X-shredders have been proposed as tools to suppress insect populations by biasing the sex ratio of the wild population toward males, thus reducing its natural reproductive potential. However, to build synthetic X-shredders based on CRISPR, the selection of gRNA targets, in the form of high-copy sequence repeats on the X chromosome of a given species, is difficult, since such repeats are not accurately resolved in genome assemblies and cannot be assigned to chromosomes with confidence. We have therefore developed the redkmer computational pipeline, designed to identify short and highly abundant sequence elements occurring uniquely on the X chromosome. Redkmer was designed to use as input minimally processed whole genome sequence data from males and females. We tested redkmer with short- and long-read whole genome sequence data of Anopheles gambiae, the major vector of human malaria, in which the X-shredding paradigm was originally developed. Redkmer established long reads as chromosomal proxies with excellent correlation to the genome assembly and used them to rank X-candidate kmers for their level of X-specificity and abundance. Among these, a high-confidence set of 25-mers was identified, many belonging to previously known X-chromosome repeats of Anopheles gambiae,including the ribosomal gene array and the selfish elements harbored within it. Data from a control strain, in which these repeats are shared with the Y chromosome, confirmed the elimination of these kmers during filtering. Finally, we show that redkmer output can be linked directly to gRNA selection and off-target prediction. In addition, the output of redkmer, including the prediction of chromosomal origin of single-molecule long reads and chromosome specific kmers, could also be used for the characterization of other biologically relevant sex chromosome sequences, a task that is frequently hampered by the repetitiveness of sex chromosome sequence content.
B Chromosomes in populations of mammals revisited
4025Vujoševi?, MR, Marija; Blagojevi?, Jelena, Genes, 9:487. 2018-01-03 00:00:00.
The study of B chromosomes (Bs) started more than a century ago, while their presence in mammals dates since 1965. As the past two decades have seen huge progress in application of molecular techniques, we decided to throw a glance on new data on Bs in mammals and to review them. We listed 85 mammals with Bs that make 1.94% of karyotypically studied species. Contrary to general view, a typical B chromosome in mammals appears both as sub- or metacentric that is the same size as small chromosomes of standard complement. Both karyotypically stable and unstable species possess Bs. The presence of Bs in certain species influences the cell division, the degree of recombination, the development, a number of quantitative characteristics, the host-parasite interactions and their behaviour. There is at least some data on molecular structure of Bs recorded in nearly a quarter of species. Nevertheless, a more detailed molecular composition of Bs presently known for six mammalian species, confirms the presence of protein coding genes, and the transcriptional activity for some of them. Therefore, the idea that Bs are inert is outdated, but the role of Bs is yet to be determined. The maintenance of Bs is obviously not the same for all species, so the current models must be adapted while bearing in mind that Bs are not inactive as it was once thought.
Behavior of homing endonuclease gene drives targeting genes required for viability or female fertility with multiplexed guide RNAs
4005Oberhofer, GI, Tobin; Hay, Bruce A., Proceedings of the National Academy of Sciences of the United States of America, 115:e9343. 2018-01-03 00:00:00.
Homing endonuclease gene (HEG)-based gene drive can bring about population suppression when genes required for viability or fertility are targeted. However, these strategies are vulnerable to failure through mechanisms that create alleles resistant to cleavage but that retain wild-type gene function. We show that resistance allele creation can be prevented through the use of guide RNAs designed to cleave a gene at four target sites. However, homing rates were modest, and the HEGs were unstable during homing. In addition, use of a promoter active in the female germline resulted in levels of HEG carryover that compromised the viability or fertility of HEG-bearing heterozygotes, thereby preventing drive. We propose strategies that can help to overcome these problems in next-generation HEG systems.A gene drive method of particular interest for population suppression utilizes homing endonuclease genes (HEGs), wherein a site-specific, nuclease-encoding cassette is copied, in the germline, into a target gene whose loss of function results in loss of viability or fertility in homozygous, but not heterozygous, progeny. Earlier work in Drosophila and mosquitoes utilized HEGs consisting of Cas9 and a single guide RNA (gRNA) that together target a specific gene for cleavage. Homing was observed, but resistant alleles immune to cleavage, while retaining wild-type gene function, were also created through nonhomologous end joining. Such alleles prevent drive and population suppression. Targeting a gene for cleavage at multiple positions has been suggested as a strategy to prevent the appearance of resistant alleles. To test this hypothesis, we generated two suppression HEGs in Drosophila melanogaster targeting genes required for embryonic viability or fertility, using a HEG consisting of CRISPR/Cas9 and gRNAs designed to cleave each gene at four positions. Rates of target locus cleavage were very high, and multiplexing of gRNAs prevented resistant allele formation. However, germline homing rates were modest, and the HEG cassette was unstable during homing events, resulting in frequent partial copying of HEGs that lacked gRNAs, a dominant marker gene, or Cas9. Finally, in drive experiments, the HEGs failed to spread due to the high fitness load induced in offspring as a result of maternal carryover of Cas9/gRNA complex activity. Alternative design principles are proposed that may mitigate these problems in future gene drive engineering.
Spindle asymmetry drives non-Mendelian chromosome segregation
13518T. Akera, L. Chmátal, E. Trimm, K. Yang, C. Aonbangkhen, D. M. Chenoweth, C. Janke, R. M. Schultz and M. A. Lampson, Science, 358:668. 2017-11-03 14:19:19.
Genetic elements compete for transmission through meiosis, when haploid gametes are created from a diploid parent. Selfish elements can enhance their transmission through a process known as meiotic drive. In female meiosis, selfish elements drive by preferentially attaching to the egg side of the spindle. This implies some asymmetry between the two sides of the spindle, but the molecular mechanisms underlying spindle asymmetry are unknown. Here we found that CDC42 signaling from the cell cortex regulated microtubule tyrosination to induce spindle asymmetry and that non-Mendelian segregation depended on this asymmetry. Cortical CDC42 depends on polarization directed by chromosomes, which are positioned near the cortex to allow the asymmetric cell division. Thus, selfish meiotic drivers exploit the asymmetry inherent in female meiosis to bias their transmission.
CRISPR’s Gene Drive Could Revive Extinct Species–or Create New Ones | Jennifer Doudna
5522Jennifer Doudna, Big Think, 2017-06-26 19:28:41.
A leading gene editing scientist, Jennifer Doudna, discusses gene drive and their applications as well as de-extinction technologies.
Gene drive for Malaria control | Andrea Crisanti |
5519TEDx, 2017-04-04 19:23:37.
Andrea discusses his team's laboratory work that has developed a revolutionary technology to spread genetic modifications from few laboratory mosquitoes to wild populations to eradicate malaria in the near future
Dodging silver bullets: good CRISPR gene-drive design is critical for eradicating exotic vertebrates
4063Prowse, TAAC, Phillip; Ross, Joshua V.; Pfitzner, Chandran; Wittmann, Talia A.; Thomas, Paul, Proceedings of the Royal Society B: Biological Sciences, 284:20170799. 2017-01-21 00:00:00.
Self-replicating gene drives that can spread deleterious alleles through animal populations have been promoted as a much needed but controversial ‘silver bullet’ for controlling invasive alien species. Homing-based drives comprise an endonuclease and a guide RNA (gRNA) that are replicated during meiosis via homologous recombination. However, their efficacy for controlling wild populations is threatened by inherent polymorphic resistance and the creation of resistance alleles via non-homologous end-joining (NHEJ)-mediated DNA repair. We used stochastic individual-based models to identify realistic gene-drive strategies capable of eradicating vertebrate pest populations (mice, rats and rabbits) on islands. One popular strategy, a sex-reversing drive that converts heterozygous females into sterile males, failed to spread and required the ongoing deployment of gene-drive carriers to achieve eradication. Under alternative strategies, multiplexed gRNAs could overcome inherent polymorphic resistance and were required for eradication success even when the probability of NHEJ was low. Strategies causing homozygotic embryonic non-viability or homozygotic female sterility produced high probabilities of eradication and were robust to NHEJ-mediated deletion of the DNA sequence between multiplexed endonuclease recognition sites. The latter two strategies also purged the gene drive when eradication failed, therefore posing lower long-term risk should animals escape beyond target islands. Multiplexing gRNAs will be necessary if this technology is to be useful for insular extirpation attempts; however, precise knowledge of homing rates will be required to design low-risk gene drives with high probabilities of eradication success.
wtf genes are prolific dual poison-antidote meiotic drivers
4060Nuckolls, NLN, M. A. B.; Eickbush, M. T.; Young, J. M.; Lange, J. J.; Yu, J. S.; Smith, G. R.; Jaspersen, S. L.; Malik, H. S.; Zanders, S. E., eLife, 6:e26033. 2017-01-18 00:00:00.
Meiotic drivers are selfish genes that bias their transmission into gametes, defying Mendelian inheritance. Despite the significant impact of these genomic parasites on evolution and infertility, few meiotic drive loci have been identified or mechanistically characterized. Here, we demonstrate a complex landscape of meiotic drive genes on chromosome 3 of the fission yeasts Schizosaccharomyces kambucha and S. pombe. We identify S. kambucha wtf4 as one of these genes that acts to kill gametes (known as spores in yeast) that do not inherit the gene from heterozygotes. wtf4 utilizes dual, overlapping transcripts to encode both a gamete-killing poison and an antidote to the poison. To enact drive, all gametes are poisoned, whereas only those that inherit wtf4 are rescued by the antidote. Our work suggests that the wtf multigene family proliferated due to meiotic drive and highlights the power of selfish genes to shape genomes, even while imposing tremendous costs to fertility.
CRISPR/Cas9 gene drives in genetically variable and nonrandomly mating wild populations
4038Drury, DWD, A. L.; Siniard, D. J.; Zentner, G. E.; Wade, M. J., Science Advances, 3:e1601910. 2017-01-16 00:00:00.
Synthetic gene drives based on CRISPR/Cas9 have the potential to control, alter, or suppress populations of crop pests and disease vectors, but it is unclear how they will function in wild populations. Using genetic data from four populations of the flour beetle Tribolium castaneum, we show that most populations harbor genetic variants in Cas9 target sites, some of which would render them immune to drive (ITD). We show that even a rare ITD allele can reduce or eliminate the efficacy of a CRISPR/Cas9-based synthetic gene drive. This effect is equivalent to and accentuated by mild inbreeding, which is a characteristic of many disease-vectoring arthropods. We conclude that designing such drives will require characterization of genetic variability and the mating system within and among targeted populations.
B chromosome in Plantago lagopus Linnaeus, 1753 shows preferential transmission and accumulation through unusual processes
4037Dhar, MKK, G.; Kaul, S., Comparative Cytogenetics, 11:375-391. 2017-01-15 00:00:00.
Plantago lagopus is a diploid (2n = 2x = 12) weed belonging to family Plantaginaceae. We reported a novel B chromosome in this species composed of 5S and 45S ribosomal DNA and other repetitive elements. In the present work, presence of B chromosome(s) was confirmed through FISH on root tip and pollen mother cells. Several experiments were done to determine the transmission of B chromosome through male and female sex tracks. Progenies derived from the reciprocal crosses between plants with (1B) and without (0B) B chromosomes were studied. The frequency of B chromosome bearing plants was significantly higher than expected, in the progeny of 1B female x 0B male. Thus, the B chromosome seems to have preferential transmission through the female sex track, which may be due to meiotic drive. One of the most intriguing aspects of the present study was the recovery of plants having more chromosomes than the standard complement of 12 chromosomes. Such plants were isolated from the progenies of B chromosome carrying plants. The origin of these plants can be explained on the basis of a two step process; formation of unreduced gametes in 1B plants and fusion of unreduced gametes with the normal gametes or other unreduced gametes. Several molecular techniques were used which unequivocally confirmed similar genetic constitution of 1B (parent) and plants with higher number of chromosomes.
Engineering species-like barriers to sexual reproduction
4057Maselko, MH, Stephen C.; Chacón, Jeremy M.; Harcombe, William R.; Smanski, Michael J., Nature Communications, 8:883. 2017-01-15 00:00:00.
Controlling the exchange of genetic information between sexually reproducing populations has applications in agriculture, eradication of disease vectors, control of invasive species, and the safe study of emerging biotechnology applications. Here we introduce an approach to engineer a genetic barrier to sexual reproduction between otherwise compatible populations. Programmable transcription factors drive lethal gene expression in hybrid offspring following undesired mating events. As a proof of concept, we target the ACT1 promoter of the model organism Saccharomyces cerevisiae using a dCas9-based transcriptional activator. Lethal overexpression of actin results from mating this engineered strain with a strain containing the wild-type ACT1 promoter.
Gene drives do not always increase in frequency: from genetic models to risk assessment
4036de Jong, TJ, Journal Fur Verbraucherschutz Und Lebensmittelsicherheit-Journal of Consumer Protection and Food Safety, 12:299-307. 2017-01-14 00:00:00.
Homing genes encode endonucleases that make a double stranded break in the DNA, destroying a target site on the homologous chromosome. When the cell repairs the break the homing allele is copied, converting a heterozygote into a homozygote. This results in gene drive (GD), an overrepresentation of the homing allele in the next generation. GD may propel CRISPR-Cas9 genes and new genes physically coupled to the GD through natural populations. I revisit the population genetic models of GD with the aim of making these models more understandable to non-specialists. What can we learn about risk evaluation from the models? A GD with no or a small effect on fitness (viability) always spreads in the population and goes to fixation. That is provided that no resistance mechanism evolves, for instance due to a mutation in the target site. However, when GDs have a large negative effect on fitness, their spread depends on a threshold or they may not spread at all. The chance of GDs increasing until fixation is much higher in systems with meiotic drive than in systems with embryo conversion. The presence or absence of a meiotic promoter is therefore relevant to take into account in the environmental risk assessment.
Introduction of a male-harming mitochondrial haplotype via ‘Trojan Females’ achieves population suppression in fruit flies
4074Wolff, JNG, N. J.; Tompkins, D. M.; Dowling, D. K., eLife, 6:e23551. 2017-01-12 00:00:00.
Pests are a global threat to biodiversity, ecosystem function, and human health. Pest control approaches are thus numerous, but their implementation costly, damaging to non-target species, and ineffective at low population densities. The Trojan Female Technique (TFT) is a prospective self-perpetuating control technique that is species-specific and predicted to be effective at low densities. The goal of the TFT is to harness naturally occurring mutations in the mitochondrial genome that impair male fertility while having no effect on females. Here, we provide proof-of-concept for the TFT, by showing that introduction of a male fertility-impairing mtDNA haplotype into replicated populations of Drosophila melanogaster causes numerical population suppression, with the magnitude of effect positively correlated with its frequency at trial inception. Further development of the TFT could lead to establishing a control strategy that overcomes limitations of conventional approaches, with broad applicability to invertebrate and vertebrate species, to control environmental and economic pests.
Novel CRISPR/Cas9 gene drive constructs reveal insights into mechanisms of resistance allele formation and drive efficiency in genetically diverse populations
4034Champer, JR, Riona; Oh, Suh Yeon; Liu, Chen; Liu, Jingxian; Clark, Andrew G.; Messer, Philipp W., PLOS Genetics, 13:e1006796. 2017-01-12 00:00:00.
Author summary Gene drive systems provide a wide array of potential applications, including new strategies for the control of vector-borne diseases. For example, a functioning gene drive system could rapidly spread a genetically modified allele designed to reduce pathogen transmission throughout a vector population. The recently developed CRISPR/Cas9-based gene drive mechanism works by converting wild type alleles to drive alleles in heterozygotes via cleavage and homology-directed repair. However, resistance alleles that are unable to be converted to drive alleles can also be generated during this process, which may pose a major obstacle to the practical use of such gene drives. In our study, we developed two CRISPR/Cas9 gene drive constructs using different promoters and target sites in the model organism Drosophila melanogaster. We observed that these constructs produced resistance alleles at high rates both in the germline and post-fertilization in the embryo. Additionally, conversion efficiency and resistance allele formation rates varied substantially among genetically diverse fly lines. Overall, we conclude that new gene drive approaches will be necessary to reduce the formation of resistance alleles, particularly in genetically diverse natural populations.
A pooled sequencing approach identifies a candidate meiotic driver in Drosophila
4072Wei, KHCR, H. M.; Rathnam, C.; Lee, J.; Lin, D. A. N.; Ji, S. Q.; Mason, J. M.; Clark, A. G.; Barbash, D. A., Genetics, 206:451-465. 2017-01-10 00:00:00.
Meiotic drive occurs when a selfish element increases its transmission frequency above the Mendelian ratio by hijacking the asymmetric divisions of female meiosis. Meiotic drive causes genomic conflict and potentially has a major impact on genome evolution, but only a few drive loci of large effect have been described. New methods to reliably detect meiotic drive are therefore needed, particularly for discovering moderate-strength drivers that are likely to be more prevalent in natural populations than strong drivers. Here, we report an efficient method that uses sequencing of large pools of backcross (BC1) progeny to test for deviations from Mendelian segregation genome-wide with single-nucleotide polymorphisms (SNPs) that distinguish the parental strains. We show that meiotic drive can be detected by a characteristic pattern of decay in distortion of SNP frequencies, caused by recombination unlinking the driver from distal loci. We further show that control crosses allow allele-frequency distortion caused by meiotic drive to be distinguished from distortion resulting from developmental effects. We used this approach to test whether chromosomes with extreme telomere-length differences segregate at Mendelian ratios, as telomeric regions are a potential hotspot for meiotic drive due to their roles in meiotic segregation and multiple observations of high rates of telomere sequence evolution. Using four different pairings of long and short telomere strains, we find no evidence that extreme telomere-length variation causes meiotic drive in Drosophila. However, we identify one candidate meiotic driver in a centromere-linked region that shows an similar to 8% increase in transmission frequency, corresponding to a similar to 54: 46 segregation ratio. Our results show that candidate meiotic drivers of moderate strength can be readily detected and localized in pools of BC1 progeny.
X chromosome drive in a widespread Palearctic woodland fly, Drosophila testacea
4052Keais, GLH, M. A.; Gowen, B. E.; Perlman, S. J., Journal of Evolutionary Biology, 30:1185-1194. 2017-01-10 00:00:00.
Selfish genes that bias their own transmission during meiosis can spread rapidly in populations, even if they contribute negatively to the fitness of their host. Driving X chromosomes provide a clear example of this type of selfish propagation. These chromosomes have important evolutionary and ecological consequences, and can be found in a broad range of taxa including plants, mammals and insects. Here, we report a new case of X chromosome drive (X drive) in a widespread woodland fly, Drosophila testacea. We show that males carrying the driving X (SR males) sire 80-100% female offspring and possess a diagnostic X chromosome haplotype that is perfectly associated with the sex ratio distortion phenotype. We find that the majority of sons produced by SR males are sterile and appear to lack a Y chromosome, suggesting that meiotic defects involving the Y chromosome may underlie X drive in this species. Abnormalities in sperm cysts of SR males reflect that some spermatids are failing to develop properly, confirming that drive is acting during gametogenesis. By screening wild-caught flies using progeny sex ratios and a diagnostic marker, we demonstrate that the driving X is present in wild populations at a frequency of similar to 10% and that suppressors of drive are segregating in the same population. The testacea species group appears to be a hot spot for X drive, and D. testacea is a promising model to compare driving X chromosomes in closely related species, some of which may even be younger than the chromosomes themselves.
A large gene family in fission yeast encodes spore killers that subvert Mendel’s law
4049Hu, WJ, Z. D.; Suo, F.; Zheng, J. X.; He, W. Z.; Du, L. L., eLife, 6:e28567. 2017-01-07 00:00:00.
Spore killers in fungi are selfish genetic elements that distort Mendelian segregation in their favor. It remains unclear how many species harbor them and how diverse their mechanisms are. Here, we discover two spore killers from a natural isolate of the fission yeast Schizosaccharomyces pombe. Both killers belong to the previously uncharacterized wtf gene family with 25 members in the reference genome. These two killers act in strain-background-independent and genome-location-independent manners to perturb the maturation of spores not inheriting them. Spores carrying one killer are protected from its killing effect but not that of the other killer. The killing and protecting activities can be uncoupled by mutation. The numbers and sequences of wtf genes vary considerably between S. pombe isolates, indicating rapid divergence. We propose that wtf genes contribute to the extensive intraspecific reproductive isolation in S. pombe, and represent ideal models for understanding how segregation-distorting elements act and evolve.
B Chromosomes – A matter of chromosome drive
4048Houben, A, Frontiers in Plant Science, 8:210. 2017-01-06 00:00:00.
B chromosomes are supernumerary chromosomes which are often preferentially inherited, deviating from usual Mendelian segregation. The balance between the so-called chromosome drive and the negative effects that the presence of Bs applies on the fitness of their host determines the frequency of Bs in a particular population. Drive is the key for understanding most B chromosomes. Drive occurs in many ways at pre-meiotic, meiotic or post-meiotic divisions, but the molecular mechanism remains unclear. The cellular mechanism of drive is reviewed based on the findings obtained for the B chromosomes of rye, maize and other species. How novel analytical tools will expand our ability to uncover the biology of B chromosome drive is discussed.
Spatial gene drives and pushed genetic waves
4068Tanaka, HS, Howard A.; Nelson, David R., Proceedings of the National Academy of Sciences of the United States of America, 114:8452. 2017-01-06 00:00:00.
Gene constructs introduced into natural environments have been proposed to solve various ecological problems. The CRISPR-Cas9 technology greatly facilitates construction of gene drives that allow desired traits to rapidly replace wild types, even if these convey a selective growth rate disadvantage s > 0. However, accidental release of a gene drive could damage ecosystems irreversibly. We have modeled the spatial spread of gene drives and find a preferred range of selective disadvantages, 0.5 < s < 0.697. In this regime, gene drives spread but only when a nucleus exceeds a critical size and intensity. By making gene drives uniquely susceptible to a compound, their advance can be stopped in two dimensions by finite-width barriers, even when interrupted by gaps.Gene drives have the potential to rapidly replace a harmful wild-type allele with a gene drive allele engineered to have desired functionalities. However, an accidental or premature release of a gene drive construct to the natural environment could damage an ecosystem irreversibly. Thus, it is important to understand the spatiotemporal consequences of the super-Mendelian population genetics before potential applications. Here, we use a reaction–diffusion model for sexually reproducing diploid organisms to study how a locally introduced gene drive allele spreads to replace the wild-type allele, although it possesses a selective disadvantage s > 0. Using methods developed by Barton and collaborators, we show that socially responsible gene drives require 0.5 < s < 0.697, a rather narrow range. In this “pushed wave” regime, the spatial spreading of gene drives will be initiated only when the initial frequency distribution is above a threshold profile called “critical propagule,” which acts as a safeguard against accidental release. We also study how the spatial spread of the pushed wave can be stopped by making gene drives uniquely vulnerable (“sensitizing drive”) in a way that is harmless for a wild-type allele. Finally, we show that appropriately sensitized drives in two dimensions can be stopped, even by imperfect barriers perforated by a series of gaps.
The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito
4046Hammond, AMK, Kyros; Bruttini, Marco; North, Ace; Galizi, Roberto; Karlsson, Xenia; Kranjc, Nace; Carpi, Francesco M.; D’Aurizio, Romina; Crisanti, Andrea; Nolan, Tony, PLOS Genetics, 13:e1007039. 2017-01-04 00:00:00.
Gene drives are selfish genetic elements that are able to bias their own inheritance among offspring. Starting from very low frequencies they can rapidly invade a population in just a few generations, even when imposing a fitness cost. Gene drives based on the precise DNA cutting enzyme CRISPR have been shown recently to be highly efficient at copying themselves from one chromosome to the other during the process of gamete formation in mosquitoes, resulting in transmission to 99% of offspring instead of the 50% expected for a single gene copy. One proposed use for CRISPR-based gene drives is in the control of mosquitoes by designing the gene drive to target mosquito genes involved in fertility, thereby reducing their overall reproductive output and leading to population suppression. Like any intervention designed to suppress a population these gene drives are expected to select for mutations in the mosquito that are resistant to the drive and restore fertility to mosquitoes. We have analyzed the origin and selection of resistant alleles in caged populations of mosquitoes initiated with a gene drive construct targeting a female fertility gene. We find the selected alleles are in-frame insertions and deletions that are resistant to cleavage and restore female fertility. Our findings allow us to improve predictions on gene drive behaviour and to make concrete recommendations on how to improve future gene drive designs by decreasing the likelihood that they generate resistance.
Potential of gene drives with genome editing to increase genetic gain in livestock breeding programs
4044Gonen, SJ, J.; Gorjanc, G.; Mileham, A. J.; Whitelaw, C. B. A.; Hickey, J. M., Genetics Selection Evolution, 49:14. 2017-01-02 00:00:00.
This paper uses simulation to explore how gene drives can increase genetic gain in livestock breeding programs. Gene drives are naturally occurring phenomena that cause a mutation on one chromosome to copy itself onto its homologous chromosome. Methods: We simulated nine different breeding and editing scenarios with a common overall structure. Each scenario began with 21 generations of selection, followed by 20 generations of selection based on true breeding values where the breeder used selection alone, selection in combination with genome editing, or selection with genome editing and gene drives. In the scenarios that used gene drives, we varied the probability of successfully incorporating the gene drive. For each scenario, we evaluated genetic gain, genetic variance (sigma(2)(A)), rate of change in inbreeding (Delta F), number of distinct quantitative trait nucleotides (QTN) edited, rate of increase in favourable allele frequencies of edited QTN and the time to fix favourable alleles. Results: Gene drives enhanced the benefits of genome editing in seven ways: (1) they amplified the increase in genetic gain brought about by genome editing; (2) they amplified the rate of increase in the frequency of favourable alleles and reduced the time it took to fix them; (3) they enabled more rapid targeting of QTN with lesser effect for genome editing; (4) they distributed fixed editing resources across a larger number of distinct QTN across generations; (5) they focussed editing on a smaller number of QTN within a given generation; (6) they reduced the level of inbreeding when editing a subset of the sires; and (7) they increased the efficiency of converting genetic variation into genetic gain. Conclusions: Genome editing in livestock breeding results in short-, medium- and long-term increases in genetic gain. The increase in genetic gain occurs because editing increases the frequency of favourable alleles in the population. Gene drives accelerate the increase in allele frequency caused by editing, which results in even higher genetic gain over a shorter period of time with no impact on inbreeding.
Driving out malaria
4598Nolan, TC, A., Scientist, 2017-01-01 00:00:00.
In recent years, researchers have sequenced the genomes of several Anopheles mosquito species, including those responsible for nearly all of the malaria transmission in Africa. With this information, they have begun to identify the genes underlying the insects’ ability to colonize human habitats, their reproductive biology, and their susceptibility to infection by the malaria parasite (Plasmodium spp.). If we know the genes, or variants of genes, that are responsible for key mosquito traits, such as parasite clearance or egg laying, we can theoretically introduce a genetic modification into the insects that reduces malaria transmission.
Prospects and challenges of CRISPR/Cas genome editing for the study and control of neglected vector-borne nematode diseases
6017M. Zamanian and E. C. Andersen, The FEBS Journal, 283:3204-3221. 2016-06-14 20:22:18.
Neglected tropical diseases caused by parasitic nematodes inflict an immense health and socioeconomic burden throughout much of the developing world. Current estimates indicate that more than two billion people are infected with nematodes, resulting in the loss of 14 million disability-adjusted life years per annum. Although these parasites cause significant mortality, they primarily cause chronic morbidity through a wide range of severe clinical ailments. Treatment options for nematode infections are restricted to a small number of anthelmintic drugs, and the rapid expansion of anthelmintic mass drug administration raises concerns of drug resistance. Preservation of existing drugs is necessary, as well as the development of new treatment options and methods of control. We focus this review on how the democratization of CRISPR/Cas9 genome editing technology can be enlisted to improve our understanding of the biology of nematode parasites and our ability to treat the infections they cause. We will first explore how this robust method of genome manipulation can be used to newly exploit the powerful model nematode Caenorhabditis elegans for parasitology research. We will then discuss potential avenues to develop CRISPR/Cas9 editing protocols in filarial nematodes. Lastly, we will propose potential ways in which CRISPR/Cas9 can be used to engineer gene drives that target the transmission of mosquito-borne filarial nematodes.
No evidence for female discrimination against male house mice carrying a selfish genetic element
4103Sutter, AL, A. K., Current Zoology, 62:675-685. 2016-01-21 00:00:00.
Meiotic drivers distort transmission to the next generation in their favor, with detrimental effects on the fitness of their homologues and the rest of the genome. Male carriers of meiotic drivers commonly inflict costs on their mates through genetic incompatibility, reduced fecundity, or biased brood sex ratios. Given these costs, evidence for female discrimination against male carriers is surprisingly rare. One of few examples is the t haplotype in house mice, a meiotic driver that shows strong transmission distortion in males and is typically homozygote lethal. As a consequence, mating between 2 t heterozygous (+/t) mice leads to high embryo mortality. Previous experiments showing that +/t females avoid this incompatibility cost by preferring +/+versus +/t males have inferred preference based on olfactory cues or brief social interactions. Evidence from mating contexts in laboratory settings and semi-natural populations has been inconclusive. Here, we investigated female choice from a large number of no-choice mating trials. We found no evidence for discrimination against +/t males based on mating, remating, and copulatory behavior. Further, we found no evidence for avoidance of incompatibility through selective interactions between gametes. The likelihood of mating showed significant effects of female weight and genotype, suggesting that our test paradigm enabled females to exhibit mate choice. We discuss the strengths and limitations of our approach. By explicitly considering selection at both the individual and gene level, we argue why precopulatory female discrimination by +/t females may be less evolutionarily stable than discrimination by all females based on postcopulatory mechanisms.
Marcus Rhoades on preferential segregation in maize
4082Birchler, JA, Genetics, 203:1489-1490. 2016-01-20 00:00:00.
Rhoades was studying a variant form of chromosome 10 with a conspicuous abnormality; it carried extensive heterochromatin at the tip of the long arm. This variant had been found by Albert Longley in indigenous maize varieties from the southwestern United States and provided to Rhoades for the pedestrian task of determining the recombination frequency between the anthocyanin pigment gene, R, and the end of the chromosome. The abnormal chromosome 10 originally carried the recessive, r, allele (colorless kernels) and was crossed to other lines carrying the dominant R (red kernels). Much to the surprise of Rhoades, when these heterozygotes were testcrossed with the recessive, there was a strong skew from a 1:1 ratio. Rather than the roughly even mix of colorless and red kernels that he expected, around two-thirds were colorless. This excess of r alleles was caused by linkage to the variant chromosome; in the few progeny that transferred the dominant R allele to the abnormal chromosome 10, subsequent testcrosses demonstrated that it was now the dominant allele that was preferentially inherited.
Random and non-random mating populations: Evolutionary dynamics in meiotic drive
4101Sarkar, B, Mathematical Biosciences, 271:29-41. 2016-01-19 00:00:00.
Game theoretic tools are utilized to analyze a one-locus continuous selection model of sex-specific meiotic drive by considering nonequivalence of the viabilities of reciprocal heterozygotes that might be noticed at an imprinted locus. The model draws attention to the role of viability selections of different types to examine the stable nature of polymorphic equilibrium. A bridge between population genetics and evolutionary game theory has been built up by applying the concept of the Fundamental Theorem of Natural Selection. In addition to pointing out the influences of male and female segregation ratios on selection, configuration structure reveals some noted results, e.g., Hardy-Weinberg frequencies hold in replicator dynamics, occurrence of faster evolution at the maximized variance fitness, existence of mixed Evolutionarily Stable Strategy (ESS) in asymmetric games, the tending evolution to follow not only a 1:1 sex ratio but also a 1:1 different alleles ratio at particular gene locus. Through construction of replicator dynamics in the group selection framework, our selection model introduces a redefining bases of game theory to incorporate non-random mating where a mating parameter associated with population structure is dependent on the social structure. Also, the model exposes the fact that the number of polymorphic equilibria will depend on the algebraic expression of population structure. (C) 2015 Elsevier Inc. All rights reserved.
Sexual antagonism and meiotic drive cause stable linkage disequilibrium and favour reduced recombination on the X chromosome
4100Rydzewski, WTC, S. A.; Lievano, G.; Lynch, V. D.; Patten, M. M., Journal of Evolutionary Biology, 29:1247-1256. 2016-01-18 00:00:00.
Sexual antagonism and meiotic drive are sex-specific evolutionary forces with the potential to shape genomic architecture. Previous theory has found that pairing two sexually antagonistic loci or combining sexual antagonism with meiotic drive at linked autosomal loci augments genetic variation, produces stable linkage disequilibrium (LD) and favours reduced recombination. However, the influence of these two forces has not been examined on the X chromosome, which is thought to be enriched for sexual antagonism and meiotic drive. We investigate the evolution of the X chromosome under both sexual antagonism and meiotic drive with two models: in one, both loci experience sexual antagonism; in the other, we pair a meiotic drive locus with a sexually antagonistic locus. We find that LD arises between the two loci in both models, even when the two loci freely recombine in females and that driving haplotypes will be enriched for male-beneficial alleles, further skewing sex ratios in these populations. We introduce a new measure of LD, D-z('), which accounts for population allele frequencies and is appropriate for instances where these are sex specific. Both models demonstrate that natural selection favours modifiers that reduce the recombination rate. These results inform observed patterns of congealment found on driving X chromosomes and have implications for patterns of natural variation and the evolution of recombination rates on the X chromosome.
A meiotic drive element in the maize pathogen Fusarium verticillioides is located within a 102 kb region of chromosome V
4098Pyle, JP, T.; Merrill, B.; Nsokoshi, C.; McCall, M.; Proctor, R. H.; Brown, D. W.; Hammond, T. M., G3-Genes Genomes Genetics, 6:2543-2552. 2016-01-16 00:00:00.
Fusarium verticillioides is an agriculturally important fungus because of its association with maize and its propensity to contaminate grain with toxic compounds. Some isolates of the fungus harbor a meiotic drive element known as Spore killer (Sk(K)) that causes nearly all surviving meiotic progeny from an Sk(K) x Spore killer-susceptible (Sk(S)) cross to inherit the Sk(K) allele. Sk(K) has been mapped to chromosome V but the genetic element responsible for meiotic drive has yet to be identified. In this study, we used cleaved amplified polymorphic sequence markers to genotype individual progeny from an Sk(K) x Sk(S) mapping population. We also sequenced the genomes of three progeny from the mapping population to determine their single nucleotide polymorphisms. These techniques allowed us to refine the location of Sk(K) to a contiguous 102 kb interval of chromosome V, herein referred to as the Sk region. Relative to Sk(S) genotypes, Sk(K) genotypes have one extra gene within this region for a total of 42 genes. The additional gene in Sk(K) genotypes, herein named SKC1 for Spore Killer Candidate 1, is the most highly expressed gene from the Sk region during early stages of sexual development. The Sk region also has three hyper-variable regions, the longest of which includes SKC1. The possibility that SKC1, or another gene from the Sk region, is an essential component of meiotic drive and spore killing is discussed.
Occasional recombination of a selfish X-chromosome may permit its persistence at high frequencies in the wild
4096Pieper, KED, K. A., Journal of Evolutionary Biology, 29:2229-2241. 2016-01-14 00:00:00.
The sex-ratio X-chromosome (SR) is a selfish chromosome that promotes its own transmission to the next generation by destroying Y-bearing sperm in the testes of carrier males. In some natural populations of the fly Drosophila neotestacea, up to 30% of the X-chromosomes are SR chromosomes. To investigate the molecular evolutionary history and consequences of SR, we sequenced SR and standard (ST) males at 11 X-linked loci that span the ST X-chromosome and at seven arbitrarily chosen autosomal loci from a sample of D. neotestacea males from throughout the species range. We found that the evolutionary relationship between ST and SR varies among individual markers, but genetic differentiation between SR and ST is chromosome-wide and likely due to large chromosomal inversions that suppress recombination. However, SR does not consist of a single multilocus haplotype: we find evidence for gene flow between ST and SR at every locus assayed. Furthermore, we do not find long-distance linkage disequilibrium within SR chromosomes, suggesting that recombination occurs in females homozygous for SR. Finally, polymorphism on SR is reduced compared to that on ST, and loci displaying signatures of selection on ST do not show similar patterns on SR. Thus, even if selection is less effective on SR, our results suggest that gene flow with ST and recombination between SR chromosomes may prevent the accumulation of deleterious mutations and allow its long-term persistence at relatively high frequencies.
Gene silencing and gene drive in dengue vector control
4095Paulraj, MGI, S.; Reegan, A. D., Indian Journal of Natural Products and Resources, 7:193-200. 2016-01-13 00:00:00.
Vector-borne diseases are the most feared diseases throughout the world. Mosquitoes are the prime human disease vectors as they are responsible for nearly one million human deaths every year. So they are declared as the most dangerous insects to mankind. Aedes aegypti and Ae. albopictus are the most significant mosquito species, because of their role in transmitting dengue virus. These blood feeding ectoparasites of man and other vertebrates have developed excellent adaptations to survive and multiply in and around human habitations. Chemical-based mosquito control method does not give good results due to rapid development of pesticide resistance in mosquitoes. The past four decades have witnessed the development of several alternate mosquito control methods. Genetic control technologies have been recently developed as efficient and ecofriendly methods. Inundate release of genetically modified mosquitoes with lethal or pathogen-resistant genes for population reduction is a recent technology in mosquito control programme. Recent developments in molecular and genome editing technologies have made it easy to produce thousands of transgenic mosquitoes for field release. The present review highlights various scientific reports and research findings on gene silencing and gene drive techniques in dengue mosquito control.
Comparative analysis of regions with distorted segregation in three diploid populations of potato
4094Manrique-Carpintero, NCC, J. J.; Veilleux, R. E.; Buell, C. R.; Douches, D. S., G3-Genes Genomes Genetics, 6:2617-2628. 2016-01-12 00:00:00.
Genes associated with gametic and zygotic selection could underlie segregation distortion, observed as alterations of expected Mendelian genotypic frequencies in mapping populations. We studied highly dense genetic maps based on single nucleotide polymorphisms to elucidate the genetic nature of distorted segregation in potato. Three intra-and interspecific diploid segregating populations were used. DRH and D84 are crosses between the sequenced doubled monoploid DM 1-3 516 R44 Solanum tuberosum Group Phureja and either RH89-039-16 S. tuberosum or 84SD22, a S. tuberosum x S. chacoense hybrid. MSX902 is an interspecific cross between 84SD22 and Ber83 S. berthaultii x 2 x species mosaic. At the 0.05 significance level, 21%, 57%, and 51% of the total markers mapped in DRH, D84, and MSX902 exhibited distorted segregation, respectively. Segregation distortion regions for DRH were located on chromosomes 9 and 12; for D84 on chromosomes 2, 3, 4, 6, 7, and 8; and on chromosomes 1, 2, 7, 9, and 12 for MSX902. In general, each population had unique segregation distortion regions and directions of distortion. Interspecific crosses showed greater levels of distorted segregation and lower recombination rates as determined from the male parents. The different genomic regions where the segregation distortion regions occurred in the three populations likely reflect unique genetic combinations producing distorted segregation.
Stability of underdominant genetic polymorphisms in population networks
4091Laruson, AJR, F. A., Journal of Theoretical Biology, 390:156-163. 2016-01-09 00:00:00.
Heterozygote disadvantage is potentially a potent driver of population genetic divergence. Also referred to as underdominance, this phenomena describes a situation where a genetic heterozygote has a lower overall fitness than either homozygote. Attention so far has mostly been given to underdominance within a single population and the maintenance of genetic differences between two populations exchanging migrants. Here we explore the dynamics of an underdominant system in a network of multiple discrete, yet interconnected, populations. Stability of genetic differences in response to increases in migration in various topological networks is assessed. The network topology can have a dominant and occasionally non-intuitive influence on the genetic stability of the system. (C) 2015 Elsevier Ltd. All rights reserved.
Pollen killer gene S35 function requires interaction with an activator that maps close to S24, another pollen killer gene in rice
4090Kubo, TY, A.; Kurata, N., G3-Genes Genomes Genetics, 6:1459-1468. 2016-01-08 00:00:00.
Pollen killer genes disable noncarrier pollens, and are responsible for male sterility and segregation distortion in hybrid populations of distantly related plant species. The genetic networks and the molecular mechanisms underlying the pollen killer system remain largely unknown. Two pollen killer genes, S24 and S35, have been found in an intersubspecific cross of Oryza sativa ssp. indica and japonica. The effect of S24 is counteracted by an unlinked locus EFS. Additionally, S35 has been proposed to interact with S24 to induce pollen sterility. These genetic interactions are suggestive of a single S24-centric genetic pathway (EFS-S24-S35) for the pollen killer system. To examine this hypothetical genetic pathway, the S35 and the S24 regions were further characterized and genetically dissected in this study. Our results indicated that S35 causes pollen sterility independently of both the EFS and S24 genes, but is dependent on a novel gene close to the S24 locus, named incentive for killing pollen (INK). We confirmed the phenotypic effect of the INK gene separately from the S24 gene, and identified the INK locus within an interval of less than 0.6 Mb on rice chromosome 5. This study characterized the genetic effect of the two independent genetic pathways of INK-S35 and EFS-S24 in indica-japonica hybrid progeny. Our results provide clear evidence that hybrid male sterility in rice is caused by several pollen killer networks with multiple factors positively and negatively regulating pollen killer genes.
Mechanisms of sex determination and transmission ratio distortion in Aedes aegypti
4089Hoang, KPT, T. M.; Ho, T. X.; Le, V. S., Parasites & Vectors, 9:49. 2016-01-07 00:00:00.
: More effective mosquito control strategies are urgently required due to the increasing prevalence of insecticide resistance. The sterile insect technique (SIT) and the release of insects carrying a dominant lethal allele (RIDL) are two proposed methods for environmentally-friendly, species-targeted population control. These methods may be more suitable for developing countries if producers reduce the cost of rearing insects. The cost of control programs could be reduced by producing all-male mosquito populations to circumvent the isolation of females before release without reducing male mating competitiveness caused by transgenes. Results: An RNAi construct targeting the RNA recognition motif of the Aedes aegypti transformer-2 (tra-2) gene does not trigger female-to-male sex conversion as commonly observed among dipterous insects. Instead, homozygous insects show greater mortality among m-chromosome-bearing sperm and mm zygotes, yielding up to 100 % males in the subsequent generations. The performance of transgenic males was not significantly different to wild-type males in narrow-cage competitive mating experiments. Conclusion: Our data provide preliminary evidence that the knockdown of Ae. aegypti tra-2 gene expression causes segregation distortion acting at the level of gametic function, which is reinforced by sex-specific zygotic lethality. This finding could promote the development of new synthetic sex distorter systems for the production of genetic sexing mosquito strains.
Rapid evolution of a Y-chromosome heterochromatin protein underlies sex chromosome meiotic drive
4088Helleu, QG, P. R.; Dubruille, R.; Ogereau, D.; Prud'homme, B.; Loppin, B.; Montchamp-Moreau, C., Proceedings of the National Academy of Sciences of the United States of America, 113:4110-4115. 2016-01-06 00:00:00.
Sex chromosome meiotic drive, the non-Mendelian transmission of sex chromosomes, is the expression of an intragenomic conflict that can have extreme evolutionary consequences. However, the molecular bases of such conflicts remain poorly understood. Here, we show that a young and rapidly evolving X-linked heterochromatin protein 1 (HP1) gene, HP1D2, plays a key role in the classical Paris sex-ratio (SR) meiotic drive occurring in Drosophila simulans. Driver HP1D2 alleles prevent the segregation of the Y chromatids during meiosis II, causing female-biased sex ratio in progeny. HP1D2 accumulates on the heterochromatic Y chromosome in male germ cells, strongly suggesting that it controls the segregation of sister chromatids through heterochromatin modification. We show that Paris SR drive is a consequence of dysfunctional HP1D2 alleles that fail to prepare the Y chromosome for meiosis, thus providing evidence that the rapid evolution of genes controlling the heterochromatin structure can be a significant source of intragenomic conflicts.
A CRISPR-Cas9 gene drive system-targeting female reproduction in the malaria mosquito vector Anopheles gambiae
4087Hammond, AG, R.; Kyrou, K.; Simoni, A.; Siniscalchi, C.; Katsanos, D.; Gribble, M.; Baker, D.; Marois, E.; Russell, S.; Burt, A.; Windbichler, N.; Crisanti, A.; Nolan, T., Nature Biotechnology, 34:78-83. 2016-01-05 00:00:00.
Gene drive systems that enable super-Mendelian inheritance of a transgene have the potential to modify insect populations over a timeframe of a few years. We describe CRISPR-Cas9 endonuclease constructs that function as gene drive systems in Anopheles gambiae, the main vector for malaria. We identified three genes (AGAP005958, AGAP011377 and AGAP007280) that confer a recessive female-sterility phenotype upon disruption, and inserted into each locus CRISPR-Cas9 gene drive constructs designed to target and edit each gene. For each targeted locus we observed a strong gene drive at the molecular level, with transmission rates to progeny of 91.4 to 99.6%. Population modeling and cage experiments indicate that a CRISPR-Cas9 construct targeting one of these loci, AGAP007280, meets the minimum requirement for a gene drive targeting female reproduction in an insect population. These findings could expedite the development of gene drives to suppress mosquito populations to levels that do not support malaria transmission.
Cas9-triggered chain ablation of cas9 as a gene drive brake
4106Wu, BL, L. Q.; Gao, X. J. J., Nature Biotechnology, 34:137-138. 2016-01-04 00:00:00.
We designed and synthesized a transgene system that we named Cas9-triggered chain ablation (CATCHA). The CATCHA transgene encodes a guide RNA (gRNA) that is expressed ubiquitously from a U6:2 promoter. The gRNA targets a site within the DNA sequence of cas9. The guide RNA is flanked by homology arms (of 1,042 bp and 1,003 bp) that match the cas9 sequences next to the gRNA-specified cleavage site (Fig. 1a). In the presence of both CATCHA and cas9, Cas9 proteins will be guided to cleave the cas9 genomic locus from which Cas9 proteins are expressed. Upon repair of the cleaved cas9 by homology-directed repair (HDR), the cas9 locus will be converted to CATCHA. Such conversion in heterozygous offspring favors amplification of CATCHA in the cas9- carrying population
The dawn of active genetics
4085Gantz, VMB, E., Bioessays, 38:50-63. 2016-01-03 00:00:00.
On December 18, 2014, a yellow female fly quietly emerged from her pupal case. What made her unique was that she had only one parent carrying a mutant allele of this classic recessive locus. Then, one generation later, after mating with a wild-type male, all her offspring displayed the same recessive yellow phenotype. Further analysis of other such yellow females revealed that the construct causing the mutation was converting the opposing chromosome with 95% efficiency. These simple results, seen also in mosquitoes and yeast, open the door to a new era of genetics wherein the laws of traditional Mendelian inheritance can be bypassed for a broad variety of purposes. Here, we consider the implications of this fundamentally new form of active genetics, its applications for gene drives, reversal and amplification strategies, its potential for contributing to cell and gene therapy strategies, and ethical/biosafety considerations associated with such active genetic elements.
Meiotic drive changes sperm precedence patterns in house mice: potential for male alternative mating tactics?
4104Sutter, AL, A. K., BMC Evolutionary Biology, 16:15. 2016-01-02 00:00:00.
Background: With female multiple mating (polyandry), male-male competition extends to after copulation (sperm competition). Males respond to this selective pressure through physiological, morphological and behavioural adaptations. Sperm competitiveness is commonly decreased in heterozygote carriers of male meiotic drivers, selfish genetic elements that manipulate the production of gametes in males. This might give carriers an evolutionary incentive to reduce the risk of sperm competition. Here, we explore this possibility in house mice. Natural populations frequently harbour a well-characterised male driver (t haplotype), which is transmitted to 90 % of heterozygous (+/t) males' offspring. Previous research demonstrated strong detrimental effects on sperm competitiveness, and suggested that +/t males are particularly disadvantaged against wild type males when first-to-mate. Low paternity success in the first-to-mate role is expected to favour male adaptations that decrease the risk of sperm competition by preventing female remating. Genotype-specific paternity patterns (sperm precedence) could lead to genetically determined alternative reproductive tactics that can spread through gene level selection. Here, we seek confirmation that +/t males are generally disadvantaged when first-to-mate and address whether males of different genotypes differ in reproductive tactics (copulatory and morphological) to maximise individual or driver fitness. Finally, we attempt to explain the mechanistic basis for alternative sperm precedence patterns in this species. Results: We confirmed that +/t males are weak sperm competitors when first to mate. When two +/t males competed, the second-to-mate was more successful, which contrasts with first male sperm precedence when wild type males competed. However, we found no differences between male genotypes in reproductive behaviour or morphology that were consistent with alternative reproductive tactics. Sperm of +/+ and +/t males differed with respect to in vitro sperm features. Premature hypermotility in +/t males' sperm can potentially explain why +/t males are very weak sperm competitors when first-to-mate. Conclusions: Our results demonstrate that meiotic drivers can have strong effects on sperm precedence patterns, and may provide a heritable basis for alternative reproductive tactics motivated by reduced sperm competitiveness. We discuss how experimental and evolutionary constraints may help explain why male genotypes did not show the predicted differences.
R2d2 drives selfish sweeps in the house mouse
4084Didion, JPM, A. P.; Yadgary, L.; Bell, T. A.; McMullan, R. C.; de Solorzano, L. O.; Britton-Davidian, J.; Bult, C. J.; Campbell, K. J.; Castiglia, R.; Ching, Y. H.; Chunco, A. J.; Crowley, J. J.; Chesler, E. J.; Forster, D. W.; French, J. E.; Gabriel, S. I.; Gatti, D. M.; Garland, T.; Giagia-Athanasopoulou, E. B.; Gimenez, M. D.; Grize, S. A.; Gunduz, I.; Holmes, A.; Hauffe, H. C.; Herman, J. S.; Holt, J. M.; Hua, K. J.; Jolley, W. J.; Lindholm, A. K.; Lopez-Fuster, M. J.; Mitsainas, G.; Mathias, M. D.; McMillan, L.; Ramalhinho, M. D. M.; Rehermann, B.; Rosshart, S. P.; Searle, J. B.; Shiao, M. S.; Solano, E.; Svenson, K. L.; Thomas-Laemont, P.; Threadgill, D. W.; Ventura, J.; Weinstock, G. M.; Pomp, D.; Churchill, G. A.; de Villena, F. P. M., Molecular Biology and Evolution, 33:1381-1395. 2016-01-02 00:00:00.
A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether "selfish" genes are capable of fixation-thereby leaving signatures identical to classical selective sweeps-despite being neutral or deleterious to organismal fitness. We previously described R2d2, a large copy-number variant that causes nonrandom segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number (R2d2(HC)) in natural populations. We replicate this finding inmultiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2(HC) rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2(HC) is also associated with significantly reduced litter sizes in heterozygous mothers, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution.
CRISPR-Cas9: Safeguarding Gene Drives
5501Harvard University, 2015-11-16 18:44:48.
In this animation, learn how effective safeguarding mechanisms developed at the Wyss Institute and Harvard Medical School can be applied to ensure gene drive research is done responsibly in the laboratory. These safeguards enable responsible scientific investigation into how gene drives could one day be leveraged for the greater good of human health, agriculture, and the environment.
National Academies of Science | Workshop: Science, Ethics, and Governance Considerations for Gene Drive Research – 2015
5544National Academy of Sciences Engineering Medicine, National Academy of Sciences, 2015-10-28 21:53:14.
Gene drive turns mosquitoes into malaria fighters
4123Pennisi, E, Science, 350:1014-1014. 2015-01-21 00:00:00.
The war against malaria has a new ally: a controversial technology for spreading genes throughout a population of animals. In the laboratory, researchers have harnessed a so-called gene drive to efficiently endow mosquitoes with genes that make them immune to the malaria parasite—and unable to spread it. On its own, gene drive won't get rid of malaria, but if successfully applied in the wild the method could help wipe out the disease, at least in some corners of the world. The approach “can bring us to zero [cases],” says Nora Besansky, a geneticist at the University of Notre Dame in South Bend, Indiana, who specializes in malaria-carrying mosquitoes
A prezygotic transmission distorter acting equally in female and male zebra finches Taeniopygia guttata
4120Knief, US, H.; Ellegren, H.; Kempenaers, B.; Forstmeier, W., Molecular Ecology, 24:3846-3859. 2015-01-18 00:00:00.
The two parental alleles at a specific locus are usually inherited with equal probability to the offspring. However, at least three processes can lead to an apparent departure from fair segregation: early viability selection, biased gene conversion and various kinds of segregation distortion. Here, we conduct a genome-wide scan for transmission distortion in a captive population of zebra finches (Taeniopygia guttata) using 1302 single-nucleotide polymorphisms (SNPs) followed by confirmatory analyses on independent samples from the same population. In the initial genome-wide scan, we found significant distortion at three linked loci on chromosome Tgu2 and we were able to replicate this finding in each of two follow-up data sets [overall transmission ratio=0.567 (95% CI=0.536-0.600), based on 1101 informative meioses]. Although the driving allele was preferentially transmitted by both heterozygous females [ratio=0.560 (95% CI=0.519-0.603)] and heterozygous males [ratio=0.575 (95% CI=0.531-0.623)], we could rule out postzygotic viability selection and biased gene conversion as possible mechanisms. Early postzygotic viability selection is unlikely, because it would result in eggs with no visible embryo and hence no opportunity for genotyping, and we confirmed that both females and males heterozygous for the driving allele did not produce a larger proportion of such eggs than homozygous birds. Biased gene conversion is expected to be rather localized, while we could trace transmission distortion in haplotypes of several megabases in a recombination desert. Thus, we here report the rare case of a prezygotically active transmission distorter operating equally effectively in female and male meioses.
Sex chromosome drive
4117Helleu, QG, P. R.; Montchamp-Moreau, C., Cold Spring Harbor Perspectives in Biology, 7:a017616. 2015-01-15 00:00:00.
Sex chromosome drivers are selfish elements that subvert Mendel's first law of segregation and therefore are over represented among the products of meiosis. The sex-biased progeny produced then fuels an extended genetic conflict between the driver and the rest of the genome. Many examples of sex chromosome drive are known, but the occurrence of this phenomenon is probably largely underestimated because of the difficulty to detect it. Remarkably, nearly all sex chromosome drivers are found in two clades, Rodentia and Diptera. Although very little is known about the molecular and cellular mechanisms of drive, epigenetic processes such as chromatin regulation could be involved in many instances. Yet, its evolutionary consequences are far-reaching, from the evolution of mating systems and sex determination to the emergence of new species.
Mating type and spore killing characterization of Fusarium verticillioides strains
4116Guo, LB, A. Z.; Geiser, D. M.; Jimenez-Gasco, M. D.; Kuldau, G. A., Mycological Progress, 14:1045. 2015-01-14 00:00:00.
Fusarium verticillioides is a heterothallic ascomycete causing maize ear rot, and produces fumonisin mycotoxins harmful to livestock and human health. A meiotic drive phenomenon called spore killing has been reported in several filamentous fungi including F. verticillioides. F. verticillioides reference genome strain M-3125 (FGSC 7600) is spore killer sensitive (SKS), and genetic crosses of M-3125 with a strain carrying SKK (the killer element) result in only four viable ascospores per ascus instead of the normal eight ascospores. We sought to identify a strain of F. verticillioides that is SKS and MAT1-2 for use in genetic analysis with M-3125. To accomplish this, we screened 50 F. verticillioides strains from the Fusarium Research Center at The Pennsylvania State University, USA for spore killing. To characterize the mating types of these strains, portions of the MAT locus idiomorphs were amplified using polymerase chain reaction, and genetic crosses were performed. The PCR amplification results show that 18 of the 50 strains are MAT1-2 and 32 are MAT1-1. Genetic crosses between M-3125 and 11 of the 18 MAT1-2 strains produced normal perithecia. Crosses between two (M-8024 and M-7815) of the 11 strains and M-3125 produced perithecia with eight ascospores per ascus, and nine others had only four ascospores per ascus, suggesting that M-8024 and M-7815 are SKS and the other nine are SKK. This study expands our knowledge of mating type and spore killing in F. verticillioides and identifies two SKS, MAT1-2 strains for use in genetic crosses with genome reference strain M-3125.
Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi
4115Gantz, VMJ, N.; Tatarenkova, O.; Fazekas, A.; Macias, V. M.; Bier, E.; James, A. A., Proceedings of the National Academy of Sciences of the United States of America, 112:e6736-e6743. 2015-01-13 00:00:00.
Genetic engineering technologies can be used both to create transgenic mosquitoes carrying antipathogen effector genes targeting human malaria parasites and to generate gene-drive systems capable of introgressing the genes throughout wild vector populations. We developed a highly effective autonomous Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9 (Cas9)-mediated gene-drive system in the Asian malaria vector Anopheles stephensi, adapted from the mutagenic chain reaction (MCR). This specific system results in progeny of males and females derived from transgenic males exhibiting a high frequency of germ-line gene conversion consistent with homology-directed repair (HDR). This system copies an similar to 17-kb construct from its site of insertion to its homologous chromosome in a faithful, site-specific manner. Dual anti-Plasmodium falciparum effector genes, a marker gene, and the autonomous gene-drive components are introgressed into similar to 99.5% of the progeny following outcrosses of transgenic lines to wild-type mosquitoes. The effector genes remain transcriptionally inducible upon blood feeding. In contrast to the efficient conversion in individuals expressing Cas9 only in the germ line, males and females derived from transgenic females, which are expected to have drive component molecules in the egg, produce progeny with a high frequency of mutations in the targeted genome sequence, resulting in near-Mendelian inheritance ratios of the transgene. Such mutant alleles result presumably from non-homologous end-joining (NHEJ) events before the segregation of somatic and germ-line lineages early in development. These data support the design of this system to be active strictly within the germ line. Strains based on this technology could sustain control and elimination as part of the malaria eradication agenda.
The mutagenic chain reaction: A method for converting heterozygous to homozygous mutations
4114V. M. Gantz and E. Bier, Science, 348:442. 2015-01-12 00:00:00.
Loss-of-function mutations may only produce a mutant phenotype when both copies of the gene are mutated. Gantz and Bier developed a method they call mutagenic chain reaction (MCR) that autocatalytically produces homozygous mutations. MCR uses the initial mutated allele to cause a mutation in the allele on the opposing chromosome and thus the homozygosity of the trait. MCR technology could have broad applications in diverse organisms.Science, this issue p. 442 An organism with a single recessive loss-of-function allele will typically have a wild-type phenotype, whereas individuals homozygous for two copies of the allele will display a mutant phenotype. We have developed a method called the mutagenic chain reaction (MCR), which is based on the CRISPR/Cas9 genome-editing system for generating autocatalytic mutations, to produce homozygous loss-of-function mutations. In Drosophila, we found that MCR mutations efficiently spread from their chromosome of origin to the homologous chromosome, thereby converting heterozygous mutations to homozygosity in the vast majority of somatic and germline cells. MCR technology should have broad applications in diverse organisms.
R2d2 and hyperdrive mechanisms (in Mouse meiosis)
4132Zanders, SEM, H. S., PLOS Genetics, 11:1-4. 2015-01-10 00:00:00.
Mendelian transmission is established during meiosis, the cell division that generates haploidgametes (e.g., sperm and eggs) from diploid germ cells. Meiosis does not, however, have to befair. Selfish genetic elements, or meiotic drivers, have evolved to cheat this process in order tobe packaged into functional gametes more often than the expected 50% probability. By biasingallele transmission in their favor, meiotic drive alleles can short-circuit natural selection, caus-ing their spread even if they are harmful to organismal fitness. Indeed, meiotic drive alleles arethought to be directly or indirectly associated with infertility in diverse eukaryotes, from fungito flies to humans [2].
Origin, evolution, and population genetics of the selfish Segregation Distorter gene duplication in European and African populations of Drosophila melanogaster
4108Brand, CLL, A. M.; Presgraves, D. C., Evolution, 69:1271-1283. 2015-01-06 00:00:00.
Meiotic drive elements are a special class of evolutionarily selfish genes that subvert Mendelian segregation to gain preferential transmission at the expense of homologous loci. Many drive elements appear to be maintained in populations as stable polymorphisms, their equilibrium frequencies determined by the balance between drive (increasing frequency) and selection (decreasing frequency). Here we show that a classic, seemingly balanced, drive system is instead characterized by frequent evolutionary turnover giving rise to dynamic, rather than stable, equilibrium frequencies. The autosomal Segregation Distorter (SD) system of the fruit fly Drosophila melanogaster is a selfish coadapted meiotic drive gene complex in which the major driver corresponds to a partial duplication of the gene Ran-GTPase activating protein (RanGAP). SD chromosomes segregate at similar, low frequencies of 1-5% in natural populations worldwide, consistent with a balanced polymorphism. Surprisingly, our population genetic analyses reveal evidence for parallel, independent selective sweeps of different SD chromosomes in populations on different continents. These findings suggest that, rather than persisting at a single stable equilibrium, SD chromosomes turn over frequently within populations.
Sex-ratio meiotic drive and Y-linked resistance in Drosophila affinis
4128Unckless, RLL, A. M.; Clark, A. G., Genetics, 199:831-840. 2015-01-06 00:00:00.
Genetic elements that cheat Mendelian segregation by biasing transmission in their favor gain a significant fitness benefit. Several examples of sex-ratio meiotic drive, where one sex chromosome biases its own transmission at the cost of the opposite sex chromosome, exist in animals and plants. While the distorting sex chromosome gains a significant advantage by biasing sex ratio, the autosomes, and especially the opposite sex chromosome, experience strong selection to resist this transmission bias. In most wellstudied sex-ratio meiotic drive systems, autosomal and/or Y-linked resistance has been identified. We specifically surveyed for Y-linked resistance to sex-ratio meiotic drive in Drosophila affinis by scoring the sex ratio of offspring sired by males with a driving X and one of several Y chromosomes. Two distinct types of resistance were identified: a restoration to 50/50 sex ratios and a complete reversal of sex ratio to all sons. We confirmed that fathers siring all sons lacked a Y chromosome, consistent with previously published work. Considerable variation in Y-chromosome morphology exists in D. affinis, but we showed that morphology does not appear to be associated with resistance to sex-ratio meiotic drive. We then used two X chromosomes (driving and standard) and three Y chromosomes (susceptible, resistant, and lacking) to examine fertility effects of all possible combinations. We find that both the driving X and resistant and lacking Y have significant fertility defects manifested in microscopic examination of testes and a 48-hr sperm depletion assay. Maintenance of variation in this sex-ratio meiotic drive system, including both the X-linked distorter and the Y-resistant effects, appear to be mediated by a complex interaction between fertility fitness and transmission dynamics.
Detrimental effects of an autosomal selfish genetic element on sperm competitiveness in house mice
4126Sutter, AL, A. K., Proceedings of the Royal Society B-Biological Sciences, 282:1-8. 2015-01-04 00:00:00.
Female multiple mating (polyandry) is widespread across many animal taxa and indirect genetic benefits are a major evolutionary force favouring polyandry. An incentive for polyandry arises when multiple mating leads to sperm competition that disadvantages sperm from genetically inferior mates. A reduction in genetic quality is associated with costly selfish genetic elements (SGEs), and studies in invertebrates have shown that males bearing sex ratio distorting SGEs are worse sperm competitors than wild-type males. We used a vertebrate model species to test whether females can avoid an autosomal SGE, the t haplotype, through polyandry. The t haplotype in house mice exhibits strong drive in t heterozygous males by affecting spermatogenesis and is associated with homozygous in utero lethality. We used controlled matings to test the effect of the t haplotype on sperm competitiveness. Regardless of mating order, t heterozygous males sired only 11% of zygotes when competing against wild-type males, suggesting a very strong effect of the t haplotype on sperm quality. We provide, to our knowledge, the first substantial evidence that polyandry ameliorates the harmful effects of an autosomal SGE arising through genetic incompatibility. We discuss potential mechanisms in our study species and the broader implications for the benefits of polyandry.
Presence of segregation distortion in sheep
4125Raed, MA, Research Journal of Biotechnology, 10:87-98. 2015-01-03 00:00:00.
The main objective of this project was the investigation of presence of segregation distortion (SD) and description of other relevant parameters of multilocus genetics in Australian Merino sheep. The SD cases investigated three flocks of 98, 79 and 92 offspring and their DNA-based identified dams and sires. DNA samples were genotyped for 28 microsatellite (MS) markers located on different chromosomes. SD was estimated by studying the paternal segregation of alleles in offspring using a bootstrap procedure. The results showed a high proportion of studied loci which demonstrated significant SD. The results provided additional data which add to the common knowledge that sheep population structure and dynamics are affected by evolutionary forces such as gene flow, selection and many other random factors. These forces were noticed in the three populations. Finally, the results obtained from many loci in this project provided evidence of Mendelian violation. Moreover, they indicated that genes affecting male-related SD are spread over the genome.
Systematic evaluation of Drosophila CRISPR tools reveals safe and robust alternatives to autonomous gene drives in basic research
4124Port, FM, N.; Bullock, S. L., G3-Genes Genomes Genetics, 5:1493-1502. 2015-01-02 00:00:00.
The Clustered Regularly Interspaced Short Palindromic Repeat/CRISPR associated (CRISPR/Cas) technology allows rapid, site-specific genome modification in a wide variety of organisms. Proof-of-principle studies in Drosophila melanogaster have used various CRISPR/Cas tools and experimental designs, leading to significant uncertainty in the community about how to put this technology into practice. Moreover, it is unclear what proportion of genomic target sites can be modified with high efficiency. Here, we address these issues by systematically evaluating available CRISPR/Cas reagents and methods in Drosophila. Our findings allow evidence-based choices of Cas9 sources and strategies for generating knock-in alleles. We perform gene editing at a large number of target sites using a highly active Cas9 line and a collection of transgenic gRNA strains. The vast majority of target sites can be mutated with remarkable efficiency using these tools. We contrast our method to recently developed autonomous gene drive technology for somatic and germline genome engineering and conclude that optimized CRISPR with independent transgenes is as efficient, more versatile, and does not represent a biosafety risk.
Genetic Control of Mosquitoes.
5597Alphey, L., Annual Review of Entomology, 59:205-224. 2014-12-17 15:50:24.
Genetics can potentially provide new, species-specific, environmentally friendly methods for mosquito control. Genetic control strategies aim either to suppress target populations or to introduce a harm-reducing novel trait. Different approaches differ considerably in their properties, especially between self-limiting strategies, where the modification has limited persistence, and self-sustaining strategies, which are intended to persist indefinitely in the target population and may invade other populations. Several methods with different molecular biology are under development and the first field trials have been completed successfully.
GM mosquitoes a ‘quantum leap’ towards tackling malaria
6940A. Vaughan, Guardian, 2014-06-10 15:54:00.
New technique injects mosquitoes with a gene that results in mostly male offspring, eventually leading to a population crash
A critical component of meiotic drive in Neurospora is located near a chromosome rearrangement
4143Harvey, AMR, D. G.; Groskreutz, K. M.; Kuntz, D. R.; Sharp, K. J.; Shiu, P. K. T.; Hammond, T. M., Genetics, 197:1165-1179. 2014-01-21 00:00:00.
Neurospora fungi harbor a group of meiotic drive elements known as Spore killers (Sk). Spore killer-2 (Sk-2) and Spore killer-3 (Sk-3) are two Sk elements that map to a region of suppressed recombination. Although this recombination block is limited to crosses between Sk and Sk-sensitive (Sk(S)) strains, its existence has hindered Sk characterization. Here we report the circumvention of this obstacle by combining a classical genetic screen with next-generation sequencing technology and three-point crossing assays. This approach has allowed us to identify a novel locus called rfk-1, mutation of which disrupts spore killing by Sk-2. We have mapped rfk-1 to a 45-kb region near the right border of the Sk-2 element, a location that also harbors an 11-kb insertion (Sk-2(INS1)) and part of a >220-kb inversion (Sk-2(INV1)). These are the first two chromosome rearrangements to be formally identified in a Neurospora Sk element, providing evidence that they are at least partially responsible for Sk-based recombination suppression. Additionally, the proximity of these chromosome rearrangements to rfk-1 (a critical component of the spore-killing mechanism) suggests that they have played a key role in the evolution of meiotic drive in Neurospora.
Genes that bias Mendelian segregation
4142Grognet, PL, H.; Malagnac, F.; Silar, P., PLOS Genetics, 10:e1004387. 2014-01-20 00:00:00.
Mendel laws of inheritance can be cheated by Meiotic Drive Elements (MDs), complex nuclear genetic loci found in various eukaryotic genomes and distorting segregation in their favor. Here, we identify and characterize in the model fungus Podospora anserina Spok1 and Spok2, two MDs known as Spore Killers. We show that they are related genes with both spore-killing distorter and spore-protecting responder activities carried out by the same allele. These alleles act as autonomous elements, exert their effects independently of their location in the genome and can act as MDs in other fungi. Additionally, Spok1 acts as a resistance factor to Spok2 killing. Genetical data and cytological analysis of Spok1 and Spok2 localization during the killing process suggest a complex mode of action for Spok proteins. Spok1 and Spok2 belong to a multigene family prevalent in the genomes of many ascomycetes. As they have no obvious cellular role, Spok1 and Spok2 Spore Killer genes represent a novel kind of selfish genetic elements prevalent in fungal genome that proliferate through meiotic distortion.
Genome rearrangements and pervasive meiotic drive cause hybrid infertility in fission yeast
4162Zanders, SEE, M. T.; Yu, J. S.; Kang, J. W.; Fowler, K. R.; Smith, G. R.; Malik, H. S., eLife, 3:e02630. 2014-01-20 00:00:00.
Hybrid sterility is one of the earliest postzygotic isolating mechanisms to evolve between two recently diverged species. Here we identify causes underlying hybrid infertility of two recently diverged fission yeast species Schizosaccharomyces pombe and S. kambucha, which mate to form viable hybrid diploids that efficiently complete meiosis, but generate few viable gametes. We find that chromosomal rearrangements and related recombination defects are major but not sole causes of hybrid infertility. At least three distinct meiotic drive alleles, one on each S. kambucha chromosome, independently contribute to hybrid infertility by causing nonrandom spore death. Two of these driving loci are linked by a chromosomal translocation and thus constitute a novel type of paired meiotic drive complex. Our study reveals how quickly multiple barriers to fertility can arise. In addition, it provides further support for models in which genetic conflicts, such as those caused by meiotic drive alleles, can drive speciation.
Dynamics of a combined medea-underdominant population transformation system
4141Gokhale, CSR, R. G.; Reed, F. A., BMC Evolutionary Biology, 14:98. 2014-01-19 00:00:00.
: Transgenic constructs intended to be stably established at high frequencies in wild populations have been demonstrated to "drive" from low frequencies in experimental insect populations. Linking such population transformation constructs to genes which render them unable to transmit pathogens could eventually be used to stop the spread of vector-borne diseases like malaria and dengue. Results: Generally, population transformation constructs with only a single transgenic drive mechanism have been envisioned. Using a theoretical modelling approach we describe the predicted properties of a construct combining autosomal Medea and underdominant population transformation systems. We show that when combined they can exhibit synergistic properties which in broad circumstances surpass those of the single systems. Conclusion: With combined systems, intentional population transformation and its reversal can be achieved readily. Combined constructs also enhance the capacity to geographically restrict transgenic constructs to targeted populations. It is anticipated that these properties are likely to be of particular value in attracting regulatory approval and public acceptance of this novel technology.
Segregation distortion affected by transgenes in early generations of rice crop-weed hybrid progeny: Implications for assessing potential evolutionary impacts from transgene flow into wild relatives
4161Yang, CW, Z.; Yang, X.; Lu, B. R., Journal of Systematics and Evolution, 52:466-476. 2014-01-19 00:00:00.
The significant role of segregation distortion as a driving force of evolution has increasingly gained recognition worldwide. Segregation distortion of parental alleles is commonly reported in hybrid progeny between crops and wild relative species, which possibly influences the evolution potential of the hybrid progeny. Whether transgene introgression into wild and weedy populations through repeated hybridization causes changes of segregation distortion of parental alleles in hybrid progeny is an important question to be addressed to understand the long-term evolution potential of the populations that have received transgenes. To study the influence of a transgene on allelic segregation, we examined gene and genotype frequencies in transgenic and non-transgenic populations of F-3 and F-4 lineages derived from hybrids between transgenic insect-resistant rice (Bt/CpTI) and weedy rice, involving randomly selected 25 simple sequence repeat markers with polymorphisms between the two parents. We found that the transgenes can significantly alter the segregation distortion pattern in hybrid progeny, particularly the direction of segregation deviated to different parents. In transgenic F-3 and F-4 populations, there are approximately 64% and 77% simple sequence repeat loci, respectively, with alleles deviated significantly to the insect-resistant cultivated rice parent; whereas, in non-transgenic F-3 and F-4 populations, approximately 68% and 58% loci, respectively, deviated significantly to the weedy rice parent. Transgenes with strong selection advantages may have evolutionary impacts on hybrid progeny by changing their pattern of allelic segregation distortion after introgression from transgenic crops to wild relatives through hybridization.
A synthetic sex ratio distortion system for the control of the human malaria mosquito
4140Galizi, RD, L. A.; Menichelli, M.; Bernardini, F.; Deredec, A.; Burt, A.; Stoddard, B. L.; Windbichler, N.; Crisanti, A., Nature Communications, 5:3977. 2014-01-18 00:00:00.
It has been theorized that inducing extreme reproductive sex ratios could be a method to suppress or eliminate pest populations. Limited knowledge about the genetic makeup and mode of action of naturally occurring sex distorters and the prevalence of co-evolving suppressors has hampered their use for control. Here we generate a synthetic sex distortion system by exploiting the specificity of the homing endonuclease I-PpoI, which is able to selectively cleave ribosomal gene sequences of the malaria vector Anopheles gambiae that are located exclusively on the mosquito's X chromosome. We combine structure-based protein engineering and molecular genetics to restrict the activity of the potentially toxic endonuclease to spermatogenesis. Shredding of the paternal X chromosome prevents it from being transmitted to the next generation, resulting in fully fertile mosquito strains that produce >95% male offspring. We demonstrate that distorter male mosquitoes can efficiently suppress caged wild-type mosquito populations, providing the foundation for a new class of genetic vector control strategies.
Biased transmission of sex chromosomes in the aphid Myzus persicae is not associated with reproductive mode
4160Wilson, ACCD, R. N.; Vorburger, C., PLOS One, 9:1-12. 2014-01-18 00:00:00.
Commonly, a single aphid species exhibits a wide range of reproductive strategies including cyclical parthenogenesis and obligate parthenogenesis. Sex determination in aphids is chromosomal; females have two X chromosomes, while males have one. X chromosome elimination at male production is generally random, resulting in equal representation of both X chromosomes in sons. However, two studies have demonstrated deviations from randomness in some lineages. One hypothesis to account for such deviations is that recessive deleterious mutations accumulate during bouts of asexual reproduction and affect male viability, resulting in overrepresentation of males with the least deleterious of the two maternal X chromosomes. This hypothesis results in a testable prediction: X chromosome transmission bias will increase with time spent in the asexual phase and should therefore be most extreme in the least sexual aphid life cycle class. Here we test this prediction in Myzus persicae. We used multiple heterozygous X-linked microsatellite markers to screen 1085 males from 95 lines of known life cycle. We found significant deviations from equal representation of X chromosomes in 15 lines; however, these lines included representatives of all life cycles. Our results are inconsistent with the hypothesis that deviations from randomness are attributable to mutation accumulation.
Genetic control of invasive fish: technological options and its role in integrated pest management
4158Thresher, REH, K.; Bax, N. J.; Teem, J.; Benfey, T. J.; Gould, F., Biological Invasions, 16:1201-1216. 2014-01-16 00:00:00.
Genetic options for the control of invasive fishes were recently reviewed and synthesized at a 2010 international symposium, held in Minneapolis/St. Paul, MN, USA. The only option currently available "off-the-shelf'' is triploidy, which can be used to produce sterile males for a release program analogous to those widely and successfully used for biological control of insect pests. However, the Trojan Y and several recombinant options that heritably distort pest population sex ratios are technologically feasible, are at or are close to proof-of-concept stage and are potentially much more effective than sterile male release programs. All genetic options at this stage require prolonged stocking programs to be effective, though gene drive systems are a potential for recombinant approaches. They are also likely to differ in their current degree of social acceptability, with chromosomal approaches (triploidy and Trojan Y) likely to be the most readily acceptable to the public and least likely to require changes in legislative or policy settings to be implemented. Modelling also suggests that the efficacy of any of these genetic techniques is enhanced by, and in turn non-additively enhance, conventional methods of pest fish control.
Male eyespan size is associated with meiotic drive in wild stalk-eyed flies (Teleopsis dalmanni)
4138Cotton, AJF, M.; Cotton, S.; Pomiankowski, A., Heredity, 112:363-369. 2014-01-16 00:00:00.
This study provides the first direct evidence from wild populations of stalk-eyed flies to support the hypothesis that male eyespan is a signal of meiotic drive. Several stalk-eyed fly species are known to exhibit X-linked meiotic drive. A recent quantitative trait locus analysis in Teleopsis dalmanni found a potential link between variation in male eyespan, a sexually selected ornamental trait, and the presence of meiotic drive. This was based on laboratory populations subject to artificial selection for male eyespan. In this study, we examined the association between microsatellite markers and levels of sex ratio bias (meiotic drive) in 12 wild T. dalmanni populations. We collected two data sets: (a) brood sex ratios of wild-caught males mated to standard laboratory females and (b) variation in a range of phenotypic traits associated with reproductive success of wild-caught males and females. In each case, we typed individuals for eight X-linked microsatellite markers, including several that previously were shown to be associated with male eyespan and meiotic drive. We found that one microsatellite marker was very strongly associated with meiotic drive, whereas a second showed a weaker association. We also found that, using both independent data sets, meiotic drive was strongly associated with male eyespan, with smaller eyespan males being associated with more female-biased broods. These results suggest that mate preference for exaggerated male eyespan allows females to avoid mating with males carrying the meiotic drive gene and is thus a potential mechanism for the maintenance and evolution of female mate preference.
A selfish gene chastened: Tribolium castaneum Medea M (4) is silenced by a complementary gene
4157Thomson, MS, Genetica, 142:161-167. 2014-01-15 00:00:00.
Maternal-effect dominant embryonic arrest (Medea) of Tribolium castaneum are autosomal factors that act maternally to cause the death of any progeny that do not inherit them. This selfish behavior is thought to result from a maternally expressed poison and zygotically expressed antidote. Medea factors and the hybrid incompatibility factor, H, have a negative interaction consistent with complementary genes of the Dobzhansky-Muller model for post-zygotic isolation. This negative interaction may result from H suppression of Medea zygotic antidote, leaving zygotes incompletely protected from maternal poison. I report here a test of the hypothesis that H also suppresses the Medea maternal poison. Viable F-1 females were generated from a cross of Medea M (4) strain males to H strain females. These females, heterozygous for both M (4) and H, failed to express M (4) maternal lethal activity when crossed to their male sibs. Transmission of non-M (4) homologues from these females was confirmed using a dominant transgenic enhanced green fluorescent protein eye color marker, tightly linked in cis to M (4) . M (4) beetles, lacking H, were selected from the F-2 population. Female descendants of these clearly expressed M (4) maternal lethal activity, indicating restoration of this activity after H was segregated away. I conclude that H, or a factor tightly linked to H, suppresses Medea M (4) maternal poison.
Centromere strength provides the cell biological basis for meiotic drive and karyotype evolution in mice
4137Chmatal, LG, S. I.; Mitsainas, G. P.; Martinez-Vargas, J.; Ventura, J.; Searle, J. B.; Schultz, R. M.; Lampson, M. A., Current Biology, 24:2295-2300. 2014-01-15 00:00:00.
Mammalian karyotypes (number and structure of chromosomes) can vary dramatically over short evolutionary time frames [1-3]. There are examples of massive karyotype conversion, from mostly telocentric (centromere terminal) to mostly metacentric (centromere internal), in 102-10 s years [4, 5]. These changes typically reflect rapid fixation of Robertsonian (Rb) fusions, a common chromosomal rearrangement that joins two telocentric chromosomes at their centromeres to create one metacentric [5]. Fixation of Rb fusions can be explained by meiotic drive: biased chromosome segregation during female meiosis in violation of Mendel's first law [3, 6, 7]. However, there is no mechanistic explanation of why fusions would preferentially segregate to the egg in some populations, leading to fixation and karyotype change, while other populations preferentially eliminate the fusions and maintain a telocentric karyotype. Here we show, using both laboratory models and wild mice, that differences in centromere strength predict the direction of drive. Stronger centromeres, manifested by increased kinetochore protein levels and altered interactions with spindle microtubules, are preferentially retained in the egg. We find that fusions preferentially segregate to the polar body in laboratory mouse strains when the fusion centromeres are weaker than those of telocentrics. Conversely, fusion centromeres are stronger relative to telocentrics in natural house mouse populations that have changed karyotype by accumulating metacentric fusions. Our findings suggest that natural variation in centromere strength explains how the direction of drive can switch between populations. They also provide a cell biological basis of centromere drive and karyotype evolution.
An X-linked sex ratio distorter in Drosophila simulans that kills or incapacitates both noncarrier sperm and sons
4156Rice, WR, G3-Genes Genomes Genetics, 4:1837-1848. 2014-01-14 00:00:00.
Genomic conflict occurs when a genomic component gains a reproductive advantage at the expense of the organism as a whole. X-linked segregation distorters kill or incapacitate Y-bearing sperm, thereby gaining a transmission advantage but also reducing male fertility and generating a female-biased sex ratio. When some damaged, Y-bearing sperm survive and fertilize eggs, then the segregation distortion phenotype could be expanded by harming or killing sons in the next generation. X-linked son-killers are predicted by theory to be favored by natural selection and evolve when brothers and sisters compete for shared limiting resources and/or when brothers reduce the inclusive fitness of their sisters via sib-mating-a phenomenon called SA-zygotic drive. Here I develop and use a process-of-elimination screen to show that an unclassified X-linked sex ratio distorter (skew) in Drosophila simulans kills or incapacitates noncarrier sperm and also kills a substantial proportion of sons, i.e., it has both a segregation distortion and a SA-zygotic drive phenotype. There are three unique X-linked segregation distorters known to occur in D. simulans named Winters, Durham, and Paris. Autosomal-dominant suppressors of Winters (Nmy) and Durham (Tmy) failed to suppress skew. A Y-linked suppressor of Paris, however, did suppress skew, and a recombination test failed to detect recombinants between these two sex ratio distorters, indicating that they are tightly linked and plausibly identical or allelic. Son-killing may be an important yet unrecognized component of other X-linked segregation distorters.
Meiotic drive impacts expression and evolution of X-linked genes in stalk-eyed flies
4155Reinhardt, JAB, C. L.; Paczolt, K. A.; Johns, P. M.; Baker, R. H.; Wilkinson, G. S., PLOS Genetics, 10:e1004362. 2014-01-13 00:00:00.
Although sex chromosome meiotic drive has been observed in a variety of species for over 50 years, the genes causing drive are only known in a few cases, and none of these cases cause distorted sex-ratios in nature. In stalk-eyed flies (Teleopsis dalmanni), driving X chromosomes are commonly found at frequencies approaching 30% in the wild, but the genetic basis of drive has remained elusive due to reduced recombination between driving and non-driving X chromosomes. Here, we used RNAseq to identify transcripts that are differentially expressed between males carrying either a driving X (X-SR) or a standard X chromosome (X-ST), and found hundreds of these, the majority of which are X-linked. Drive-associated transcripts show increased levels of sequence divergence (dN/dS) compared to a control set, and are predominantly expressed either in testes or in the gonads of both sexes. Finally, we confirmed that X-SR and X-ST are highly divergent by estimating sequence differentiation between the RNAseq pools. We found that X-linked transcripts were often strongly differentiated (whereas most autosomal transcripts were not), supporting the presence of a relatively large region of recombination suppression on X-SR presumably caused by one or more inversions. We have identified a group of genes that are good candidates for further study into the causes and consequences of sex-chromosome drive, and demonstrated that meiotic drive has had a profound effect on sequence evolution and gene expression of X-linked genes in this species.
Analysis of segregation distortion and its relationship to hybrid barriers in rice
4154Reflinur, K, B.; Jang, S. M.; Chu, S. H.; Bordiya, Y.; Akter, M. B.; Lee, J.; Chin, J. H.; Koh, H. J., Rice, 7:3. 2014-01-12 00:00:00.
Segregation distortion (SD) is a frequently observed occurrence in mapping populations generated from crosses involving divergent genotypes. In the present study, ten genetic linkage maps constructed from reciprocal F-2 and BC1F1 mapping populations derived from the parents Dasanbyeo (indica) and Ilpumbyeo (japonica) were used to identify the distribution, effect, and magnitude of the genetic factors underlying the mechanisms of SD between the two subspecies. ResultsSD loci detected in the present study were affected by male function, female function, and zygotic selection. The most pronounced SD loci were mapped to chromosome 3 (transmitted through male gametes), chromosome 5 (transmitted through male gametes), and chromosome 6 (transmitted through female gametes). The level of SD in BC1F1 populations which defined by chi-square value independence multiple tests was relatively low in comparison to F-2 populations. Dasanbyeo alleles were transmitted at a higher frequency in both F-2 and BC1F1 populations, suggesting that indica alleles are strongly favored in inter-subspecific crosses in rice. SD loci in the present study corresponded to previously reported loci for reproductive barriers. In addition, new SD loci were detected on chromosomes 2 and 12. ConclusionThe identification of the distribution of SD and the effect of genetic factors causing SD in genetic mapping populations provides an opportunity to survey the whole genome for new SD loci and their relationships to reproductive barriers. This provides a basis for future research on the elucidation of the genetic mechanisms underlying SD in rice, and will be useful in molecular breeding programs.
Multiple sex chromosomes in the light of female meiotic drive in amniote vertebrates
4153Pokorna, MA, M.; Kratochvil, L., Chromosome Research, 22:35-44. 2014-01-11 00:00:00.
It is notable that the occurrence of multiple sex chromosomes differs significantly between major lineages of amniote vertebrates. In this respect, birds are especially conspicuous, as multiple sex chromosomes have not been observed in this lineage so far. On the other hand, in mammals, multiple sex chromosomes have evolved many times independently. We hypothesize that this contrast can be related to the different involvement of sex-specific sex chromosomes in female meiosis subjected to the female meiotic drive under male versus female heterogamety. Essentially, the male-specific Y chromosome is not involved in female meiosis and is therefore sheltered against the effects of the female meiotic drive affecting the X chromosome and autosomes. Conversely, the Z and W sex chromosomes are both present in female meiosis. Nonrandom segregation of these sex chromosomes as a consequence of their rearrangements connected with the emergence of multiple sex chromosomes would result in a biased sex ratio, which should be penalized by selection. Therefore, the emergence of multiple sex chromosomes should be less constrained in the lineages with male rather than female heterogamety. Our broader phylogenetic comparison across amniotes supports this prediction. We suggest that our results are consistent with the widespread occurrence of female meiotic drive in amniotes.
Meiotic drive influences the outcome of sexually antagonistic selection at a linked locus
4152Patten, MM, Journal of Evolutionary Biology, 27:2360-2370. 2014-01-10 00:00:00.
Most meiotic drivers, such as the t-haplotype in Mus and the segregation distorter (SD) in Drosophila, act in a sex-specific manner, gaining a transmission advantage through one sex although suffering only the fitness costs associated with the driver in the other. Their inheritance is thus more likely through one of the two sexes, a property they share with sexually antagonistic alleles. Previous theory has shown that pairs of linked loci segregating for sexually antagonistic alleles are more likely to remain polymorphic and that linkage disequilibrium accrues between them. I probe this similarity between drive and sexual antagonism and examine the evolution of chromosomes experiencing these selection pressures simultaneously. Reminiscent of previous theory, I find that: the opportunity for polymorphism increases for a sexually antagonistic locus that is physically linked to a driving locus; the opportunity for polymorphism at a driving locus also increases when linked to a sexually antagonistic locus; and stable linkage disequilibrium accompanies any polymorphic equilibrium. Additionally, I find that drive at a linked locus favours the fixation of sexually antagonistic alleles that benefit the sex in which drive occurs. Further, I show that under certain conditions reduced recombination between these two loci is selectively favoured. These theoretical results provide clear, testable predictions about the nature of sexually antagonistic variation on driving chromosomes and have implications for the evolution of genomic architecture.
Transmission distortion affecting human noncrossover but not crossover recombination: A hidden source of meiotic drive
4149Odenthal-Hesse, LB, I. L.; Veselis, A.; Jeffreys, A. J.; May, C. A., PLOS Genetics, 10:e1004106. 2014-01-07 00:00:00.
Author Summary Meiosis is an essential feature of sexual reproduction that maintains chromosome number over generations. This specialised form of cell division creates gametes containing a single copy of each chromosome so that each parent contributes half their genetic information to an offspring. Accurate partitioning first requires intimate association of the two parental copies of each chromosome and concomitant exchange between them. These exchanges consist of both large-scale reciprocal crossovers, essential for correct chromosome segregation, and very localised gene conversion events, or noncrossovers, thought to be involved in correct chromosome pairing. Ordinarily, the reshuffling of genetic variants between generations by recombination will not alter their population frequency only their haplotypic context, with a parent passing on a given variant to 50% of its gametes according to Mendel's law of inheritance. However, by screening for both types of recombinant amongst the sperm DNA of healthy men, we have identified a novel form of biased transmission that is restricted to noncrossovers and favours eventual fixation of one variant over another in the population. This previously undetected source of meiotic drive will not alter recombination propensity but is likely to be a common and potent force acting on the human genome. Meiotic recombination ensures the correct segregation of homologous chromosomes during gamete formation and contributes to DNA diversity through both large-scale reciprocal crossovers and very localised gene conversion events, also known as noncrossovers. Considerable progress has been made in understanding factors such as PRDM9 and SNP variants that influence the initiation of recombination at human hotspots but very little is known about factors acting downstream. To address this, we simultaneously analysed both types of recombinant molecule in sperm DNA at six highly active hotspots, and looked for disparity in the transmission of allelic variants indicative of any cis-acting influences. At two of the hotspots we identified a novel form of biased transmission that was exclusive to the noncrossover class of recombinant, and which presumably arises through differences between crossovers and noncrossovers in heteroduplex formation and biased mismatch repair. This form of biased gene conversion is not predicted to influence hotspot activity as previously noted for SNPs that affect recombination initiation, but does constitute a powerful and previously undetected source of recombination-driven meiotic drive that by extrapolation may affect thousands of recombination hotspots throughout the human genome. Intriguingly, at both of the hotspots described here, this drive favours strong (G/C) over weak (A/T) base pairs as might be predicted from the well-established correlations between high GC content and recombination activity in mammalian genomes.
The organization and evolution of the Responder satellite in species of the Drosophila melanogaster group: dynamic evolution of a target of meiotic drive
4145Larracuente, AM, BMC Evolutionary Biology, 14:233. 2014-01-03 00:00:00.
: Satellite DNA can make up a substantial fraction of eukaryotic genomes and has roles in genome structure and chromosome segregation. The rapid evolution of satellite DNA can contribute to genomic instability and genetic incompatibilities between species. Despite its ubiquity and its contribution to genome evolution, we currently know little about the dynamics of satellite DNA evolution. The Responder (Rsp) satellite DNA family is found in the pericentric heterochromatin of chromosome 2 of Drosophila melanogaster. Rsp is well-known for being the target of Segregation Distorter (SD) an autosomal meiotic drive system in D. melanogaster. I present an evolutionary genetic analysis of the Rsp family of repeats in D. melanogaster and its closely-related species in the melanogaster group (D. simulans, D. sechellia, D. mauritiana, D. erecta, and D. yakuba) using a combination of available BAC sequences, whole genome shotgun Sanger reads, Illumina short read deep sequencing, and fluorescence in situ hybridization. Results: I show that Rsp repeats have euchromatic locations throughout the D. melanogaster genome, that Rsp arrays show evidence for concerted evolution, and that Rsp repeats exist outside of D. melanogaster, in the melanogaster group. The repeats in these species are considerably diverged at the sequence level compared to D. melanogaster, and have a strikingly different genomic distribution, even between closely-related sister taxa. Conclusions: The genomic organization of the Rsp repeat in the D. melanogaster genome is complex it exists of large blocks of tandem repeats in the heterochromatin and small blocks of tandem repeats in the euchromatin. My discovery of heterochromatic Rsp-like sequences outside of D. melanogaster suggests that SD evolved after its target satellite and that the evolution of the Rsp satellite family is highly dynamic over a short evolutionary time scale (<240,000 years).
Elimination of Y chromosome-bearing spermatids during spermiogenesis in an autosomal sex-ratio mutant of Drosophila simulans
4183Yasuno, YI, Y. H.; Yamamoto, M. T., Genes & Genetic Systems, 88:113-126. 2013-01-21 00:00:00.
Sex ratio distortion, which is commonly abbreviated as sex-ratio, has been studied in many Drosophila species, but the mechanism remains largely unknown. Here, we report on the sex-ratio mutant of D. simulans named excess of females (exf). The third chromosomal recessive mutation results in a sex ratio of approximately 0.2 or less (males/total). Cytological observation demonstrated that meiosis appeared to be completed normally, but that most Y chromosome-bearing nuclei failed to elongate during spermiogenesis, as revealed by fluorescence in situ hybridization using sex chromosome-specific probes. These aberrant nuclei contained membranous inclusions as revealed by electron microscopic analysis. Most of the aberrant exf spermatids failed to individualize and mature, suggesting that a later stage of spermiogenesis is involved in prevention of production of sperm with abnormal morphology. On the one hand, in exf seminal vesicles, sperm nuclei with a length of 5-8.5 mu m were occasionally observed, in addition to those with wild-type sperm dimensions, that is, a length of approximately 10 mu m. Thus, spermatids with less severe nuclear defects can escape elimination and be released into the seminal vesicles as mature sperm. Furthermore, we constructed His2AvD-GFP and ProtamineB-eGFP transgenic lines in D. simulans, and examined the processes involved in replacement of chromatin proteins over a time course, according to nuclear morphology. We found that both normal and abnormal sperm heads demonstrated equal chromatin replacement during late spermiogenesis. Our results suggest that exf belongs to a unique class of meiotic drive systems in that (1) intranuclear membranous inclusions cause failure of nuclear shaping of Y-bearing spermatids without affecting the histone-protamine transition, and (2) a portion of the aberrant spermatids differentiate into mature sperm; these are transferred to and stored by females.
Sex-biased gene expression during head development in a sexually dimorphic stalk-eyed fly
4182Wilkinson, GSJ, P. M.; Metheny, J. D.; Baker, R. H., PLOS One, 8:1-10. 2013-01-20 00:00:00.
Stalk-eyed flies (family Diopsidae) are a model system for studying sexual selection due to the elongated and sexually dimorphic eye-stalks found in many species. These flies are of additional interest because their X chromosome is derived largely from an autosomal arm in other flies. To identify candidate genes required for development of dimorphic eyestalks and investigate how sex-biased expression arose on the novel X, we compared gene expression between males and females using oligonucleotide microarrays and RNA from developing eyestalk tissue or adult heads in the dimorphic diopsid, Teleopsis dalmanni. Microarray analysis revealed sex-biased expression for 26% of 3,748 genes expressed in eye-antennal imaginal discs and concordant sex-biased expression for 86 genes in adult heads. Overall, 415 female-biased and 482 male-biased genes were associated with dimorphic eyestalk development but not differential expression in the adult head. Functional analysis revealed that male-biased genes are disproportionately associated with growth and mitochondrial function while female-biased genes are associated with cell differentiation and patterning or are novel transcripts. With regard to chromosomal effects, dosage compensation occurs by elevated expression of X-linked genes in males. Genes with female-biased expression were more common on the X and less common on autosomes than expected, while male-biased genes exhibited no chromosomal pattern. Rates of protein evolution were lower for female-biased genes but higher for genes that moved on or off the novel X chromosome. These findings cannot be due to meiotic sex chromosome inactivation or by constraints associated with dosage compensation. Instead, they could be consistent with sexual conflict in which female-biased genes on the novel X act primarily to reduce eyespan in females while other genes increase eyespan in both sexes. Additional information on sex-biased gene expression in other tissues and related sexually monomorphic species could confirm this interpretation.
Association of polyandry and sex-ratio drive prevalence in natural populations of Drosophila neotestacea
4179Pinzone, CAD, K. A., Proceedings of the Royal Society B-Biological Sciences, 280:20131397. 2013-01-17 00:00:00.
Selfish genetic elements bias their own transmission to the next generation, even at the expense of the fitness of their carrier. Sex-ratio (SR) meiotic drive occurs when an X-chromosome causes Y-bearing sperm to die during male spermatogenesis, so that it is passed on to all of the male's offspring, which are all daughters. How SR is maintained as a stable polymorphism in the absence of genetic suppressors of drive is unknown. Here, we investigate the potential for the female remating rate to affect SR dynamics in natural populations, using the fly Drosophila neotestacea. In controlled laboratory conditions, females from populations where SR is rare mate more often than females from populations where SR is common. Furthermore, only when males mate multiply does the average fertility of SR males relative to wild-type males decrease to a level that can prevent SR from spreading. Our results suggest that differences in the female mating rate among populations may contribute to SR dynamics in the wild, and thus also affect the outcome of this intragenomic conflict. In line with this, we also present evidence of a localized population crash due to SR that may have resulted from habitat fragmentation along with a reduced mating rate.
Transmission rate variation among three B chromosome variants in the fish Prochilodus lineatus (Characiformes, Prochilodontidae)
4178Penitente, MV, T. A.; Senhorini, J. A.; Bortolozzi, J.; Foresti, F.; Porto-Foresti, F., Anais Da Academia Brasileira De Ciencias, 85:1371-1377. 2013-01-16 00:00:00.
Cytogenetic studies were developed in Prochilodus lineatus (Valenciennes 1836), describing an interesting system of small supernumerary chromosomes. The purpose of this work is to study the frequency and morphology of B chromosomes in individuals from the parental line and the inheritance patterns of these elements in individuals obtained from controlled crosses in the species P. lineatus. The transmission rate of B chromosomes, revealed a k(B)=0.388 for the acrocentric type, a kB=0.507 for the metacentric type and a k(B)=0.526 for the submetacentric type. The obtained results raise hypothesis that B-acrocentric chromosomes are involved in an extinction process in this species, while the metacentric and submetacentric supernumerary elements comprises a neutral mechanism and follows a Mendelian transmission rate.
Modeling the dynamics of a non-limited and a self-limited gene drive system in structured Aedes aegypti populations
4175Legros, MX, C. G.; Morrison, A.; Scott, T. W.; Lloyd, A. L.; Gould, F., PLOS One, 8:e83354. 2013-01-13 00:00:00.
Recently there have been significant advances in research on genetic strategies to control populations of disease-vectoring insects. Some of these strategies use the gene drive properties of selfish genetic elements to spread physically linked anti-pathogen genes into local vector populations. Because of the potential of these selfish elements to spread through populations, control approaches based on these strategies must be carefully evaluated to ensure a balance between the desirable spread of the refractoriness-conferring genetic cargo and the avoidance of potentially unwanted outcomes such as spread to non-target populations. There is also a need to develop better estimates of the economics of such releases. We present here an evaluation of two such strategies using a biologically realistic mathematical model that simulates the resident Aedes aegypti mosquito population of Iquitos, Peru. One strategy uses the selfish element Medea, a non-limited element that could permanently spread over a large geographic area; the other strategy relies on Killer-Rescue genetic constructs, and has been predicted to have limited spatial and temporal spread. We simulate various operational approaches for deploying these genetic strategies, and quantify the optimal number of released transgenic mosquitoes needed to achieve definitive spread of Medea-linked genes and/or high frequencies of Killer-Rescue-associated elements. We show that for both strategies the most efficient approach for achieving spread of anti-pathogen genes within three years is generally to release adults of both sexes in multiple releases over time. Even though females in these releases should not transmit disease, there could be public concern over such releases, making the less efficient male-only release more practical. This study provides guidelines for operational approaches to population replacement genetic strategies, as well as illustrates the use of detailed spatial models to assist in safe and efficient implementation of such novel genetic strategies.
Transmission ratio distortion: review of concept and implications for genetic association studies
4173Huang, LOL, A.; Infante-Rivard, C., Human Genetics, 132:245-263. 2013-01-11 00:00:00.
Transmission ratio distortion (TRD) occurs when one of the two alleles from either parent is preferentially transmitted to the offspring. This leads to a statistical departure from the Mendelian law of inheritance, which states that each of the two parental alleles is transmitted to offspring with a probability of 0.5. A number of mechanisms are thought to induce TRD such as meiotic drive, gametic competition, and embryo lethality. TRD has been extensively studied in animals, but the prevalence of TRD in humans remains largely unknown. Nevertheless, understanding the TRD phenomenon and taking it into consideration in many aspects of human genetics has potential benefits that have not been sufficiently emphasized in the current literature. In this review, we discuss the importance of TRD in three distinct but related fields of genetics: developmental genetics which studies the genetic abnormalities in zygotic and embryonic development, statistical genetics/genetic epidemiology which utilizes population study designs and statistical models to interpret the role of genes in human health, and population genetics which is concerned with genetic diversity in populations in an evolutionary context. From the perspective of developmental genetics, studying TRD leads to the identification of the processes and mechanisms for differential survival observed in embryos. As a result, it is a genetic force which affects allele frequency at the population, as well as, at the organismal level. Therefore, it has implications on genetic diversity of the population over time. From the perspective of genetic epidemiology, the TRD influence on a marker locus is a confounding factor which has to be adequately dealt with to correctly interpret linkage or association study results. These aspects are developed in this review. In addition to these theoretical notions, a brief summary of the empirical evidence of the TRD phenomenon in human and mouse studies is provided. The objective of our paper is to show the potentially important role of TRD in many areas of genetics, and to create an incentive for future research.
Mutations to the piRNA Pathway Component Aubergine Enhance Meiotic Drive of Segregation Distorter in Drosophila melanogaster
4172Gell, SLR, R. A., Genetics, 193:771-784. 2013-01-10 00:00:00.
Diploid sexual reproduction involves segregation of allelic pairs, ensuring equal representation of genotypes in the gamete pool. Some genes, however, are able to "cheat" the system by promoting their own transmission. The Segregation distorter (Sd) locus in Drosophila melanogaster males is one of the best-studied examples of this type of phenomenon. In this system the presence of Sd on one copy of chromosome 2 results in dysfunction of the non-Sd-bearing (Sd(+)) sperm and almost exclusive transmission of Sd to the next generation. The mechanism by which Sd wreaks such selective havoc has remained elusive. However, its effect requires a target locus on chromosome 2 known as Responder (Rsp). The Rsp locus comprises repeated copies of a satellite DNA sequence and Rsp copy number correlates with sensitivity to Sd. Under distorting conditions during spermatogenesis, nuclei with chromosomes containing greater than several hundred Rsp repeats fail to condense chromatin and are eliminated. Recently, Rsp sequences were found as small RNAs in association with Argonaute family proteins Aubergine (Aub) and Argonaute3 (AGO3). These proteins are involved in a germ-line-specific RNAi mechanism known as the Piwi-interacting RNA (piRNA) pathway, which specifically suppresses transposon activation in the germline. Here, we evaluate the role of piRNAs in segregation distortion by testing the effects of mutations to piRNA pathway components on distortion. Further, we specifically targeted mutations to the aub locus of a Segregation Distorter (SD) chromosome, using ends-out homologous recombination. The data herein demonstrate that mutations to piRNA pathway components act as enhancers of SD.
The design and in vivo evaluation of engineered I-OnuI-based enzymes for HEG gene drive
4169Chan, YST, R.; Jarjour, J.; Huen, D. S.; Stoddard, B. L.; Russell, S., PLOS One, 8:e74254. 2013-01-07 00:00:00.
The homing endonuclease gene (HEG) drive system, a promising genetic approach for controlling arthropod populations, utilises engineered nucleases to spread deleterious mutations that inactivate individual genes throughout a target population. Previous work with a naturally occurring LAGLIDADG homing endonuclease (I-SceI) demonstrated its feasibility in both Drosophila and Anopheles. Here we report on the next stage of this strategy: the redesign of HEGs with customized specificity in order to drive HEG-induced 'homing' in vivo via break-induced homologous recombination. Variants targeting a sequence within the Anopheles AGAP004734 gene were created from the recently characterized I-OnuI endonuclease, and tested for cleavage activity and frequency of homing using a model Drosophila HEG drive system. We observed cleavage and homing at an integrated reporter for all endonuclease variants tested, demonstrating for the first time that engineered HEGs can cleave their target site in insect germline cells, promoting targeted mutagenesis and homing. However, in comparison to our previously reported work with I-SceI, the engineered I-OnuI variants mediated homing with a reduced frequency, suggesting that site-specific cleavage activity is insufficient by itself to ensure efficient homing. Taken together, our experiments take a further step towards the development of a viable HEG-based population control strategy for insects.
Optimising homing endonuclease gene drive performance in a semi-refractory species: The Drosophila melanogaster experience
4168Chan, YSH, D. S.; Glauert, R.; Whiteway, E.; Russell, S., PLOS One, 8:e54130. 2013-01-06 00:00:00.
Homing endonuclease gene (HEG) drive is a promising insect population control technique that employs meganucleases to impair the fitness of pest populations. Our previous studies showed that HEG drive was more difficult to achieve in Drosophila melanogaster than Anopheles gambiae and we therefore investigated ways of improving homing performance in Drosophila. We show that homing in Drosophila responds to increased expression of HEGs specifically during the spermatogonia stage and this could be achieved through improved construct design. We found that 39-UTR choice was important to maximise expression levels, with HEG activity increasing as we employed Hsp70, SV40, vasa and beta Tub56D derived UTRs. We also searched for spermatogonium-specific promoters and found that the Rcd-1r promoter was able to drive specific expression at this stage. Since Rcd-1 is a regulator of differentiation in other species, it suggests that Rcd-1r may serve a similar role during spermatogonial differentiation in Drosophila. Contrary to expectations, a fragment containing the entire region between the TBPH gene and the bgcn translational start drove strong HEG expression only during late spermatogenesis rather than in the germline stem cells and spermatogonia as expected. We also observed that the fraction of targets undergoing homing was temperature-sensitive, falling nearly four-fold when the temperature was lowered to 18 degrees C. Taken together, this study demonstrates how a few simple measures can lead to substantial improvements in the HEG-based gene drive strategy and reinforce the idea that the HEG approach may be widely applicable to a variety of insect control programs.
Natural variation of the Y chromosome suppresses sex ratio distortion and modulates testis-specific gene expression in Drosophila simulans
4167Branco, ATT, Y.; Hartl, D. L.; Lemos, B., Heredity, 111:8-15. 2013-01-05 00:00:00.
X-linked sex-ratio distorters that disrupt spermatogenesis can cause a deficiency in functional Y-bearing sperm and a female-biased sex ratio. Y-linked modifiers that restore a normal sex ratio might be abundant and favored when a X-linked distorter is present. Here we investigated natural variation of Y-linked suppressors of sex-ratio in the Winters systems and the ability of these chromosomes to modulate gene expression in Drosophila simulans. Seventy-eight Y chromosomes of worldwide origin were assayed for their resistance to the X-linked sex-ratio distorter gene Dox. Y chromosome diversity caused males to sire similar to 63% to similar to 98% female progeny. Genome-wide gene expression analysis revealed hundreds of genes differentially expressed between isogenic males with sensitive (high sex ratio) and resistant (low sex ratio) Y chromosomes from the same population. Although the expression of about 75% of all testis-specific genes remained unchanged across Y chromosomes, a subset of post-meiotic genes was upregulated by resistant Y chromosomes. Conversely, a set of accessory gland-specific genes and mitochondrial genes were downregulated in males with resistant Y chromosomes. The D. simulans Y chromosome also modulated gene expression in XXY females in which the Y-linked protein-coding genes are not transcribed. The data suggest that the Y chromosome might exert its regulatory functions through epigenetic mechanisms that do not require the expression of protein-coding genes. The gene network that modulates sex ratio distortion by the Y chromosome is poorly understood, other than that it might include interactions with mitochondria and enriched for genes expressed in post-meiotic stages of spermatogenesis.
Local dynamics of a fast-evolving sex-ratio system in Drosophila simulans
4166Bastide, HG, P. R.; Ogereau, D.; Cazemajor, M.; Montchamp-Moreau, C., Molecular Ecology, 22:5352-5367. 2013-01-04 00:00:00.
By distorting Mendelian transmission to their own advantage, X-linked meiotic drive elements can rapidly spread in natural populations, generating a sex-ratio bias. One expected consequence is the triggering of a co-evolutionary arms race between the sex chromosome that carries the distorter and suppressors counteracting its effect. Such an arms race has been theoretically and experimentally established and can have many evolutionary consequences. However, its dynamics in contemporary populations is still poorly documented. Here, we investigate the fate of the young X-linked Paris driver in Drosophila simulans from sub-Saharan Africa to the Middle East. We provide the first example of the early dynamics of distorters and suppressors: we find consistent evidence that the driving chromosomes have been rising in the Middle East during the last decade. In addition, identical haplotypes are at high frequencies around the two co-evolving drive loci in remote populations, implying that the driving X chromosomes share a recent common ancestor and suggesting that East Africa could be the cradle of the Paris driver. The segmental duplication associated with drive presents an unusual structure in West Africa, which could reflect a secondary state of the driver. Together with our previous demonstration of driver decline in the Indian Ocean where suppression is complete, these data provide a unique picture of the complex dynamics of a co-evolutionary arms race currently taking place in natural populations of D.simulans.
The contribution of female meiotic drive to the evolution of neo-sex chromosomes
4197Yoshida, KK, J., Evolution, 66:3198-3208. 2012-01-15 00:00:00.
Sex chromosomes undergo rapid turnover in certain taxonomic groups. One of the mechanisms of sex chromosome turnover involves fusions between sex chromosomes and autosomes. Sexual antagonism, heterozygote advantage, and genetic drift have been proposed as the drivers for the fixation of this evolutionary event. However, all empirical patterns of the prevalence of multiple sex chromosome systems across different taxa cannot be simply explained by these three mechanisms. In this study, we propose that female meiotic drive may contribute to the evolution of neo-sex chromosomes. The results of this study showed that in mammals, the XY1Y2 sex chromosome system is more prevalent in species with karyotypes of more biarmed chromosomes, whereas the X1X2Y sex chromosome system is more prevalent in species with predominantly acrocentric chromosomes. In species where biarmed chromosomes are favored by female meiotic drive, X-autosome fusions (XY1Y2 sex chromosome system) will be also favored by female meiotic drive. In contrast, in species with more acrocentric chromosomes, Y-autosome fusions (X1X2Y sex chromosome system) will be favored just because of the biased mutation rate toward chromosomal fusions. Further consideration should be given to female meiotic drive as a mechanism in the fixation of neo-sex chromosomes.
From genes to games: Cooperation and cyclic dominance in meiotic drive
4196Traulsen, AR, F. A., Journal of Theoretical Biology, 299:120-125. 2012-01-14 00:00:00.
Evolutionary change can be described on a genotypic level or a phenotypic level. Evolutionary game theory is typically thought of as a phenotypic approach, although it is frequently argued that it can also be used to describe population genetic evolution. Interpreting the interaction between alleles in a diploid genome as a two player game leads to interesting alternative perspectives on genetic evolution. Here we focus on the case of meiotic drive and illustrate how meiotic drive can be directly and precisely interpreted as a social dilemma, such as the prisoners dilemma or the snowdrift game, in which the drive allele takes more than its fair share. Resistance to meiotic drive can lead to the well understood cyclic dominance found in the rock-paper-scissors game. This perspective is well established for the replicator dynamics, but there is still considerable ground for mutual inspiration between the two fields. For example, evolutionary game theorists can benefit from considering the stochastic evolutionary dynamics arising from finite population size. Population geneticists can benefit from game theoretic tools and perspectives on genetic evolution. (c) 2011 Elsevier Ltd. All rights reserved.
Genetic mapping a meiotic driver that causes sex ratio distortion in the mosquito Aedes aegypti
4195Shin, DM, A.; Severson, D. W., Journal of Heredity, 103:303-307. 2012-01-13 00:00:00.
An endogenous meiotic driver in the dengue and yellow fever vector mosquito Aedes aegypti can cause highly male-biased sex ratio distortion in crosses from suitable genetic backgrounds. We previously selected a strain that carries a strong meiotic drive gene (D) linked with the maledetermining allele (M) on chromosome 1 in A. aegypti. Here, we performed segregation analysis of the M-D locus among backcross (BC1) progeny from a driver male and drive- sensitive females. Assessment of sex ratios among BC2 progeny showed; similar to 5.2% recombination between the M-D locus and the sex determination locus. Multipoint linkage mapping across this region revealed consistent marker orders and recombination frequencies with the existing reference linkage map and placed the M-D locus within a 6.5-cm interval defined by the LF159 locus and microsatellite marker 446GAA, which should facilitate future positional cloning efforts.
No evidence of mate discrimination against males carrying a sex ratio distorter in Drosophila pseudoobscura
4194Price, TARL, Z.; Smith, D. T.; Hurst, G. D. D.; Wedell, N., Behavioral Ecology and Sociobiology, 66:561-568. 2012-01-12 00:00:00.
Selfish genetic elements (SGEs) that spread by manipulating spermatogenesis often have highly deleterious effects on males that carry them. Females that mate with male carriers of SGEs can also suffer significant costs: they receive fewer and poorer-quality sperm, their offspring will inherit the deleterious allele, and the sex ratio of their offspring will be biased towards the more common sex. To counter these costs, females are therefore expected to prefer to mate with males that do not carry sex ratio distorters or other deleterious selfish genetic elements. However, despite the potential costs, there are few examples of female choice against males carrying SGEs. We searched for evidence of a female preference in fruit fly Drosophila pseudoobscura against males carrying a costly meiotic driving X-chromosome Sex Ratio (SR). In a series of five non-competitive mate preference experiments, we find no evidence that females prefer to mate with non-SR males. Our use of five separate experiments, involving more than 800 females, makes it unlikely that this lack of a difference was due to low power or simple chance. We suggest that the lack of female choice against SGE-carrying males may be due to strong selection on SGEs to be indistinguishable from alternative alleles. Furthermore, polyandry, either in direct response to receiving an ejaculate from an SGE-carrying male or carried out indiscriminately when at risk of mating with carriers, may be an alternative response by females to limit the exposure of their offspring to SGEs.
Evaluating the evidence for transmission distortion in human pedigrees
4193Meyer, WKA, B.; Ober, C.; Ebner, T.; Tiemann-Boege, I.; Hudson, R. R.; Przeworski, M., Genetics, 191:215-232. 2012-01-11 00:00:00.
Children of a heterozygous parent are expected to carry either allele with equal probability. Exceptions can occur, however, due to meiotic drive, competition among gametes, or viability selection, which we collectively term "transmission distortion" (TD). Although there are several well-characterized examples of these phenomena, their existence in humans remains unknown. We therefore performed a genome-wide scan for TD by applying the transmission disequilibrium test (TDT) genome-wide to three large sets of human pedigrees of European descent: the Framingham Heart Study (FHS), a founder population of European origin (HUTT), and a subset of the Autism Genetic Resource Exchange (AGRE). Genotyping error is an important confounder in this type of analysis. In FHS and HUTT, despite extensive quality control, we did not find sufficient evidence to exclude genotyping error in the strongest signals. In AGRE, however, many signals extended across multiple SNPs, a pattern highly unlikely to arise from genotyping error. We identified several candidate regions in this data set, notably a locus in 10q26.13 displaying a genome-wide significant TDT in combined female and male transmissions and a signature of recent positive selection, as well as a paternal TD signal in 6p21.1, the same region in which a significant TD signal was previously observed in 30 European males. Neither region replicated in FHS, however, and the paternal signal was not visible in sperm competition assays or as allelic imbalance in sperm. In maternal transmissions, we detected no strong signals near centromeres or telomeres, the regions predicted to be most susceptible to female-specific meiotic drive, but we found a significant enrichment of top signals among genes involved in cell junctions. These results illustrate both the potential benefits and the challenges of using the TDT to study transmission distortion and provide candidates for investigation in future studies.
The Selfish Segregation Distorter Gene Complex of Drosophila melanogaster
4190Larracuente, AMP, D. C., Genetics, 192:33-53. 2012-01-08 00:00:00.
Segregation Distorter (SD) is an autosomal meiotic drive gene complex found worldwide in natural populations of Drosophila melanogaster. During spermatogenesis, SD induces dysfunction of SD+ spermatids so that SD/SD+ males sire almost exclusively SD-bearing progeny rather than the expected 1:1 Mendelian ratio. SD is thus evolutionarily "selfish," enhancing its own transmission at the expense of its bearers. Here we review the molecular and evolutionary genetics of SD. Genetic analyses show that the SD is a multilocus gene complex involving two key loci-the driver, Segregation distorter (Sd), and the target of drive, Responder (Rsp)-and at least three upward modifiers of distortion. Molecular analyses show that Sd encodes a truncated duplication of the gene RanGAP, whereas Rsp is a large pericentromeric block of satellite DNA. The Sd-RanGAP protein is enzymatically wild type but mislocalized within cells and, for reasons that remain unclear, appears to disrupt the histone-to-protamine transition in drive-sensitive spermatids bearing many Rsp satellite repeats but not drive-insensitive spermatids bearing few or no Rsp satellite repeats. Evolutionary analyses show that the Sd-RanGAP duplication arose recently within the D. melanogaster lineage, exploiting the preexisting and considerably older Rsp satellite locus. Once established, the SD haplotype collected enhancers of distortion and suppressors of recombination. Further dissection of the molecular genetic and cellular basis of SD-mediated distortion seems likely to provide insights into several important areas currently understudied, including the genetic control of spermatogenesis, the maintenance and evolution of satellite DNAs, the possible roles of small interfering RNAs in the germline, and the molecular population genetics of the interaction of genetic linkage and natural selection.
Complex genetic nature of sex-independent transmission ratio distortion in Asian rice species: the involvement of unlinked modifiers and sex-specific mechanisms
4189Koide, YS, Y.; Ikenaga, M.; Sawamura, N.; Matsubara, K.; Onishi, K.; Kanazawa, A.; Sano, Y., Heredity, 108:242-247. 2012-01-07 00:00:00.
Transmission ratio distortion (TRD), in which one allele is transmitted more frequently than the opposite allele, is presumed to act as a driving force in the emergence of a reproductive barrier. TRD acting in a sex-specific manner has been frequently observed in interspecific and intraspecific hybrids across a broad range of organisms. In contrast, sex-independent TRD (SITRD), which results from preferential transmission of one of the two alleles in the heterozygote through both sexes, has been detected in only a few plant species. We previously reported an S-6 locus-mediated SITRD, in which the S-6 allele from an Asian wild rice strain (Oryza rufipogon) was transmitted more frequently than the S-6(a) allele from an Asian cultivated rice strain (O. sativa) through both male and female gametes in heterozygous plants. Here, we report on the effect of a difference in genetic background on S-6 locus-mediated SITRD, based on the analysis using near-isogenic lines and the original wild strain as a parental strain for crossing. We found that the degree of TRD through the male gametes varied depending on the genetic background of the female (pistil) plants. Despite the occurrence of TRD through both male and female gametes, abnormality was detected in ovules, but not in pollen grains, in the heterozygote. These results suggest the involvement of unlinked modifiers and developmentally distinct, sex-specific genetic mechanisms in S-6 locus-mediated SITRD, raising the possibility that SITRD driven by a single locus may be affected by multiple genetic factors harbored in natural populations. Heredity (2012) 108, 242-247; doi:10.1038/hdy.2011.64; published online 27 July 2011
Molecular dissection of Neurospora Spore killer meiotic drive elements
4187Hammond, TMR, D. G.; Xiao, H.; Shiu, P. K. T., Proceedings of the National Academy of Sciences of the United States of America, 109:12093-12098. 2012-01-05 00:00:00.
Meiotic drive is a non-Mendelian inheritance phenomenon in which certain selfish genetic elements skew sexual transmission in their own favor. In some cases, progeny or gametes carrying a meiotic drive element can survive preferentially because it causes the death or malfunctioning of those that do not carry it. In Neurospora, meiotic drive can be observed in fungal spore killing. In a cross of Spore killer (Sk) x WT (Sk-sensitive), the ascospores containing the Spore killer allele survive, whereas the ones with the sensitive allele degenerate. Sk-2 and Sk-3 are the most studied meiotic drive elements in Neurospora, and they each theoretically contain two essential components: a killer element and a resistance gene. Here we report the identification and characterization of the Sk resistance gene, rsk (resistant to Spore killer). rsk seems to be a fungal-specific gene, and its deletion in a killer strain leads to self-killing. Sk-2, Sk-3, and naturally resistant isolates all use rsk for resistance. In each killer system, rsk sequences from an Sk strain and a resistant isolate are highly similar, suggesting that they share the same origin. Sk-2, Sk-3, and sensitive rsk alleles differ from each other by their unique indel patterns. Contrary to long-held belief, the killer targets not only late but also early ascospore development. The WT RSK protein is dispensable for ascospore production and is not a target of the spore-killing mechanism. Rather, a resistant version of RSK likely neutralizes the killer element and prevents it from interfering with ascospore development.
Local selection underlies the geographic distribution of sex-ratio drive in Drosophila neotestacea
4186Dyer, KA, Evolution, 66:973-984. 2012-01-04 00:00:00.
Selfish genetic elements promote their own transmission to the next generation, often at a cost to the host individual. A sex-ratio (SR) driving X chromosome prevents the maturation of Y-bearing sperm, and as a result is transmitted to 100% of the offspring, all of which are female. Because the spread of a SR chromosome can result in a female-biased population sex ratio, the ecological and evolutionary consequences of harboring this selfish element can be severe. In this study, we show that the prevalence of SR drive in Drosophila neotestacea varies between 0% and 30% among populations, and is common in the south whereas rare in the north. The prevalence of SR is not associated with the presence of suppressors of drive, geographic distance, or genetic distance based on autosomal microsatellite loci. Instead, our results indicate that ecological selection on SR drive varies among populations, as the prevalence of SR is highly correlated with climatic factors, with the severity of winter the best determinant of SR frequency. Thus, ecological and demographic factors may have significant consequences for the short and long term evolutionary dynamics of selfish elements and the manner with which they coevolve with the rest of the genome.
Nondisjunction in favor of a Chromosome: The mechanism of rye B chromosome drive during pollen mitosis
4184Banaei-Moghaddam, AMS, V.; Kumke, K.; Weiss, O.; Klemme, S.; Nagaki, K.; Macas, J.; Gonzalez-Sanchez, M.; Heredia, V.; Gomez-Revilla, D.; Gonzalez-Garcia, M.; Vega, J. M.; Puertas, M. J.; Houben, A., Plant Cell, 24:4124-4134. 2012-01-02 00:00:00.
B chromosomes (Bs) are supernumerary components of the genome and do not confer any advantages on the organisms that harbor them. The maintenance of Bs in natural populations is possible by their transmission at higher than Mendelian frequencies. Although drive is the key for understanding B chromosomes, the mechanism is largely unknown. We provide direct insights into the cellular mechanism of B chromosome drive in the male gametophyte of rye (Secale cereale). We found that nondisjunction of Bs is accompanied by centromere activity and is likely caused by extended cohesion of the B sister chromatids. The B centromere originated from an A centromere, which accumulated B-specific repeats and rearrangements. Because of unequal spindle formation at the first pollen mitosis, nondisjoined B chromatids preferentially become located toward the generative pole. The failure to resolve pericentromeric cohesion is under the control of the B-specific nondisjunction control region. Hence, a combination of nondisjunction and unequal spindle formation at first pollen mitosis results in the accumulation of Bs in the generative nucleus and therefore ensures their transmission at a higher than expected rate to the next generation.
Reduced polymorphism associated with X chromosome meiotic drive in the stalk-eyed fly Teleopsis dalmanni
4202Christianson, SJB, C. L.; Wilkinson, G. S., PLOS One, 6:e27254. 2011-01-20 00:00:00.
Sex chromosome meiotic drive has been suggested as a cause of several evolutionary genetic phenomena, including genomic conflicts that give rise to reproductive isolation between new species. In this paper we present a population genetic analysis of X chromosome drive in the stalk-eyed fly, Teleopsis dalmanni, to determine how this natural polymorphism influences genetic diversity. We analyzed patterns of DNA sequence variation at two X-linked regions (comprising 1325 bp) approximately 50 cM apart and one autosomal region (comprising 921 bp) for 50 males, half of which were collected in the field from one of two allopatric locations and the other half were derived from lab-reared individuals with known brood sex ratios. These two populations are recently diverged but exhibit partial postzygotic reproductive isolation, i.e. crosses produce sterile hybrid males and fertile females. We find no nucleotide or microsatellite variation on the drive X chromosome, whereas the same individuals show levels of variation at autosomal regions that are similar to field-collected flies. Furthermore, one field-caught individual collected 10 years previously had a nearly identical X haplotype to the drive X, and is over 2% divergent from other haplotypes sampled from the field. These results are consistent with a selective sweep that has removed genetic variation from much of the drive X chromosome. We discuss how this finding may relate to the rapid evolution of postzygotic reproductive isolation that has been documented for these flies.
Insect population control by homing endonuclease-based gene drive: An evaluation in Drosophila melanogaster
4201Chan, YSN, D. A.; Huen, D. S.; Russell, S., Genetics, 188:33-44. 2011-01-19 00:00:00.
Insects play a major role as vectors of human disease as well as causing significant agricultural losses. Harnessing the activity of customized homing endonuclease genes (HEGs) has been proposed as a method for spreading deleterious mutations through populations with a view to controlling disease vectors. Here, we demonstrate the feasibility of this method in Drosophila melanogaster, utilizing the well-characterized HEG, I-SceI. In particular, we show that high rates of homing can be achieved within spermatogonia and in the female germline. We show that homed constructs continue to exhibit HEG activity in the subsequent generation and that the ectopic homing events required for initiating the strategy occur at an acceptable rate. We conclude that the requirements for successful deployment of a HEG-based gene drive strategy can be satisfied in a model dipteran and that there is a reasonable prospect of the method working in other dipterans. In characterizing the system we measured repair outcomes at the spermatogonial, spermatocyte, and spermatid stages of spermatogenesis. We show that homologous recombination is restricted to spermatogonia and that it immediately ceases when they become primary spermatocytes, indicating that the choice of DNA repair pathway in the Drosophila testis can switch abruptly during differentiation.
B Chromosomes and Sex in Animals
4200Camacho, JPMS, M.; Cabrero, J., Sexual Development, 5:155-166. 2011-01-18 00:00:00.
Supernumerary (B) chromosomes are dispensable elements found in many eukaryote genomes in addition to standard (A) chromosomes. In many respects, B chromosomes resemble sex chromosomes, so that a common ancestry for them has frequently been suggested. For instance, B chromosomes in grasshoppers, and other insects, show a pycnotic cycle of condensation-decondensation during meiosis remarkably similar to that of the X chromosome. In some cases, B chromosome size is even very similar to that of the X chromosome. These resemblances have led to suggest the X as the B ancestor in many cases. In addition, sex chromosome origin from B chromosomes has also been suggested. In this article, we review the existing evidence for both evolutionary pathways, as well as sex differences for B frequency at adult and embryo progeny levels, B chromosome effects or B chromosome transmission. In addition, we review cases found in the literature showing sex-ratio distortion associated with B chromosome presence, the most extreme case being the paternal sex ratio (PSR) chromosomes in some Hymenoptera. We finally analyse the possibility of B chromosome regularisation within the host genome and, as a consequence of it, whether B chromosomes can become regular members of the host genome. Copyright (C) 2011 S. Karger AG, Basel
Rapid rise and fall of selfish sex-ratio X Chromosomes in Drosophila simulans: Spatiotemporal analysis of phenotypic and molecular data
4199Bastide, HC, M.; Ogereau, D.; Derome, N.; Hospital, F.; Montchamp-Moreau, C., Molecular Biology and Evolution, 28:2461-2470. 2011-01-17 00:00:00.
Sex-ratio drive, which has been documented in several Drosophila species, is induced by X-linked segregation distorters. Contrary to Mendel's law of independent assortment, the sex-ratio chromosome (X(SR)) is inherited by more than half the offspring of carrier males, resulting in a female-biased sex ratio. This segregation advantage allows X(SR) to spread in populations, even if it is not beneficial for the carriers. In the cosmopolitan species D. simulans, the Paris sex-ratio is caused by recently emerged selfish X(SR) chromosomes. These chromosomes have triggered an intragenomic conflict, and their propagation has been halted over a large area by the evolution of complete drive suppression. Previous molecular population genetics analyses revealed a selective sweep indicating that the invasion of X(SR) chromosomes was very recent in Madagascar (likely less than 100 years ago). Here, we show that X(SR) chromosomes are now declining at this location as well as in Mayotte and Kenya. Drive suppression is complete in the three populations, which display little genetic differentiation and share swept haplotypes, attesting to a common and very recent ancestry of the X(SR) chromosomes. Patterns of DNA sequence variation also indicate a fitness cost of the segmental duplication involved in drive. The data suggest that X(SR) chromosomes started declining first on the African continent, then in Mayotte, and finally in Madagascar and strongly support a scenario of rapid cycling of X chromosomes. Once drive suppression has evolved, standard X(ST) chromosomes locally replace costly X(SR) chromosomes in a few decades.
Stability properties of underdominance in finite subdivided populations
4198Altrock, PMT, A.; Reed, F. A., PLOS Computational Biology, 7:10. 2011-01-16 00:00:00.
In isolated populations underdominance leads to bistable evolutionary dynamics: below a certain mutant allele frequency the wildtype succeeds. Above this point, the potentially underdominant mutant allele fixes. In subdivided populations with gene flow there can be stable states with coexistence of wildtypes and mutants: polymorphism can be maintained because of a migration-selection equilibrium, i.e., selection against rare recent immigrant alleles that tend to be heterozygous. We focus on the stochastic evolutionary dynamics of systems where demographic fluctuations in the coupled populations are the main source of internal noise. We discuss the influence of fitness, migration rate, and the relative sizes of two interacting populations on the mean extinction times of a group of potentially underdominant mutant alleles. We classify realistic initial conditions according to their impact on the stochastic extinction process. Even in small populations, where demographic fluctuations are large, stability properties predicted from deterministic dynamics show remarkable robustness. Fixation of the mutant allele becomes unlikely but the time to its extinction can be long.
A synthetic homing endonuclease-based gene drive system in the human malaria mosquito
4211Windbichler, NM, M.; Papathanos, P. A.; Thyme, S. B.; Li, H.; Ulge, U. Y.; Hovde, B. T.; Baker, D.; Monnat, R. J.; Burt, A.; Crisanti, A., Nature, 473:212-215. 2011-01-09 00:00:00.
Genetic methods of manipulating or eradicating disease vector populations have long been discussed as an attractive alternative to existing control measures because of their potential advantages in terms of effectiveness and species specificity(1-3). The development of genetically engineered malaria-resistant mosquitoes has shown, as a proof of principle, the possibility of targeting the mosquito's ability to serve as a disease vector(4-7). The translation of these achievements into control measures requires an effective technology to spread a genetic modification from laboratory mosquitoes to field populations(8). We have suggested previously that homing endonuclease genes (HEGs), a class of simple selfish genetic elements, could be exploited for this purpose(9). Here we demonstrate that a synthetic genetic element, consisting of mosquito regulatory regions(10) and the homing endonuclease gene I-SceI(11-13), can substantially increase its transmission to the progeny in transgenic mosquitoes of the human malaria vector Anopheles gambiae. We show that the I-SceI element is able to invade receptive mosquito cage populations rapidly, validating mathematical models for the transmission dynamics of HEGs. Molecular analyses confirm that expression of I-SceI in the male germline induces high rates of site-specific chromosomal cleavage and gene conversion, which results in the gain of the I-SceI gene, and underlies the observed genetic drive. These findings demonstrate a new mechanism by which genetic control measures can be implemented. Our results also show in principle how sequence-specific genetic drive elements like HEGs could be used to take the step from the genetic engineering of individuals to the genetic engineering of populations.
Transcript profiling of the meiotic drive phenotype in testis of Aedes aegypti using suppressive subtractive hybridization
4209Shin, DYJ, L. Z.; Lobo, N. F.; Severson, D. W., Journal of Insect Physiology, 57:1220-1226. 2011-01-07 00:00:00.
The meiotic drive gene in Aedes aegypti is tightly linked with the sex determination locus on chromosome 1, and causes highly male-biased sex ratios. We prepared cDNA libraries from testes from the Ae. aegypti 137 strain (driving) and RED strain (non-driving), and used suppressive subtraction hybridization techniques to enrich for 137 testes-specific transcripts. Expressed sequence tags (ESTs) were obtained from a total of 2784 randomly selected clones from the subtracted 137 (subT37) library as well as the primary libraries for each strain (pT37 and pRED). Sequence analysis identified a total of 171 unique genes in the subT37 library and 299 unique genes among the three libraries. The majority of genes enriched in the subT37 library were associated with signal transduction, development, reproduction, metabolic process and cell cycle functions. Further, as observed with meiotic drive systems in Drosophila and mouse, a number of these genes were associated with signaling cascades that involve the Ras superfamily of regulatory small GTPases. Differential expression of several of these genes was verified in Ae. aegypti pupal testes using qRT-PCR. This study increases our understanding of testes gene expression enriched in adult males from the meiotic drive strain as well as insights into the basic testes transcriptome in Ae. aegypti. (C) 2011 Elsevier Ltd. All rights reserved.
A novel sperm-delivered toxin causes late-stage embryo lethality and transmission ratio distortion in C. elegans
4208Seidel, HSA, M.; Li, J. L.; van Oudenaarden, A.; Rockman, M. V.; Kruglyak, L., PLOS Biology, 9:e1001115. 2011-01-06 00:00:00.
The evolutionary fate of an allele ordinarily depends on its contribution to host fitness. Occasionally, however, genetic elements arise that are able to gain a transmission advantage while simultaneously imposing a fitness cost on their hosts. We previously discovered one such element in C. elegans that gains a transmission advantage through a combination of paternal-effect killing and zygotic self-rescue. Here we demonstrate that this element is composed of a sperm-delivered toxin, peel-1, and an embryo-expressed antidote, zeel-1. peel-1 and zeel-1 are located adjacent to one another in the genome and co-occur in an insertion/deletion polymorphism. peel-1 encodes a novel four-pass transmembrane protein that is expressed in sperm and delivered to the embryo via specialized, sperm-specific vesicles. In the absence of zeel-1, sperm-delivered PEEL-1 causes lethal defects in muscle and epidermal tissue at the 2-fold stage of embryogenesis. zeel-1 is expressed transiently in the embryo and encodes a novel six-pass transmembrane domain fused to a domain with sequence similarity to zyg-11, a substrate-recognition subunit of an E3 ubiquitin ligase. zeel-1 appears to have arisen recently, during an expansion of the zyg-11 family, and the transmembrane domain of zeel-1 is required and partially sufficient for antidote activity. Although PEEL-1 and ZEEL-1 normally function in embryos, these proteins can act at other stages as well. When expressed ectopically in adults, PEEL-1 kills a variety of cell types, and ectopic expression of ZEEL-1 rescues these effects. Our results demonstrate that the tight physical linkage between two novel transmembrane proteins has facilitated their co-evolution into an element capable of promoting its own transmission to the detriment of organisms carrying it.
Inverse Medea as a novel gene drive system for socal population replacement: A theoretical analysis
4206Marshall, JMH, B. A., Journal of Heredity, 102:336-341. 2011-01-04 00:00:00.
One strategy to control mosquito-borne diseases, such as malaria and dengue fever, on a regional scale is to use gene drive systems to spread disease-refractory genes into wild mosquito populations. The development of a synthetic Medea element that has been shown to drive population replacement in laboratory Drosophila populations has provided encouragement for this strategy but has also been greeted with caution over the concern that transgenes may spread into countries without their consent. Here, we propose a novel gene drive system, inverse Medea, which is strong enough to bring about local population replacement but is unable to establish itself beyond an isolated release site. The system consists of 2 genetic components-a zygotic toxin and maternal antidote-which render heterozygous offspring of wild-type mothers unviable. Through population genetic analysis, we show that inverse Medea will only spread when it represents a majority of the alleles in a population. The element is best located on an autosome and will spread to fixation provided any associated fitness costs are dominant and to very high frequency otherwise. We suggest molecular tools that could be used to build the inverse Medea system and discuss its utility for a confined release of transgenic mosquitoes.
Selective microspore abortion correlated with aneuploidy: an indication of meiotic drive
4204Furness, CAR, P. J., Sexual Plant Reproduction, 24:1-8. 2011-01-02 00:00:00.
Selective megaspore abortion (monomegaspory) probably arose once in seed plants and occurs routinely in more than 70% of angiosperm species, representing one of the key characters of a heterosporous life history. In contrast, selective microspore abortion leading to pollen dispersal as pseudomonads (here termed monomicrospory) apparently arose at least twice independently within angiosperms, though it occurs in a limited number of taxa. Remarkably, similar examples of monomicrospory occur in members of two distantly related angiosperm families: the sedge family (Cyperaceae) and the epacrid subfamily (Styphelioideae) of the eudicot family Ericaceae. In sedges, monomicrospory is derived directly from normal tetrads, whereas epacrid pseudomonads apparently evolved via an intermediate stage, in which variable sterility occurs in a single tetrad. Our comparison of these two examples of selective microspore abortion highlights a correlation with aneuploidy, indicating that non-random chromosome segregation caused by monomicrospory could drive chromosomal mutations to rapid fixation through meiotic drive.
Changes in sperm tail development associated with Y chromosome meiotic drive leading to an excess of males in the medfly Ceratitis capitata (Diptera: Tephritidae)
4218Rendon, PAB, R. D.; Wood, R. J., Biological Journal of the Linnean Society, 101:351-359. 2010-01-16 00:00:00.
The Mediterranean fruit fly Ceratitis capitata (Wied.) normally produces the sexes in equal ratio but strains carrying the Y chromosome meiotic drive MP (male-producing) factor show an excess of males. This is associated with a loss of sperm, and abnormal sperm structure in terms of multiple axonemes, atypical numbers of mitochondrial derivatives, and sometimes an incorrect initial orientation of paracrystalline bodies to the axoneme. Sperms are bundled together within spermatocysts, and those with depleted content and abnormalities occur in the same MP testes as normal spermatocysts. The maximum number of sperms per cyst in control strains was 256, each with a single axoneme originating from a single centriole (kinetosome). The maximum per cyst in MP strains was also 256 but MP cysts contained up to 300 axonemes, providing evidence of multiplication of centrioles. The structural changes in MP sperm are discussed in relation to similar abnormalities reported in the mosquito Aedes aegypti inheriting the Y chromosome meiotic drive haplotype MD. The evolutionary significance of this phenomenon is considered. (C) 2010 The Linnean Society of London, Biological Journal of the Linnean Society, 2010, 101, 351-359.
Games in tetrads: Segregation, recombination, and meiotic drive
4215Haig, D, American Naturalist, 176:404-413. 2010-01-13 00:00:00.
The two alleles at a heterozygous locus segregate during meiosis, sometimes at meiosis I and sometimes at meiosis II. The timing of segregation is determined by the pattern of crossing-over between a locus and its attached centromeres. Genes near centromeres can exploit this process by driving against spores from which the genes separated at meiosis I. Other genes, located distal to centromeres, can benefit from driving against spores from which they separated at meiosis II. Asymmetric female meiosis is particularly susceptible to such forms of drive. Selection on modifiers of recombination favors changes in the location of chiasmata that increase the proportion of tetrads of high average fitness by changing the timing of segregation. Such changes increase the frequency of driving alleles. This source of selection on recombination does not depend on effects on linkage disequilibrium. Recombinational responses to meiotic drive may contribute to sex differences in overall recombination and sex differences in the localization of chiasmata.
Segregation analysis of a sex ratio distortion locus in congenic mice
4214Casellas, JF, C. R.; Verdugo, R. A.; Medrano, J. F., Journal of Heredity, 101:351-359. 2010-01-12 00:00:00.
The congenic HG.CAST-(D17Mit196-D17Mit190) (HQ17(hg/hg)) mouse strain showed a significant departure on the expected 50%/50% offspring sex ratio in more than 2400 progeny (55.7% females). The entire pedigree file included data from 13 nonoverlapping purebred generations and an F-2 cross with the C57BL/6J inbred strain. Offspring sex ratio data were analyzed on the basis of 40 purebred HQ17(hg/hg) sires and 29 F-1 HQ17(hg/hg) x B6 sires under a Bayesian Binomial segregation model accounting for 4 different autosomal inheritance models of gene action (i.e., additive, dominance, recessive, and overdominance) and X-linked and Y-linked loci. For each model, the segregation effect was evaluated as a single regression coefficient for all sires or assuming 2 independent regression coefficients accounting for offspring sex ratio departures in purebred and F-1 sires, respectively. The deviance information criterion clearly favored the autosomal dominance model with different regression coefficients for the 2 groups of sires. Under this model, the dominance effect increased the percentage of female offspring by 4.3% (HQ17(hg/hg) purebred sires) and 8.2% (F-1 sires) with the highest posterior density regions ranging from 0.5% to 10.6% and from 1.3% to 14.4%, respectively. This article provides significant evidence of genetic determinism for sex ratio distortion in the HQ17(hg/hg) strain and develops new analytical tools to perform segregation studies on dichotomous traits.
Segregation distortion in chicken and the evolutionary consequences of female meiotic drive in birds
4213Axelsson, EA, A.; Van, A. P.; Li, L.; Megens, H. J.; Vereijken, A. L. J.; Crooijmans, Rpma; Groenen, M. A. M.; Ellegren, H.; Willerslev, E.; Nielsen, R., Heredity, 105:290-298. 2010-01-11 00:00:00.
As all four meiotic products give rise to sperm in males, female meiosis result in a single egg in most eukaryotes. Any genetic element with the potential to influence chromosome segregation, so that it is preferentially included in the egg, should therefore gain a transmission advantage; a process termed female meiotic drive. We are aware of two chromosomal components, centromeres and telomeres, which share the potential to influence chromosome movement during meioses and make the following predictions based on the presence of female meiotic drive: (1) centromere-binding proteins should experience rapid evolution as a result of a conflict between driving centromeres and the rest of the genome; and (2) segregation patterns should be skewed near centromeres and telomeres. To test these predictions, we first analyze the molecular evolution of seven centromere-binding proteins in nine divergent bird species. We find strong evidence for positive selection in two genes, lending support to the genomic conflict hypothesis. Then, to directly test for the presence of segregation distortion, we also investigate the transmission of B9000 single-nucleotide polymorphisms in 197 chicken families. By simulating fair Mendelian meioses, we locate chromosomal regions with statistically significant transmission ratio distortion. One region is located near the centromere on chromosome 1 and a second region is located near the telomere on the p-arm of chromosome 1. Although these observations do not provide conclusive evidence in favour of the meiotic drive/genome conflict hypothesis, they do lend support to the hypothesis that centromeres and telomeres drive during female meioses in chicken. Heredity (2010) 105, 290-298; doi:10.1038/hdy.2009.193; published online 27 January 2010
Using underdominance to bi-stably transform local populations
4212Altrock, PMT, A.; Reeves, R. G.; Reed, F. A., Journal of Theoretical Biology, 267:62-75. 2010-01-10 00:00:00.
Underdominance refers to natural selection against individuals with a heterozygous genotype. Here, we analyze a single-locus underdominant system of two large local populations that exchange individuals at a certain migration rate. The system can be characterized by fixed points in the joint allele frequency space. We address the conditions under which underdominance can be applied to transform a local population that is receiving wildtype immigrants from another population. In a single population, underdominance has the benefit of complete removal of genetically modified alleles (reversibility) and coexistence is not stable. The two population system that exchanges migrants can result in internal stable states, where coexistence is maintained, but with additional release of wildtype individuals the system can be reversed to a fully wildtype state. This property is critically controlled by the migration rate. We approximate the critical minimum frequency required to result in a stable population transformation. We also concentrate on the destabilizing effects of fitness and migration rate asymmetry. Practical implications of our results are discussed in the context of utilizing underdominance to genetically modify wild populations. This is of importance especially for genetic pest management strategies, where locally stable and potentially reversible transformations of populations of disease vector species are of interest. (C) 2010 Elsevier Ltd. All rights reserved.
Molecular signature of epistatic selection: interrogating genetic interactions in the sex-ratio meiotic drive of Drosophila simulans
4222Chevin, LMB, H.; Montchamp-Moreau, C.; Hospital, F., Genetics Research, 91:171-182. 2009-01-20 00:00:00.
Fine scale analyses Of signatures of selection allow assessing quantitative aspects of a Species' evolutionary genetic history, such as the strength of selection on genes. When several selected loci lie in the same genomic region, their epistatic interactions may also be investigated. Here. we Study how the neutral polymorphism pattern was shaped by two close recombining loci that cause 'sex-ratio' meiotic drive in Drosophila simulans, as an example of strong selection with potentially strong epistasis. We compare the polymorphism data observed in a natural population with the results of forward stochastic simulations under several contexts of epistasis between the candidate loci for the drive. We compute the likelihood of different possible scenarios. in order to determine which configuration is most consistent with the data. Our results highlight that fine scale analyses of well-chosen candidate genomic regions provide information-rich data that can be used to investigate the genotype-phenotype-fitness map. which can hardly be Studied in genome-wide analyses. We also emphasize that initial conditions and time of observation (here, time after the Interruption Of a partial selective sweep) are crucial parameters in the interpretation of real data, while these are often overlooked in theoretical studies.
Assessment of transmission distortion on chromosome 6p in healthy individuals using tagSNPs
4231Santos, PSCH, J.; Schlattmann, P.; Konig, I. R.; Ziegler, A.; Uchanska-Ziegler, B., European Journal of Human Genetics, 17:1182-1189. 2009-01-09 00:00:00.
The best-documented example for transmission distortion (TD) to normal offspring are the t haplotypes on mouse chromosome 17. In healthy humans, TD has been described for whole chromosomes and for particular loci, but multiple comparisons have presented a statistical obstacle in wide-ranging analyses. Here we provide six high-resolution TD maps of the short arm of human chromosome 6 (Hsa6p), based on single-nucleotide polymorphism (SNP) data from 60 trio families belonging to two ethnicities that are available through the International HapMap Project. We tested all approximately 70 000 previously genotyped SNPs within Hsa6p by the transmission disequilibrium test. TagSNP selection followed by permutation testing was performed to adjust for multiple testing. A statistically significant evidence for TD was observed among male parents of European ancestry, due to strong and wide-ranging skewed segregation in a 730 kb long region containing the transcription factor-encoding genes SUPT3H and RUNX2, as well as the microRNA locus MIRN586. We also observed that this chromosomal segment coincides with pronounced linkage disequilibrium (LD), suggesting a relationship between TD and LD. The fact that TD may be taking place in samples not selected for a genetic disease implies that linkage studies must be assessed with particular caution in chromosomal segments with evidence of TD. European Journal of Human Genetics (2009) 17, 1182-1189; doi:10.1038/ejhg.2009.16; published online 4 March 2009
Multi-Locus Assortment (MLA) for transgene dispersal and elimination in mosquito populations
4230Rasgon, JL, PLOS One, 4:e5833. 2009-01-08 00:00:00.
: Replacement of wild-type mosquito populations with genetically modified versions is being explored as a potential strategy to control vector-borne diseases. Due to lower expected relative fitness of transgenic individuals, transgenes must be driven into populations for these scenarios to be successful. Several gene drive mechanisms exist in a theoretical sense but none are currently workable in mosquitoes. Even if strategies were workable, it would be very difficult to recall released transgenes in the event of unforeseen consequences. What is needed is a way to test transgenes in the field for feasibility, efficacy and safety prior to releasing an active drive mechanism. Methodology/Principal Findings: We outline a method, termed Multi-locus assortment (MLA), to spread transgenes into vector populations by the release of genetically-modified mosquitoes carrying multiple stable transgene inserts. Simulations indicate that [1] insects do not have to carry transgenes at more than 4 loci, [2] transgenes can be maintained at high levels by sequential small releases, the frequency of which depends on the construct fitness cost, and [3] in the case of unforeseen negative non-target effects, transgenes can be eliminated from the population by halting transgenic releases and/or mass releases of wild-type insects. We also discuss potential methods to create MLA mosquito strains in the laboratory. Conclusions/Significance: While not as efficient as active drive mechanisms, MLA has other advantages: [1] MLA strains can be constructed for some mosquito species with currently-available technology, [2] MLA will allow the ecological components of transgenic mosquito releases to be tested before actual gene drive mechanisms are ready to be deployed, [3] since MLA is not self-propagating, the risk of an accidental premature release into nature is minimized, and [4] in the case that active gene drive mechanisms prove impossible to develop, the MLA approach can be used as a back-up transgene dispersal mechanism for disease control efforts in some systems.
Large-scale selective sweep among Segregation Distorter chromosomes in African populations Drosophila melanogaster
4229Presgraves, DCG, P. R.; Cherukuri, A.; Lyttle, T. W., PLOS Genetics, 5:e1000463. 2009-01-07 00:00:00.
Segregation Distorter (SD) is a selfish, coadapted gene complex on chromosome 2 of Drosophila melanogaster that strongly distorts Mendelian transmission; heterozygous SD/SD(+) males sire almost exclusively SD-bearing progeny. Fifty years of genetic, molecular, and theory work have made SD one of the best-characterized meiotic drive systems, but surprisingly the details of its evolutionary origins and population dynamics remain unclear. Earlier analyses suggested that the SD system arose recently in the Mediterranean basin and then spread to a low, stable equilibrium frequency (1-5%) in most natural populations worldwide. In this report, we show, first, that SD chromosomes occur in populations in sub-Saharan Africa, the ancestral range of D. melanogaster, at a similarly low frequency (similar to 2%), providing evidence for the robustness of its equilibrium frequency but raising doubts about the Mediterranean-origins hypothesis. Second, our genetic analyses reveal two kinds of SD chromosomes in Africa: inversion-free SD chromosomes with little or no transmission advantage; and an African-endemic inversion-bearing SD chromosome, SD-Mal, with a perfect transmission advantage. Third, our population genetic analyses show that SD-Mal chromosomes swept across the African continent very recently, causing linkage disequilibrium and an absence of variability over 39% of the length of the second chromosome. Thus, despite a seemingly stable equilibrium frequency, SD chromosomes continue to evolve, to compete with one another, or evade suppressors in the genome.
Sex ratio distorter reduces sperm competitive ability in an insect
4243Price, TARB, A. J.; Avent, T. D.; Snook, R. R.; Hurst, G. D. D.; Wedell, N., Evolution, 62:1644-1652. 2008-01-21 00:00:00.
Selfish genetic elements (SGEs) are ubiquitous in animals and often associated with low male fertility due to reduced sperm number in male carriers. In the fruit fly Drosophila pseudoobscura, the meiotic driving X chromosome "sex ratio" kills Y-bearing sperm in carrier males (SR males), resulting in female only broods. We competed SR males against the ejaculates of noncarrying standard males (ST males), and quantified the number of sperm transferred by SR and ST males to females. We show that SR males are very poor sperm competitors, which is partly related to transfer of fewer sperm during mating. However, sperm numbers alone cannot explain the observed paternity reduction, indicating SR males' sperm may be of reduced quality, possibly due to damage during the killing of the noncarrying Y-sperm. The reduction in sperm competitive ability due to SR is large enough to potentially stabilize the spread of sex ratio drive through populations. The poor sperm competitive ability of SR males coupled with their low fitness as mates could favor increased remating by females to reduce paternity by SR males. Given the generally poor performance of SGE-carrying males in sperm competition, this may generate strong selective pressure favoring polyandry in many species.
Defects in nuclear transport enhance segregation distortion
4242McElroy, JMM, R. A.; McLean, J. R., Fly, 2:280-290. 2008-01-20 00:00:00.
The equal segregation of chromosomes into gametes is a central tenet of Mendelian genetics. It is this process that is responsible for generating predictable outcomes of crosses, as well as subjecting all chromosomes to the natural selective pressures that exert themselves on a population. Meiotic drive systems violate the principle, and result in a distortion of normal Mendelian ratios. Examples of such meiotic drive systems exist in many organisms, including insects, mammals and plants (reviewed in Lyttle).1 The most clearly understood of these is the Segregation Distorter (SD) system in Drosophila melanogaster. SD was first observed because males carrying one SD chromosome and one normal (SD+) chromosome failed to transmit the normal chromosome to their offspring, causing transmission ratios of near 100% of the SD chromosome.2 T
Transmission ratio distortion in Arabidopsis lyrata: effects of population divergence and the S-locus
4241Leppala, JB, J. S.; Schierup, M. H.; Savolainen, O., Heredity, 100:71-78. 2008-01-19 00:00:00.
We investigated transmission ratio distortion within an Icelandic population of Arabidopsis lyrata using 16 molecular markers unlinked to the S-locus. Transmission ratio distortion was found more often than expected by chance at the gametic level, but not at the genotypic or zygotic level. The gametic effect may be due to meiotic drive or selection acting postmeiotically. At the gametic level, 10.9% of the tests were significant, which is substantially lower than earlier observed in an interpopulation cross (allowing for differences in power)-suggesting that the high level of transmission ratio distortion in the interpopulation cross is due to population divergence. It is also substantially lower than previously observed in intrapopulation crosses at the self-incompatibility locus, suggesting inherent fitness differences of the self-incompatibility alleles. We discuss the possible role of deleterious alleles accumulating at loci under balancing selection. Zygotic effects play a larger role in the interpopulation cross than in the intrapopulation crosses suggesting that Dobzhansky-Muller incompatibilities may be accumulating between the widely diverged populations.
The evolution of sex-independent transmission ratio distortion involving multiple allelic interactions at a single locus in rice
4240Koide, YI, M.; Sawamura, N.; Nishimoto, D.; Matsubara, K.; Onishi, K.; Kanazawa, A.; Sano, Y., Genetics, 180:409-420. 2008-01-18 00:00:00.
Transmission ratio distortion (TRD) is frequently observed in inter-and intraspecific hybrids of plants, leading to a violation of Mendelian inheritance. Sex-independent TRD (siTRD) was detected in a hybrid between Asian cultivated rice and its wild ancestor. Here we examined how siTRD is controlled by the S-6 locus via a mechanism in which the S-6 allele acts as a gamete eliminator, and both the male and female gametes possessing the opposite allele (S-6(a)) are aborted only in heterozygotes (S-6/S-6(a)). Fine mapping revealed that the S-6 locus is located neaar the centromere of chromosome 6. Tescross experiments using near-isogenic lines (NILs) carrying either the S-6 or S-6(a) alleles revealed that Asian rice strains frequently harbor an additional allele (S-6(n)) the presence of which, in heterozygotic states (S-6/S-6(n) and S-6(a)/S-6(n)), does not result in siTRD. A prominent reduction in the nucleotide diversity of S-6 or S-6(a) carries relative to that of S-6(n) carries was detected in the chromosomal region. These results suggest that the two incompatible alleles (S-6/S-6(a)) arose independently from S-6(n) and established genetically discontinuous relationships between limited constituents of the Asian rice population.
A Killer–Rescue system for self-limiting gene drive of anti-pathogen constructs
4238Gould, FH, Yunxin; Legros, Mathieu; Lloyd, Alun L., Proceedings of the Royal Society B: Biological Sciences, 275:2823-2829. 2008-01-16 00:00:00.
A number of genetic mechanisms have been suggested for driving anti-pathogen genes into natural populations. Each of these mechanisms requires complex genetic engineering, and most are theoretically expected to permanently spread throughout the target species' geographical range. In the near term, risk issues and technical limits of molecular methods could delay the development and use of these mechanisms. We propose a gene-drive mechanism that can be self-limiting over time and space, and is simpler to build. This mechanism involves one gene that codes for toxicity (killer) and a second that confers immunity to the toxic effects (rescue). We use population-genetic models to explore cases with one or two independent insertions of the killer gene and one insertion of the rescue gene. We vary the dominance and penetrance of gene action, as well as the magnitude of fitness costs. Even with the fitness costs of 10 per cent for each gene, the proportion of mosquitoes expected to transmit the pathogen decreases below 5 per cent for over 40 generations after one 2?:?1 release (engineered?:?wild) or after four 1?:?2 releases. Both the killer and rescue genes will be lost from the population over time, if the rescue construct has any associated fitness cost. Molecular approaches for constructing strains are discussed.
Selective sweeps in a 2-locus model for sex-ratio meiotic drive in Drosophila simulans
4235Derome, NB, E.; Ogereau, D.; Veuille, M.; Montchamp-Moreau, C., Molecular Biology and Evolution, 25:409-416. 2008-01-13 00:00:00.
A way to identify loci subject to positive selection is to detect the signature of selective sweeps in given chromosomal regions. It is revealed by the departure of DNA polymorphism patterns from the neutral equilibrium predicted by coalescent theory. We surveyed DNA sequence variation in a region formerly identified as causing "sex-ratio" meiotic drive in Drosophila simulans. We found evidence that this system evolved by positive selection at 2 neighboring loci, which thus appear to be required simultaneously for meiotic drive to occur. The 2 regions are approximately 150-kb distant, corresponding to a genetic distance of 0.1 cM. The presumably large transmission advantage of chromosomes carrying meiotic drive alleles at both loci has not erased the individual signature of selection at each locus. This chromosome fragment combines a high level of linkage disequilibrium between the 2 critical regions with a high recombination rate. As a result, 2 characteristic traits of selective sweeps-the reduction of variation and the departure from selective neutrality in haplotype tests-show a bimodal pattern. Linkage disequilibrium level indicates that, in the natural population from Madagascar used in this study, the selective sweep may be as recent as 100 years.
The population genetics of using homing endonuclease genes in vector and pest management
4234Deredec, AB, A.; Godfray, H. C. J., Genetics, 179:2013-2026. 2008-01-12 00:00:00.
Homing endonuclease genes (HEGs) encode proteins that in the heterozygous state cause double- strand breaks in the homologous chromosome at the precise position opposite the HFG. If the double-strand break is repaired using the homologous chromosome, the HEG becomes homozygous, and this represents it Powerful genetic drive mechanism that might he used as it tool managing vector or pest populations. HEGs may be used to decrease population fitness to drive down population densities (possibly causing local extinction) or, in disease vectors, to knock out a gene required for pathogen transmission. The relative advantages of HEGs thia target viability or fecundity, that are active in one sex or both, and whose target. is expressed before or after homing are explored. The conditions under which escape mutants arise are also analyzed. A different strategy is to place HEGs on the Y chromosome that cause one, or more breaks on the X chromosome and so disrupt. sex ratio. This strategy can cause severe sex-ratio biases with efficiencies that depend on the details of sperm Competition and zygote mortality. This strategy is probably less susceptible to escape mutants, especially when multiple X shredders are used.
Targeting the X chromosome during spermatogenesis induces Y chromosome transmission ratio distortion and early dominant embryo lethality in Anopheles gambiae
4247Windbichler, NP, P. A.; Crisanti, A., PLOS Genetics, 4:1-9. 2008-01-05 00:00:00.
We have exploited the high selectivity of the homing endonuclease I-PpoI for the X-linked Anopheles gambiae 28S ribosomal genes to selectively target X chromosome carrying spermatozoa. Our data demonstrated that in heterozygous males, the expression of I-PpoI in the testes induced a strong bias toward Y chromosome-carrying spermatozoa. Notably, these male mosquitoes also induced complete early dominant embryo lethality in crosses with wild-type females. Morphological and molecular data indicated that all spermatozoa, irrespectively of the inheritance of the transgene, carried a substantial amount of I-PpoI protein that could attack the maternally inherited chromosome X of the embryo. Besides the obvious implications for implementing vector control measures, our data demonstrated the feasibility of generating synthetic sex distorters and revealed the intriguing possibility of manipulating maternally inherited genes using wild-type sperm cells carrying engineered endonucleases.
Meiotic drive and sex determination: molecular and cytological mechanisms of sex ratio adjustment in birds
4246Rutkowska, JB, A. V., Philosophical Transactions of the Royal Society B-Biological Sciences, 363:1675-1686. 2008-01-04 00:00:00.
Differences in relative fitness of male and female offspring across ecological and social environments should favour the evolution of sex-determining mechanisms that enable adjustment of brood sex ratio to the context of breeding. Despite the expectation that genetic sex determination should not produce consistent bias in primary sex ratios, extensive and adaptive modifications of offspring sex ratio in relation to social and physiological conditions during reproduction are often documented. Such discordance emphasizes the need for empirical investigation of the proximate mechanisms for modifying primary sex ratios, and suggests epigenetic effects on sex-determining mechanisms as the most likely candidates. Birds, in particular, are thought to have an unusually direct opportunity to modify offspring sex ratio because avian females are heterogametic and because the sex-determining division in avian meiosis occurs prior to ovulation and fertilization. However, despite evidence of strong epigenetic effects on sex determination in pre-ovulatory avian oocytes, the mechanisms behind such effects remain elusive. Our review of molecular and cytological mechanisms of avian meiosis uncovers a multitude of potential targets for selection on biased segregation of sex chromosomes, which may reflect the diversity of mechanisms and levels on which such selection operates in birds. Our findings indicate that pronounced differences between sex chromosomes in size, shape, size of protein bodies, alignment at the meiotic plate, microtubule attachment and epigenetic markings should commonly produce biased segregation of sex chromosomes as the default state, with secondary evolution of compensatory mechanisms necessary to maintain unbiased meiosis. We suggest that it is the epigenetic effects that modify such compensatory mechanisms that enable context-dependent and precise adjustment of primary sex ratio in birds. Furthermore, we highlight the features of avian meiosis that can be influenced by maternal hormones in response to environmental stimuli and may account for the precise and adaptive patterns of offspring sex ratio adjustment observed in some species.
Sexually antagonistic “Zygotic Drive” of the sex Chromosomes
4245Rice, WRG, S.; Friberg, U., PLOS Genetics, 4:e1000313. 2008-01-03 00:00:00.
Genomic conflict is perplexing because it causes the fitness of a species to decline rather than improve. Many diverse forms of genomic conflict have been identified, but this extant tally may be incomplete. Here, we show that the unusual characteristics of the sex chromosomes can, in principle, lead to a previously unappreciated form of sexual genomic conflict. The phenomenon occurs because there is selection in the heterogametic sex for sex-linked mutations that harm the sex of offspring that does not carry them, whenever there is competition among siblings. This harmful phenotype can be expressed as an antagonistic green-beard effect that is mediated by epigenetic parental effects, parental investment, and/or interactions among siblings. We call this form of genomic conflict sexually antagonistic "zygotic drive'', because it is functionally equivalent to meiotic drive, except that it operates during the zygotic and postzygotic stages of the life cycle rather than the meiotic and gametic stages. A combination of mathematical modeling and a survey of empirical studies is used to show that sexually antagonistic zygotic drive is feasible, likely to be widespread in nature, and that it can promote a genetic "arms race'' between the homo- and heteromorphic sex chromosomes. This new category of genomic conflict has the potential to strongly influence other fundamental evolutionary processes, such as speciation and the degeneration of the Y and W sex chromosomes. It also fosters a new genetic hypothesis for the evolution of enigmatic fitness-reducing traits like the high frequency of spontaneous abortion, sterility, and homosexuality observed in humans.
Selfish genetic elements promote polyandry in a fly
4244Price, TARH, D. J.; Lewis, Z.; Hurst, G. D. D.; Wedell, N., Science, 322:1241-1243. 2008-01-02 00:00:00.
It is unknown why females mate with multiple males when mating is frequently costly and a single copulation often provides enough sperm to fertilize all a female's eggs. One possibility is that remating increases the fitness of offspring, because fertilization success is biased toward the sperm of high- fitness males. We show that female Drosophila pseudoobscura evolved increased remating rates when exposed to the risk of mating with males carrying a deleterious sex ratio- distorting gene that also reduces sperm competitive ability. Because selfish genetic elements that reduce sperm competitive ability are generally associated with low genetic fitness, they may represent a common driver of the evolution of polyandry.
Homing endonuclease mediated gene targeting in Anopheles gambiae cells and embryos
4259Windbichler, NP, P. A.; Catteruccia, F.; Ranson, H.; Burt, A.; Crisanti, A., Nucleic Acids Research, 35:5922-5933. 2007-01-17 00:00:00.
Homing endonuclease genes (HEGs) are selfish genetic elements that combine the capability to selectively disrupt specific gene sequences with the ability to rapidly spread from a few individuals to an entire population through homologous recombination repair events. Because of these properties, HEGs are regarded as promising candidates to transfer genetic modifications from engineered laboratory mosquitoes to wild-type populations including Anopheles gambiae the vector of human malaria. Here we show that I-SceI and I-PpoI homing endonucleases cleave their recognition sites with high efficiency inA. gambiae cells and embryos and we demonstrate HEG-induced homologous and non-homologous repair events in a variety of functional assays. We also propose a gene drive system for mosquitoes that is based on our finding that I-PpoI cuts genomic rDNA located on the X chromosome in A. gambiae, which could be used to selectively incapacitate X-carrying spermatozoa thereby imposing a severe male-biased sex ratio.
Viability effects and not meoitic drive cause dramatic departures from Mendelian inheritance for malic enzyme in hybrids of Tigriopus californicus populations
4258Willett, CSB, J. N., Journal of Evolutionary Biology, 20:1196-1205. 2007-01-16 00:00:00.
The genetic basis of post-zygotic reproductive isolation is beginning to be untangled in closely related species, but less is known about the genetics of reproductive isolation between divergent populations. Here, two genes encoding malic enzyme (ME) are isolated from the copepod Tigriopus californicus and their influence upon lowered viability in F-2 hybrids of genetically divergent populations is determined. Each ME gene has diverged extensively between T. californicus populations and one gene shows evidence for a recent selective sweep. Segregation patterns of genotypes for both ME genes in adult F-2 hybrids reveal dramatic departures from Mendelian inheritance, deviations that are not seen in F-2 nauplii implying that selection is acting during development based upon the genotype at these ME genes. These results imply that selection against deleterious gene combinations and not aberrant segregation (i.e. meiotic drive) is likely to lead to dramatic departures from Mendelian inheritance observed in these crosses.
A sex-ratio meiotic drive system in Drosophila simulans. I: An autosomal suppressor
4256Tao, YM, J. P.; Araripe, L.; Ke, Y.; Hartl, D. L., PLOS Biology, 5:2560-2575. 2007-01-14 00:00:00.
Sex ratio distortion (sex-ratio for short) has been reported in numerous species such as Drosophila, where distortion can readily be detected in experimental crosses, but the molecular mechanisms remain elusive. Here we characterize an autosomal sex-ratio suppressor from D. simulans that we designate as not much yang (nmy, polytene chromosome position 87F3). Nmy suppresses an X-linked sex-ratio distorter, contains a pair of near-perfect inverted repeats of 345 bp, and evidently originated through retrotransposition from the distorter itself. The suppression is likely mediated by sequence homology between the suppressor and distorter. The strength of sex-ratio is greatly enhanced by lower temperature. This temperature sensitivity was used to assign the sex-ratio etiology to the maturation process of the Y-bearing sperm, a hypothesis corroborated by both light microscope observations and ultrastructural studies. It has long been suggested that an X-linked sex-ratio distorter can evolve by exploiting loopholes in the meiotic machinery for its own transmission advantage, which may be offset by other changes in the genome that control the selfish distorter. Data obtained in this study help to understand this evolutionary mechanism in molecular detail and provide insight regarding its evolutionary impact on genomic architecture and speciation.
A sex-ratio meiotic drive system in Drosophila simulans. II: An X-linked distorter
4255Tao, YA, L.; Kingan, S. B.; Ke, Y.; Xiao, H.; Hartl, D. L., PLOS Biology, 5:2576-2588. 2007-01-13 00:00:00.
The evolution of heteromorphic sex chromosomes creates a genetic condition favoring the invasion of sex-ratio meiotic drive elements, resulting in the biased transmission of one sex chromosome over the other, in violation of Mendel's first law. The molecular mechanisms of sex-ratio meiotic drive may therefore help us to understand the evolutionary forces shaping the meiotic behavior of the sex chromosomes. Here we characterize a sex-ratio distorter on the X chromosome (Dox) in Drosophila simulans by genetic and molecular means. Intriguingly, Dox has very limited coding capacity. It evolved from another X-linked gene, which also evolved de nova. Through retrotransposition, Dox also gave rise to an autosomal suppressor, not much yang (Nmy). An RNA interference mechanism seems to be involved in the suppression of the Dox distorter by the Nmy suppressor. Double mutant males of the genotype dox; nmy are normal for both sex-ratio and spermatogenesis. We postulate that recurrent bouts of sex-ratio meiotic drive and its subsequent suppression might underlie several common features observed in the heterogametic sex, including meiotic sex chromosome inactivation and achiasmy.
Neurospora spore killers Sk-2 and Sk-3 suppress meiotic silencing by unpaired DNA
4254Raju, NBM, R. L.; Shiu, P. T., Genetics, 176:43-52. 2007-01-12 00:00:00.
In Neurosphora, crassa., pairing of homologous DNA segments is monitored during meiotic prophase I. Any genes not paired with a homolog, as well as any paired homologs of that gene, are silenced during the sexual phase by a mechanism known as meiotic silencing by unpaired DNA (MSUD). Two genes required for MSUD have been described previously: Sad-1 (Suppressor of ascus dominance), encoding an RNA-directed RNA polymerase, and sad-2, encoding a protein that controls the perinuclear localization of SAD-1. Inactivation of either sad-1 or sad-2 suppresses MSUD. We have now shown that MSUD is also suppressed by either of two Spore killer strains, Sk-2 and Sk-3. These were both known to contain a haplotype segment that behaves as a meiotic drive element in heterozygous crosses of killer X sensitive. Progeny ascospores not carrying the killer element fail to mature and are inviable. Crosses homozygous for either of the killer haplotypes suppress MSUD even though ascospores are not killed. The killer activity maps to the same 30-unit-long region within which recombination is suppressed in killer X sensitive crosses. We suggest that the region contains a suppressor of MSUD.
Meiotic drive by the Y-linked D gene in Aedes aegypti (L.) (Diptera : Culicidae) is associated with disruption of spermiogenesis, leading to premature senescence of spermatozoa
4253Owusu-Daaku, KOB, R. D.; Wood, R. J., Arthropod Structure & Development, 36:233-243. 2007-01-11 00:00:00.
Y chromosome meiotic drive in the mosquito Aedes aegypti, due to the gene D (Distorter) in coupling with M (male determination) [the MD haplotype], is associated with spermiogenic disruption, leading to senescence, at a rate Proportionate to male excess. Spermiogenesis was compared between 'Enhanced Mutant' males with a strongly female-depleted sex ratio (8.9% females), 'Mutant' males showing a lesser degree of distortion (38.3% females), and two controls with normal sex ratios (51.2% and 49.2% females). Sections of testes dissected front mature pupae and adults aged 0, 4, 8, 12 and 16 days were examined by transmission electron microscopy. A difference between Mutant and control spermiogenesis was apparent as early as the pupal stage when some Mutant spermatids showed extra tail elements (axonemes and/or mitochondrial derivatives). The same was true of Enhanced Mutant males but to a more extreme degree. Sperm senescence was evident in Enhanced Mutant testes from day 0 of adult life but in Mutant testes not until day 4. Progressive disorganisation was associated with many loose organelles, and disturbance of the anterior-posterior axis of gamete differentiation within the testis. Degenerative changes of a similar kind in the controls did not become apparent until day 8. These findings are discussed with respect to other characteristics of this meiotic drive system, in terms of a theory of inhibition of reduction division in spermatogenesis associated with fragmentation of the X chromosome, leading to the formation of a restitution nucleus as early as rnetaphase 1. (c) 2007 Elsevier Ltd. All rights reserved.
Identification and characterization of segregation distortion loci along chromosome 5B in tetraploid wheat
4252Kumar, SG, B. S.; Faris, J. D., Molecular Genetics and Genomics, 278:187-196. 2007-01-10 00:00:00.
Segregation distortion genes are widespread in plants and animals and function by their effect on competition among gametes for preferential fertilization. In this study, we evaluated the segregation distortion of molecular markers in multiple reciprocal backcross populations derived from unique cytogenetic stocks involving the durum cultivar Langdon (LDN) and wild emmer accessions that allowed us to study the effects of chromosome 5B in isolation. No segregation distortion of female gametes was observed, but three populations developed to analyze segregation of male gametes had genomic regions containing markers with skewed segregation ratios. One region of distortion was due to preferential transmission of LDN alleles over wild emmer alleles through male gametes. Another region required the presence of LDN 5B chromosomes in the female for preferential fertilization by male gametes harboring LDN alleles indicating that the corresponding genes in the female gametes can govern genes affecting segregation distortion of male gametes. A third region of distortion was the result of preferential transmission of wild emmer alleles over LDN alleles through male gametes. These results indicate the existence of different distorter/meiotic drive elements among different genotypes and show that distortion factors along wheat chromosome 5B differ in chromosomal location as well as underlying mechanisms.
Chromosome-wide linkage disequilibrium as a consequence of meiotic drive
4249Dyer, KAC, B.; Jaenike, J., Proceedings of the National Academy of Sciences of the United States of America, 104:1587-1592. 2007-01-07 00:00:00.
Adaptation by natural selection proceeds most efficiently when alleles compete solely on the basis of their effects on the survival and reproduction of their carriers. A major condition for this is equal Mendelian segregation, but meiotic drive can short-circuit this process. The evolution of drive often involves multiple, interacting genetic components, together with enhancers and suppressors of drive. Chromosomal inversions that suppress crossing over are also frequently associated with drive systems. This study investigates the effects of these processes on patterns of molecular evolution in the fly Drosophila recens, which is polymorphic for a driving X chromosome (X-D). Whereas standard wild-type chromosomes exhibit high levels of polymorphism at multiple loci, all of the X-D chromosomes effectively carry a single multilocus haplotype that spans at least 130 cM. The X-D is associated with a complex set of inversions that completely suppresses recombination between the standard wild-type chromosome and X-D in heterozygous females, which maintain nonrandom associations among loci that presumably interact epistatically for the expression of drive. The long-term costs of foregoing recombination may be substantial; in combination with its low equilibrium frequency, this makes the XD chromosome susceptible to the accumulation of deleterious mutations. Consistent with this, X-D chromosomes are apparently fixed for a recessive mutation that causes female sterility. Thus, the X-D in D. recens appears to be in chromosome-wide linkage disequilibrium and in the early stages of mutational degradation.
The hitchhiking effect of an autosomal meiotic drive gene
4263Chevin, LMH, F., Genetics, 173:1829-1832. 2006-01-21 00:00:00.
Transmission-ratio distortion is a departure from a 1:1 segregation of alleles in the gametes of a heterozygous individual. The so-called driving allele is strongly selected regardless of its effect on the fitness of the carrying individual. It may then have an important impact on neutral polymorphism due to the genetic hitchhiking effect. We study this hitchhiking effect in the case of true meiotic drive in autosomes and show that it is more dependent on the recombination rate than in the classical case of a gene positively selected at the organism level.
Population dynamics of an endogenous meiotic drive system in Aedes aegypti in Trinidad
4260Cha, SJC, D. D.; Severson, D. W., American Journal of Tropical Medicine and Hygiene, 75:70-77. 2006-01-18 00:00:00.
An endogenous meiotic drive system was previously reported to be segregating in the yellow fever mosquito Aedes aegypti L. (Diptera: Culicidae) population in Trinidad. The meiotic driver (M-D) is tightly linked to the male determining locus and selectively targets sensitive responders linked to the female determining allele, causing fragmentation of female gametes. This results in highly male-biased progeny. The M-D system was initially studied as a genetic tool for population control with limited success, but recently interest has focused on its potential for population replacement. This study examines the distribution and dynamics of the M-D system in Trinidad natural populations. We obtained ovitrap samples from seven geographically distinct regions and determined the allele frequencies of the driver (M-D) and sensitive (m(s)) versus insensitive (m(i)) responders, respectively. Frequencies of the M-D allele ranged from 0.1 to 0.5 and were low at the two major port cities, Port of Spain and San Fernando, suggesting the effects of frequent immigration by non-driving genotypes. Frequencies of the m(i) allele ranged from 0.4 to 0.7, suggesting the effects of strong selection by the driver. In addition, our results show that the driver and sensitivity of responders in the Trinidad populations are highly polymorphic. Continued studies of the dynamics of the M-D system in natural populations are critical to considerations of its use in population replacement.
Fitness effects of X chromosome drive in the stalk-eyed fly, Cyrtodiopsis dalmanni
4271Wilkinson, GSJ, P. M.; Kelleher, E. S.; Muscedere, M. L.; Lorsong, A., Journal of Evolutionary Biology, 19:1851-1860. 2006-01-09 00:00:00.
Sex-ratio (SR) males produce predominantly female progeny because most Y chromosome sperm are rendered nonfunctional. The resulting transmission advantage of X-SR chromosomes should eventually cause population extinction unless segregation distortion is masked by suppressors or balanced by selection. By screening male stalk-eyed flies, Cyrtodiopsis dalmanni, for brood sex ratio we found unique SR alleles at three X-linked microsatellite loci and used them to determine if SR persists as a balanced polymorphism. We found that X-SR/X-ST females produced more offspring than other genotypes and that SR males had lower sperm precedence and exhibited lower fertility when mating eight females in 24 h. Adult survival was independent of SR genotype but positively correlated with eye span. We infer that the SR polymorphism is likely maintained by a combination of weak overdominance for female fecundity and frequency dependent selection acting on male fertility. Our discovery of two SR haplotypes in the same population in a 10-year period further suggests that this SR polymorphism may be evolving rapidly.
Segregation distortion in Arabidopsis C24/Col-0 and Col-0/C24 recombinant inbred line populations is due to reduced fertility caused by epistatic interaction of two loci
4270Torjek, OW-W, H.; Meyer, R. C.; von Korff, M.; Kusterer, B.; Rautengarten, C.; Altmann, T., Theoretical and Applied Genetics, 113:1551-1561. 2006-01-08 00:00:00.
A new large set of reciprocal recombinant inbred lines (RILs) was created between the Arabidopsis accessions Col-0 and C24 for quantitative trait mapping approaches, consisting of 209 Col-0 x C24 and 214 C24 x Col-0 F-7 RI lines. Genotyping was performed using 110 evenly distributed framework single nucleotide polymorphism markers, yielding a genetic map of 425.70 cM, with an average interval of 3.87 cM. Segregation distortion (SD) was observed in several genomic regions during the construction of the genetic map. Linkage disequilibrium analysis revealed an association between a distorted region at the bottom of chromosome V and a non-distorted region on chromosome IV. A detailed analysis of the RILs for these two regions showed that an SD occurred when homozygous Col-0 alleles on chromosome IV coincided with homozygous C24 alleles at the bottom of chromosome V. Using nearly isogenic lines segregating for the distorted region we confirmed that this genotypic composition leads to reduced fertility and fitness.
Male biased sex ratio in the Mediterranean fruit fly Ceratitis capitata, an example of Y-chromosome meiotic drive
4268Shahjahan, RMR, P. A.; Cook, L. M.; Wood, R. J., Heredity, 96:464-470. 2006-01-06 00:00:00.
A case of Y-chromosome meiotic drive is reported in the Mediterranean fruit fly Ceratitis capitata. It arose in an irradiated male and results in excess of males. Male excess is inherited strictly from father to son. A Y-linked factor MP (male producer) is proposed. Higher drive can be selected, but distortion declines rapidly in the absence of selection. Hybrid males from crosses between driving males and nondriving females also show drive but to a reduced extent, suggesting the action of suppressors. Sex ratio distortion is independent of postzygotic mortality, and is not associated with an obvious chromosome arrangement. Spermiogenesis in driving males is characterised by abnormalities in sperm tails and reduced numbers in some sperm cysts, whereas neighbouring cysts of the same MP testis are essentially wild type. The average number of missing sperms plus deformed sperms approximates to the average depression in female recovery among the progenies of siblings, suggesting that most of the missing or abnormal sperms would have given rise to females, that is, they would have been X-bearing. To explain the heterogeneity between neighbouring cysts, a theory is proposed that links it to variation in X-chromosome sensitivity to MP, arising by random suppression of the genetic basis of sensitivity during the six mitotic divisions in the origin of the cyst from its stem cell before meiosis.
The maize Ab 10 meiotic drive system maps to supernumerary sequences in a large complex haplotype
4267Mroczek, RJM, J. R.; Luce, A. C.; Hiatt, E. N.; Dawe, R. K., Genetics, 174:145-154. 2006-01-05 00:00:00.
The meiotic drive system on maize abnormal chromosome 10 (Ab10) is contained within a terminal domain of chromatin that extends the long arm of Ab10 to similar to 1.3 times the size of normal chromosome 10L. Ab10 type I (Ab10-I) does not recombine with normal chromosome 10 (N10) over an similar to 32-cM terminal region of the long arm. Comparative RFLP mapping demonstrates that multiple independent rearrangements are responsible for the current organization of Ab10-I, including a set of nested inversions and at least one long supernumerary segment at the end of the chromosome. Four major meiotic drive functions, i.e., the recombination effect, smd3, 180-bp neocentromere activity, and the distal tip function, all map to the distal supernumerary segment. TR-1-mediated neocentromere activity (the fifth known drive function) is nonessential in the type II variant of Ab10 and maps to a central region that may include a second supernumerary insertion. Both neocentromere activity and the recombination effect behave as dominant gain-of-function mutations, consistent with the view that meiotic drive involves new or alien gene products. These and other data suggest that the Ab10 meiotic drive system was initially acquired from a related species and that a complex haplotype evolved around it.
Organization of the sex-ratio meiotic drive region in Drosophila simulans
4266Montchamp-Moreau, CO, D.; Chaminade, N.; Colard, A.; Aulard, S., Genetics, 174:1365-1371. 2006-01-04 00:00:00.
Sex-ratio meiotic drive is the preferential transmission of the X chromosome by XY males, which occurs in several Drosophila species and results in female-biased progeny. Although the trait has long been known to exist, its molecular basis remains completely unknown. Here we report a fine-mapping experiment designed to characterize the major drive locus on a sex-ratio X chromosome of Drosophila simulans originating from the Seychelles (X-SRG). This primary locus was found to contain two interacting elements at least, both of which are required for drive expression. One of them was genetically tracked to a tandem duplication containing six annotated genes (Trf2, CG32712, CG12125, CG1440, CG12123, org-1), and the other to a candidate region located similar to 110 kb away and spanning seven annotated genes. RT-PCR showed that all but two of these genes were expressed in the testis of both sex-ratio and standard males. In situ hybridization to polytene chromosomes revealed a complete association of the duplication with the sex-ratio trait in random samples of X chromosomes from Madagascar and Reunion.
Sex-ratio meiotic drive in Drosophila simulans: cellular mechanism, candidate genes and evolution
4265Montchamp-Moreau, C, Biochemical Society Transactions, 34:562-565. 2006-01-03 00:00:00.
The sex-ratio trait, reported in a dozen Drosophila species, is a type of naturally occurring meiotic drive in which the driving elements are located on the X chromosome. Typically, as the result of a shortage of Y bearing spermatozoa, males carrying a sex-ratio X chromosome produce a large excess of female offspring. The presence of sex-ratio chromosomes in a species can have considerable evolutionary consequences, because they can affect individual fitness and trigger extended intragenomic conflict. Here, I present the main results of the study performed in Drosophilosimulans. In this species, the loss of Y-bearing spermatozoa is related to the inability of the Y chromosome sister-chromatids to separate properly during meiosis II. Fine genetic mapping has shown that the primary sex-ratio locus on the X chromosome contains two distorter elements acting synergistically, both of which are required for drive expression. one element has been genetically mapped to a tandem duplication. To infer the natural history of the trait, the pattern of DNA sequence polymorphism in the surrounding chromosomal region is being analysed in natural populations of D. simulans harbouring sex-ratio X chromosomes. Initial results have revealed the recent spread of a distorter allele.
Transmission ratio distortion in the human body louse, Pediculus humanus (Insecta : Phthiraptera)
4264McMeniman, CJB, S. C., Heredity, 96:63-68. 2006-01-02 00:00:00.
We studied inheritance at three microsatellite loci in eight F-1 and two F-2 families of the body (clothes) louse of humans, Pediculus humanus. The alleles of heterozygous female-parents were always inherited in a Mendelian fashion in these families. Alleles from heterozygous male-parents, however, were inherited in two different ways: (i) in a Mendelian fashion and (ii) in a non-Mendelian fashion, where males passed to their offspring only one of their two alleles, that is, 100% nonrandom transmission. In male body lice, where there was non-Mendelian inheritance, the paternally inherited set of alleles was eliminated. We interpret this pattern of inheritance as evidence for extreme transmission ratio distortion of paternal alleles in this species.
Maternal transmission ratio distortion at the mouse Om locus results from meiotic drive at the second meiotic division
4283Wu, GMH, L. P.; Han, Z. M.; Gao, S. R.; Latham, K. E.; de Villena, F. P. M.; Sapienza, C., Genetics, 170:327-334. 2005-01-21 00:00:00.
We have observed maternal transmission ratio distortion (TRD) in favor of DDK alleles at the Ovum mutant (Om) locus on mouse chromosome I I among the offspring of (C57BL/6 X DDK) F, females and C57BL/6 males. Although significant lethality occurs in this backcross (similar to 50%), differences in the level of TRD found in recombinant vs. nonrecombinant chromosomes among offspring argue that TRD is due to nonrandom segregation of chromatids at the second meiotic division, i.e., true meiotic drive. We tested this hypothesis directly, by determining the centromere and Om genotypes of individual chromatids in zygote stage embryos. We found similar levels of TRD in favor of DDK alleles at Om in the female pronucleus and TRD in favor of C57BL/6 alleles at Om in the second polar body. In those embryos for which complete dyads have been reconstructed, TRD was present only in those inheriting heteromorphic dyads. These results demonstrate that meiotic drive occurs at MII and that preferential death of one genotypic class of embryo does not play a large role in the TRD.
Evidence of susceptibility and resistance to cryptic X-linked meiotic drive in natural populations of Drosophila melanogaster
4281Reed, FAR, R. G.; Aquadro, C. F., Evolution, 59:1280-1291. 2005-01-19 00:00:00.
There is mounting evidence consistent with a general role of positive selection acting on the Drosophila melanogaster X-chromosome. However, this positive selection need not necessarily arise from forces that are adaptive to the organism. Nonadaptive meiotic drive may exist on the X-chromosome and contribute to forces of selection. Females from a reference D. melanogaster line, containing the X-linked marker white, were crossed to males from 49 isofemale lines established from seven African and five non-African natural populations to detect naturally occurring meiotic drive. Several lines exhibited a departure from expected Mendelian transmission of X-chromosomes to the third generation (F-2) offspring, particularly those from hybrid African male parents. F2 viability was not correlated with skewed chromosomal inheritance. However, a significant difference in viability between cosmopolitan and tropical African crosses was observed. Recombination analysis supports the presence of a male-acting meiotic drive element near the centromeric region of the X-chromosome and putative recessive autosomal drive suppression. There is also evidence of another female-acting drive element linked to white. The possible role meiotic drive may contribute in shaping levels of genetic variation in D. melanogaster, and additional ways to test this hypothesis are discussed.
Transposable element insertion location bias and the dynamics of gene drive in mosquito populations
4280Rasgon, JLG, F., Insect Molecular Biology, 14:493-500. 2005-01-18 00:00:00.
Some vector-borne disease control strategies using transgenic mosquitoes require transgene spread to high frequency in populations. Transposable elements (TEs) are DNA sequences that replicate and transpose within the genomes of other organisms and may therefore be represented in the next generation in higher frequencies than predicted by Mendelian segregation. This over-representation has allowed some TEs to spread through natural populations. Transgenes incorporated within a TE sequence are expected to be driven into populations as long as there is a positive balance between fitness costs and over-representation. Models have been used to examine parameters that affect this balance but did not take into account biased insertion of TEs to linked sites in the genome. A simulation model was created to examine the impact of insertion bias on TE spread in mosquito populations. TEs that induce no fitness costs are predicted to increase in frequency over a wide range of parameter values but spread is slower for lower levels of transposition and non-local movement. If TEs are costly, high proportions of local movement can slow or halt spread. To function as a robust transgene drive mechanism a TE should replicate and transpose > 10%/insert/generation, induce < 1% fitness cost/insert, and move preferentially to unlinked sites in the genome.
Segregation distortion in hybrids between the Bogota and USA subspecies of Drosophila pseudoobscura
4279Orr, HAI, S., Genetics, 169:671-682. 2005-01-17 00:00:00.
We show that, contrary to claims in the literature, "sterile" males resulting from the cross of the Bogota and USA subspecies of Drosophila pseudoobscura are weakly fertile. Surprisingly, these hybrid males produce almost all daughters when crossed to females of any genotype (pure Bogota, pure USA, hybrid F-1). Several lines of evidence suggest that this sex ratio distortion is caused by sex chromosome segregation distortion in hybrid males. We genetically analyze this normally cryptic segregation distortion and show that it involves several regions of the Bogota X chromosome that show strong epistatic interactions with each other. We further show that segregation distortion is normally masked within the Bogota subspecies by amosomal suppressors. Our analysis shows that the genetic basis of hybrid segregation distortion is similar to that of hybrid male sterility between the same subspecies. Indeed the severity of segregation distortion is correlated with the severity of sterility among hybrids. We discuss the possibility that hybrid sterility in this paradigmatic case of incipient speciation is caused by segregation distortion.
Degeneration and domestication of a selfish gene in yeast: Molecular evolution versus site-directed mutagenesis
4278Koufopanou, VB, A., Molecular Biology and Evolution, 22:1535-1538. 2005-01-16 00:00:00.
VDE is a homing endonuclease gene in yeasts with an unusual evolutionary history including horizontal transmission, degeneration, and domestication into the mating-type switching locus HO. We investigate here the effects of these features on its molecular evolution. In addition, we correlate rates of evolution with results from site-directed mutagenesis studies. Functional elements have, lower rates of evolution than degenerate ones and higher conservation at functionally important sites. However, functionally important and unimportant sites are equally likely to have been involved in the evolution of new function during the domestication of VDE into HO. The domestication event also indicates that VDE has been lost in some species and that VDE has been present in yeasts for more than 50 Myr.
Evolution of autosomal suppression of the sex-ratio trait in Drosophila
4302Vaz, SCC, A. B., Genetics, 166:265-277. 2004-01-20 00:00:00.
The sex-ratio trait is the production of female-biased progenies due to X-linked meiotic drive in males of several Drosophila species. The driving X chromosome (called SR) is not fixed due to at least two stabilizing factors: natural selection (favoring ST, the nondriving standard X) and drive suppression by either Y-linked or autosomal genes. The evolution of autosomal suppression is explained by Fisher's principle, a mechanism of natural selectin that leads to equal proportion of males and females in a sexually reproducing population. In fact, sex-ratio expression is partially suppressed by autosomal genes in at least three Drosophila species. The population genetics of this system is not completely understood. In this article we develop a mathematical model for the evolution of autosomal suppressors of SR (sup alleles) and show that: (i) an autosomal suppressor cannot invade when SR is very deleterious in males (c < 1/3, where c is the fitness of SR/Y males); (ii) "SR/ST, sup/+" polymorphisms occur when SR is partially deleterious (similar to0.3 < c < 1); while (iii) SR neutrality (c = 1) results in sup fixation and thus in total abolishment of drive. So, surprisingly, as long as there is any selection against SR/Y males, neutral autosomal suppressors will not be fixed. In that case, when a polymorphic equilibrium exists, the average female proportion in SR/Y males' progeny is given approximately by (ac + 1 - a + roota(9) ( c + 1 )(2) + 1 - 4ac)/4ac, where a is the fitness of SR/ST females.
B chromosomes and genome size in flowering plants
4301Trivers, RB, A.; Palestis, B. G., Genome, 47:1-8. 2004-01-19 00:00:00.
B chromosomes are extra chromosomes found in some, but not all, individuals within a species, often maintained by giving themselves an advantage in transmission, i.e. they drive. Here we show that the presence of B chromosomes correlates to and varies strongly and positively with total genome size (excluding the Bs and corrected for ploidy) both at a global level and via a comparison of independent taxonomic contrasts. B chromosomes are largely absent from species with small genomes; however, species with large genomes are studied more frequently than species with small genomes and Bs are more likely to be reported in well-studied species. We controlled for intensity of study using logistic regression. This regression analysis also included effects of degree of outbreeding, which is positively associated with Bs and genome size, and chromosome number, which is negatively associated with Bs and genome size, as well as variable ploidy (more than one ploidy level in a species). Genome size, breeding system and chromosome number all contribute independently to the distribution of B chromosomes, while variable ploidy does not have a significant effect. The genome size correlates are consistent with reduced selection against extra DNA in species with large genomes and with increased generation of B sequences from large A genomes.
Evolution of divergent DNA recognition specificities in VDE homing endonucleases from two yeast species
4299Posey, KLK, V.; Burt, A.; Gimble, F. S., Nucleic Acids Research, 32:3947-3956. 2004-01-17 00:00:00.
Homing endonuclease genes (HEGs) are mobile DNA elements that are thought to confer no benefit to their host. They encode site-specific DNA endonucleases that perpetuate the element within a species population by homing and disseminate it between species by horizontal transfer. Several yeast species contain the VMA1 HEG that encodes the intein-associated VMA1-derived endonuclease (VIDE). The evolutionary state of VDEs from 12 species was assessed by assaying their endonuclease activities. Only two enzymes are active, PI-ZbaI from Zygosaccharomyces bailii and PI-ScaI from Saccharomyces cariocanus. PI-ZbaI cleaves the Z-bailii recognition sequence significantly faster than the Saccharomyces cerevisiae site, which differs at six nucleotide positions. A mutational analysis indicates that PI-ZbaI cleaves the S.cerevisiae substrate poorly due to the absence of a contact that is analogous to one made in PI-SceI between Gln-55 and nucleotides +9/+10. PI-ZbaI cleaves the Z.bailii substrate primarily due to a single base-pair substitution (A/T+5 --> T/A(+5)). Structural modeling of the PI-ZbaI/DNA complex suggests that Arg-331, which is absent in PI-SceI, contacts T/A(+5), and the reduced activity observed in a PI-ZbaI R331 A mutant provides evidence for this interaction. These data illustrate that homing endonucleases evolve altered specificity as they adapt to recognize alternative target sites.
Rapid suppression of drive for a parasitic B chromosome
4298Perfectti, FC, J. M.; Mesa, J. A.; Cabrero, J.; Bakkali, M.; Lopez-Leon, M. D.; Camacho, J. P. M., Cytogenetic and Genome Research, 106:338-343. 2004-01-16 00:00:00.
The persistence of parasitic B chromosomes in natural populations depends on both B ability to drive and host response to counteracting it. In the grasshopper Eyprepocnemis plorans, the B-24 chromosome is the most widespread B chromosome variant in the Torrox area ( Malaga, Spain). Its evolutionary success, replacing its ancestral neutralized B variant, B-2, was based on meiotic drive in females, as we showed in a sample caught in 1992. In females collected six years later, mean B-24 transmission ratio (k(B)) was 0.523, implying a very rapid decrease from the 0.696 observed in 1992. This shows that B-24 neutralization is running very fast and suggests that it might most likely be based on a single gene of major effect. Copyright (C) 2004 S. Karger AG, Basel.
B chromosomes are more frequent in mammals with acrocentric karyotypes: support for the theory of centromeric drive
4296Palestis, BGB, A.; Jones, R. N.; Trivers, R., Proceedings of the Royal Society B-Biological Sciences, 271:S22-S24. 2004-01-14 00:00:00.
The chromosomes of mammals tend to be either mostly acrocentric (having one long arm) or mostly bi-armed, with few species having intermediate karyotypes. The theory of centromeric drive suggests that this observation reflects a bias during female meiosis, favouring either more centromeres or fewer, and that the direction of this bias changes frequently over evolutionary time. B chromosomes are selfish genetic elements found in some individuals within some species. B chromosomes are often harmful, but persist because they drive (i.e. they are transmitted more frequently than expected). We predicted that species with mainly acrocentric chromosomes would be more likely to harbour B chromosomes than those with mainly bi-armed chromosomes, because female meiosis would favour more centromeres over fewer in species with one-armed chromosomes. Our results show that B chromosomes are indeed more common in species with acrocentric chromosomes, across all mammals, among rodents, among non-rodents and in a test of independent taxonomic contrasts. These results provide independent evidence supporting the theory of centromeric drive and also help to explain the distribution of selfish DNA across species. In addition, we demonstrate an association between the shape of the B chromosomes and the shape of the typical ('A') chromosomes.
Reinvestigation of an endogenous meiotic drive system in the mosquito, Aedes aegypti (Diptera : Culicidae)
4295Mori, AC, D. D.; Graham, D. H.; Severson, D. W., Journal of Medical Entomology, 41:1027-1033. 2004-01-13 00:00:00.
We have initiated efforts to determine the molecular basis for the M-D meiotic drive system in the mosquito, Aedes aegypti. The effect of the M-D gene is a highly male-biased sex ratio, but varies depending on the frequency and sensitivity of a susceptible responder m(s) allele. The M-D system has potential as a mechanism for driving trangenes for pathogen resistance into natural Ae. aegypti populations. Because all previously existing laboratory strains carrying the M-D gene have been lost, we have selected for a new strain, T37, that carries a strong driver. Matings between T37 males and drive-susceptible in m(s) females result in progeny with highly biased sex ratios, wherein only approximate to14.7% females are produced. We discuss the potential for identifying M-D candidate genes based on comparisons with the well-described Drosophila melanogaster segregation distorter (SD) meiotic drive system and considerations for release of transgenic Ae. aegypti into natural populations where M-D and insensitive m(i) alleles are likely segregating.
Identification of quantitative trait loci affecting sex determination in the eastern treehole mosquito (Ochlerotatus triseriatus)
4290Graham, DHH, J. L.; Black, W. C., Journal of Heredity, 95:35-45. 2004-01-08 00:00:00.
Laboratory colonies of the eastern treehole mosquito (Ochlerotatus triseriatus (Say)) exhibit a consistent female-biased sex ratio. This is unusual among mosquito species, in which heritable sex ratio distortion is usually male biased and mediated by meiotic drive. Quantitative trait loci (QTL) affecting sex were mapped in an F-1 intercross to better understand the genetics underlying this female bias. In P-1 and F-1 parents and in 146 F-2 individuals with a female-biased sex ratio (106 females:40 males), regions of seven cDNA loci were analyzed with single-strand conformation polymorphism (SSCP) analysis to identify and orient linkage groups. Genotypes were also scored at 73 random amplified polymorphic DNA (RAPD)-SSCP loci. In addition to the sex locus, at least four QTL affecting sex determination were detected with interval mapping on linkage groups I and II. Alleles at the sex locus cumulatively accounted for approximately 61-77% of the genetic variance in sex. Alleles at QTL adjacent to the sex locus and at a QTL on the opposite end of linkage group I increased the proportion of females, but alleles at a QTL on linkage group I and a second QTL on linkage group II increased the proportion of males. The female-biased sex ratio observed in laboratory colonies of O. triseriatus is most easily explained by the existence of multiple female biased distorter loci, as have been observed in other Diptera.
Inverted meiosis and meiotic drive in mealybugs
4285Bongiorni, SF, P.; Pippoletti, D.; Prantera, G., Chromosoma, 112:331-341. 2004-01-03 00:00:00.
In the males of lecanoid coccids, or mealybugs, an entire, paternally derived, haploid chromosome set becomes heterochromatic after the seventh embryonic mitotic cycle. In females, both haploid sets are euchromatic throughout the life cycle. In mealybugs, as in all homopteran species, chromosomes are holocentric. Holocentric chromosomes are characterized by the lack of a localized centromere and consequently of a localized kinetic activity. In monocentric species, sister chromatid cohesion and monopolar attachment play a pivotal role in regulating chromosome behavior during the two meiotic divisions. Both these processes rely upon the presence of a single, localized centromere and as such cannot be properly executed by holocentric chromosomes. Here we furnish further evidence that meiosis is inverted in both sexes of mealybugs and we suggest how this might represent an adaptation to chromosome holocentrism. Moreover, we reveal that at the second meiotic division in males a monopolar spindle is formed, to which only euchromatic chromosomes become attached. By this mechanism the paternally derived, heterochromatic, haploid chromosome set strictly segregates from the euchromatic one, and it is then excluded from the genetic continuum as a result of meiotic drive.
The B chromosome polymorphism of the grasshopper Eyprepocnemis plorans in North Africa. IV. Transmission of rare B chromosome variants
4284Bakkali, MC, J. P. M., Cytogenetic and Genome Research, 106:332-337. 2004-01-02 00:00:00.
In addition to the principal B chromosome (B-1) in Moroccan populations of the grasshopper Eyprepocnemis plorans, nine B chromosome variants appeared at low frequency. The transmission of five of these rare B chromosome variants through females was analysed in three natural populations. Sixteen controlled crosses provided useful information on the transmission of B-M2, B-M6 and B-M7 in Smir, B-M3 and B-M6 in SO. DE. A. (Societe de Developpement Agricole lands near Ksar-el-Kebir city), and B-M2 and BM10 in Mechra, all located in Morocco. Since six female parents carried two different B variants, a total of 22 progeny analyses could be studied. Intraindividual variation in B transmission rate (k(B)) was observed among the successive egg pods in 26.7% of the females, but this variation did not show a consistent temporal pattern. Only the B-M2 and B-M6 variants in Smir showed net drive, although variation was high among crosses, especially for B-M2. These two variants are thus good candidates for future regenerations ( the replacement of a neutralized B, B-1 in this case, by a new driving variant, B-M2 or B-M6) in Smir, the northern population where the B polymorphism is presumably older. The analysis of all crosses performed in the three populations, including those reported previously for the analysis of B-1 transmission, showed that the largest variance in k(B) among crosses stands at the individual level, and not at population or type of B levels. The implications of these findings for the occurrence of possible regeneration processes in Moroccan populations are discussed. Copyright (C) 2004 S. Karger AG, Basel.
Analysis of two additional loci in Neurospora crassa related to Spore killer-2
4319Turner, BC, Fungal Genetics and Biology, 39:142-150. 2003-01-17 00:00:00.
Two new loci found in one strain of Neurospora crassa (P2604) collected in Malaya are related to the meiotic drive system Spore killer Sk-2. Sk-2 was found in Neurospora intermedia and introgressed into N. crassa. P2604 showed high resistance to killing when crossed to Sk-2. This resistance was found to be linked to, but not allelic to, resistance locus r(Sk-2) on LGIIIL. Analysis showed that the high resistance phenotype of P2604 requires resistance alleles at two different loci on LGIIIR. Strains carrying a resistance allele at only the proximal or the distal locus, respectively, were obtained and intercrossed. Highly resistant strains were obtained by rejoining the two genes. The proximal locus alone confers a low level of resistance. This locus was named pr(Sk-2) for partial resistance to Sk-2. The distal locus was named mod(pr) because its only known phenotype is to modify pr(Sk-2). (C) 2003 Elsevier Science (USA). All rights reserved.
Common features of segregation distortion in plants and animals
4318Taylor, DRI, P. K., Genetica, 117:27-35. 2003-01-16 00:00:00.
Segregation distortion is increasingly recognized as a potentially powerful evolutionary force. This runs counter to the perception that non-Mendelian genes are rare genetic curiosities, a view that seems to be supported by the near ubiquity of the Mendelian system of inheritance. There are several reasons why segregation distortion may be more important than is evidenced by known empirical examples. One possibility is that the types of segregation distorters we have found are only a subset of a broader range of non-Mendelian systems, many of which go undetected. In this paper, we review what is known about the sex-linked meiotic drive system in the plant, Silene latifolia, and present some data on the mechanism of segregation distortion. We outline the general features that segregation distorters in plants and animals have in common. In some cases, such as the paucity of systems that directly alter meiotic segregation, there are likely to be inherent constraints on the range of systems that can possibly occur. Other generalities, however, support the notion that many forms of meiotic drive are possible, and that the known examples of segregation distortion are likely to be only subset of those that can possibly occur. Non-Mendelian genes may therefore have greater evolutionary importance than their current abundance in nature would suggest.
Genetic dissection of hybrid incompatibilities between Drosophila simulans and D-mauritiana. III. Heterogeneous accumulation of hybrid incompatibilities, degree of dominance, and implications for Haldane’s rule
4317Tao, YH, D. L., Evolution, 57:2580-2598. 2003-01-15 00:00:00.
The genetic basis of Haldane's rule was investigated through estimating the accumulation of hybrid incompatibilities between Drosophila simulans and D. mauritiana by means of introgression. The accumulation of hybrid male sterility (HMS) is at least 10 times greater than that of hybrid female sterility (HFS) or hybrid lethality (HL). The degree of dominance for HMS and HL in a pure D. simulans background is estimated as 0.23-0.29 and 0.33-0.39, respectively; that for HL in an F-1 background is unlikely to be very small. Evidence obtained here was used to test the Turelli-Orr model of Haldane's rule. Composite causes, especially, faster-male evolution and recessive hybrid incompatibilities, underlie Haldane's rule in heterogametic male taxa such as Drosophila (XY male and XX female). However, if faster-male evolution is driven by sexual selection, it contradicts Haldane's rule for sterility in heterogametic-female taxa such as Lepidoptera (ZW female and ZZ male). The hypothesis of a faster-heterogametic-sex evolution seems to fit the current data best. This hypothesis states that gametogenesis in the heterogametic sex, instead of in males per se, evolves much faster than in the homogametic sex, in part because of sex-ratio selection. This hypothesis not only explains Haldane's rule in a simple way, but also suggests that genomic conflicts play a major role in evolution and speciation.
Meiotic drive – Bickering genes shape evolution – Not all genes follow the rules of inheritance; now researchers are discovering how organisms adapt to the troublemakers
4316Pennisi, E, Science, 301:1837-1839. 2003-01-14 00:00:00.
Reproduction is supposed to be an equal opportunity event. Consider humans: In developing sperm, the sex chromosomes sort 50:50 such that half the sperm carry the male-defining Y chromosome and the rest sport an X. Only the randomness of fertilization leads to families of nine girls and no boys, for example. The same supposedly holds true for the rest of the genome. But in humans, flies, mice, and perhaps many other organisms, guerrilla warfare within the genome sometimes pits one element against another. This often takes on the appearance of a battle between the sexes, but it is really a fight between genes. In this struggle, typically one or more of the X chromosome’s genes strike out against the Y’s genes. Genes on other chromosomes also can get caught up in this struggle, causing an escalating arms race.
The aging effect in the segregation distorter system of Drosophila melanogaster
4315Oh, SCN, J. G., Korean Journal of Genetics, 25:237-242. 2003-01-13 00:00:00.
The SD/SD+ heterozygous male of Drosophila melanogaster transmits the SD second chromosome to its progeny in excess of the Mendelian frequency of 0.5. The k value is defined as the frequency of the SD chromosome recovered among progeny from such a male. This value has been shown to be affected by the age of the male parent: it tends to decrease with increasing age of the parental male, and this aging effect is heritable. The present study indicates that there is a genotypic condition in which the effect of male age is to increase the k value, and this increase is heritable. Thus, a heritable aging effect can occur in both increasing and decreasing the k values, depending upon the genotypes.
Transmission ratio distortion in mice
4314Lyon, MF, Annual Review of Genetics, 37:393-408. 2003-01-12 00:00:00.
The most studied example of transmission ratio distortion (TRD) in mice is that of the t-complex. This is a variant-region of Chromosome 17 which exists as a polymorphism in wild mice. Males heterozygous for a t-haplotype and a normal Chr 17 transmit-the t haplotype to >50% of their young, up to 99%.- Homozygous males are-sterile. The TRD produced by-the t-complex, is due to the action of three or more distorter genes (Tcd) on a responder. gene (Tcr). t-Haplotypes are maintained intact by crossover suppression induced by four neighboring inversions, the Tcd and by Tcr loci lying in different inversions. Sperm formation is normal in t/t males, but sperm function is impaired through gross defects in sperm motility. The responder gene has been identified as a fusion gene formed from a sperm motility kinase and a ribosomal S6 kinase. Three candidate distorter genes have also been identified as genes coding for dynein chains, and thus possibly involved in sperm flagellar function.
Closing the (Ran)GAP on segregation distortion in Drosophila
4313Kusano, AS, C.; Chan, H. Y. E.; Ganetzky, B., Bioessays, 25:108-115. 2003-01-11 00:00:00.
Segregation Distorter (SD) is a meiotic drive system in Drosophila that causes preferential transmission of the SD chromosome from SD/SD+ males owing to induced dysfunction of SD+ spermatids. Since its discovery in 1956, SD and its mode of action have baffled biologists. Recently, substantial progress has been made in elucidating this puzzle. Sd, the primary gene responsible for distortion encodes a mutant RanGAP, a key protein in the Ran signaling pathway required for nuclear transport and other nuclear functions. The mutant protein is enzymatically active but mislocalized to nuclei, which apparently disrupts Ran signaling by reducing intranuclear Ran-GTP levels. Some evidence suggests that a defect in nuclear transport may be the main cause of sperm dysfunction. Although important questions remain, the basic mechanism of distortion is now understood sufficiently well that specific hypotheses can be formulated and tested. This previously mysterious genetic system may now offer unique insights into novel aspects of regulation by Ran. (C) 2003 Wiley Periodicals, Inc.
Responder (Rsp) alleles in the Segregation Distorter (SD) system of meiotic drive in Drosophila may represent a complex family of satellite repeat sequences
4311Houtchens, KL, T. W., Genetica, 117:291-302. 2003-01-09 00:00:00.
In D. melanogaster males carrying Segregation Distorter (SD) second chromosomes, sperm receiving sensitive alleles of the Responder (Rsp) locus are subject to high rates of dysfunction. The Rsp region is located in 2R immediately adjacent to the centromere in heterochromatic band 39, and covers roughly 600 kb of material, of which approximately 85 kb is comprised of several hundred copies of a 240-bp satellite DNA sequence. Cytological observations as well as molecular analysis of rearrangements which bisect h39 indicate that sensitivity of the Rsp target to SD action is also subdivisible, and sensitivities of the component pieces appear to be correlated with copy number of the 240 bp repeat. In an attempt to examine possible higher order sequence structure for these blocks, PCR using single primers derived from a canonical repeat was used to identify potential reversals of direction of tandem arrays; that is, head-to-head or tail-to-tail junctions. Surprisingly, for two different Rsp alleles, only a single such reversal product for each was identified, differing in size and sequence between alleles. Sequencing of PCR products identified diverged copies of the canonical repeats that would not have been found using the levels of DNA stringency employed in earlier studies. Examination of Southern digests and slot-blots for DNA quantification indicates that adding the estimated numbers of such diverged copies to the canonical repeat copies discovered earlier is potentially sufficient to account for the entire 600 kb Rsp region. This adds strength to the hypothesis that this extended family of repeats is in fact the target of SD-mediated sperm dysfunction. Implications of these results for understanding the evolution of repetitive DNA are also discussed.
Four loci on abnormal chromosome 10 contribute to meiotic drive in maize
4309Hiatt, END, R. K., Genetics, 164:699-709. 2003-01-07 00:00:00.
We provide a genetic analysis of the meiotic drive system on maize abnormal chromosome 10 (Ab10) that causes preferential segregation of specific chromosomal regions to the reproductive megaspore. The data indicate that at least four chromosomal regions contribute to meiotic drive, each providing distinct functions that can be differentiated from each other genetically and/or phenotypically. Previous reports established that meiotic drive requires neocentromere activity at specific tandem repeat arrays (knobs) and that two regions on Ab10 are involved in trans-activating neocentromeres. Here we confirm and extend data suggesting that only one of the neocentromere-activating regions is sufficient to move many knobs. We also confirm the localization of a locus/loci on Ab10, thought to be a prerequisite for meiotic drive, which promotes recombination in structural heterozygotes. In addition, we identified two new and independent functions required for meiotic drive. One was identified through the characterization of a deletion derivative of Ab10 [Df(L)] and another as a newly identified meiotic drive mutation (suppressor Of meiotic drive 3). In the absence of either function, meiotic drive is abolished but neocentromere activity and the recombination effect typical of Ab10 are unaffected. These results demonstrate that neocentromere activity and increased recombination are not the only events required for meiotic drive.
The meiotic drive system on maize abnormal chromosome 10 contains few essential genes
4308Hiatt, END, R. K., Genetica, 117:67-76. 2003-01-06 00:00:00.
In maize, a distal portion of abnormal chromosome 10 (Ab10) causes the meiotic drive of itself as well as many unlinked heterochromatic regions known as knobs. The Ab10 drive system, which encodes trans- as well as cis-acting components, occupies a large region of chromosome 10L equivalent to similar to3% of the genome. Here we describe five new structural mutations of Ab10 (five deletions and a duplication) that arose from a screen for meiotic drive mutants. The high frequency of breakage events, detected both genetically and cytologically, suggest that the chromosome may be especially unstable. Very large deletions within the drive system are female-transmissible and plants homozygous for deficiencies lacking much of this interval can be grown to maturity. The data suggest that few genes required for normal growth and development lie within the portion of Ab10 responsible for meiotic drive. These and other published data suggest that meiotic drive systems tend to evolve in gene-sparse or otherwise information-poor regions of the genome where they are less likely to negatively affect individual fitness.
Sexual transmission of the Het-s prion leads to meiotic drive in Poldospora anserina
4307Dalstra, HJPS, K.; Debets, A. J. M.; Saupe, S. J.; Hoekstra, R. F., Proceedings of the National Academy of Sciences of the United States of America, 100:6616-6621. 2003-01-05 00:00:00.
In the filamentous fungus Podospora anserina, two phenomena are associated with polymorphism at the het-s locus, vegetative incompatibility and ascospore abortion. Two het-s alleles occur naturally, het-s and het-S. The het-s encoded protein is a prion propagating as a self-perpetuating amyloid aggregate. When prion-infected [Het-s] hyphae fuse with [Het-S] hyphae, the resulting heterokaryotic cells necrotize. [Het-s] and [Het-S] strains are sexually compatible. When, however, a female [Het-s] crosses with [Het-S], a significant percentage of het-S spores abort, in a way similar to spore killing in Neurospora and Podospora. We report here that sexual transmission of the [Het-s] prion after nonisogamous mating in the reproductive cycle of Podospora is responsible for the killing of het-S spores. Progeny of crosses between isogenic strains with distinct wild-type or introduced, ectopic het-s/S alleles were cytologically and genetically analyzed. The effect of het-s/S overexpression, ectopic het-s/S expression, absence of het-s expression, loss of [Het-s] prion infection, and the distribution patterns of HET-s/S-GFP proteins were categorized during meiosis and ascospore formation. This study unveiled a het-S spore-killing system that is governed by dosage of and interaction between the [Het-s] prion and the HET-S protein. Due to this property of the [Het-s] prion, the het-s allele acts as a meiotic drive element favoring maintenance of the prion-forming allele in natural populations.
Marcus Rhoades, preferential segregation and meiotic drive
4305Birchler, JAD, R. K.; Doebley, J. F., Genetics, 164:835-841. 2003-01-03 00:00:00.
LONG before microarray biologists coined and promoted the term “discovery science,” maize geneticists were avid practitioners of this mode of investigation. In fact, one might say that for a number of years, the field of maize genetics basically operated as discovery science. Many have speculated about why maize remains a model organism for genetic analysis, given its long life cycle relative to other species. It has many virtues, sometimes little understood or appreciated by outsiders, but the maize geneticist’s style of science devoted to discovery and an unusually strong commitment to cooperation probably contributes to this trend. One of the great practitioners of this style of science was Marcus Rhoades (Figure 1), who often advised beginning graduate students: “Just get in the lab and start to work; you can’t help but find something.” “What are the facts?” was his common refrain to model building and theorizing. Along with his penchant for discovery was a dogged experimentalist attack to explore the parameters and dimensions of a new finding.
Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot
4322Jeffreys, AJN, R., Nature Genetics, 31:267-271. 2002-01-20 00:00:00.
Human DNA diversity arises ultimately from germline mutation that creates new haplotypes that can be reshuffled by meiotic recombination. Reciprocal crossover generates recombinant haplotypes but should not influence the frequencies of alleles in a population. We demonstrate crossover asymmetry at a recombination hot spot in the major histocompatibility complex(1), whereby reciprocal exchanges in sperm map to different locations in the hot spot. We identify a single-nucleotide polymorphism at the center of the hot spot and show that, when heterozygous, it seems sufficient to cause this asymmetry, apparently by influencing the efficiency of highly localized crossover initiation. As a consequence, crossovers in heterozygotes are accompanied by biased gene conversion, most likely occurring by gap repair(2), that can also affect nearby polymorphisms through repair of an extended gap. The result is substantial over-transmission of the recombination-suppressing allele and neighboring markers to crossover products. Computer simulations show that this meiotic drive, although weak at the population level, is sufficient to favor eventual fixation of the recombination-suppressing variant. These findings provide an explanation for the relatively uniform widths of human crossover hot spots and suggest that hot spots may be generally prone to extinction by meiotic drive(3).
X chromosome effect on maternal recombination and meiotic drive in the mouse
4321de la Casa-Esperon, EL-O, J. C.; de Villena, F. P. M.; Briscoe, T. L.; Malette, J. M.; Vaughan, J. E.; Morgan, K.; Sapienza, C., Genetics, 161:1651-1659. 2002-01-19 00:00:00.
We observed that maternal meiotic drive favoring the inheritance of DDK alleles at the Om locus on mouse chromosome 11 was correlated with the X chromosome inactivation phenotype of (C57BL/6Pgk1(a) X DDK)F-1 mothers. The basis for this unexpected observation appears to lie in the well-documented effect of recombination on meiotic drive that results from nonrandom segregation of chromosomes. Our analysis of genome-wide levels of meiotic recombination in females that vary in their X-inactivation phenotype indicates that an allelic difference at an X-linked locus is responsible for modulating levels of recombination in oocytes.
Does Stellate cause meiotic drive in Drosophila melanogaster?
4320Belloni, MT, P.; Bozzetti, M. P.; Palumbo, G.; Robbins, L. G., Genetics, 161:1551-1559. 2002-01-18 00:00:00.
Drosophila melanogaster males deficient for the crystal (cry) locus of the Y chromosome that carry between 15 and 60 copies of the X-linked Stellate (Ste) gene are semisterile, have elevated levels of nondisjunction, produce distorted sperm genotype ratios (meiotic drive), and evince hyperactive transcription of Ste in the testes. Ste seems to be the active element in this system, and it has been proposed that the ancestral Ste gene was "selfish" and increased in frequency because it caused meiotic drive. This hypothetical evolutionary history is based on the idea that Ste overexpression, and not the lack of cry, causes the meiotic drive of cry(-) males. To test whether this is true, we have constructed a Ste-deleted X chromosome and examined the phenotype of Ste(-)/cry(-) males. If hyperactivity of Ste were necessary for the transmission defects seen in cry- males, cry males completely deficient for.Ste would be normal. Although it is impossible to construct a completely Ste(-) genotype, we find that Ste(-)/cry(-) males have exactly the same phenotype as Ste(+)/cry(-) males. The deletion of all X chromosome Ste copies not only does not eliminate meiotic drive and nondisjunction, but it also does not even reduce them below the levels produced when the X carries 15 copies of Ste.
Sperm competition and the dynamics of X chromosome drive: Stability and extinction
4326Taylor, JEJ, J., Genetics, 160:1721-1731. 2002-01-04 00:00:00.
Several empirical studies of sperm competition in populations polymorphic for a driving X chromosome have revealed that Sex-ratio males (those carrying a driving X) are at a disadvantage relative to Standard males. Because the frequency of the driving X chromosome determines the population-level sex ratio and thus alters male and female mating rates, the evolutionary consequences of sperm competition for sex chromosome meiotic drive are subtle. As the SR allele increases in frequency, the ratio of females to males also increases, causing an increase in the male mating rate and a decrease in the female mating rate. While the former change may exacerbate the disadvantage of Sex-ratio males during sperm competition, the latter change decreases the incidence of sperm competition within the population. We analyze a model of the effects of sperm competition on a driving X chromosome and show that these opposing trends in male and female mating rates call result in two coexisting locally stable equlibria, one corresponding to a balanced polymorphism of the SR and ST alleles and the second to fixation of the ST allele. Stochastic fluctuations of either the Population sex ratio or the SR frequency call then drive the population away from the balanced polymorphism and into the basin of attraction for the second equilibrium, resulting in fixation of the SR allele and extinction of the population.
Segregation distortion induced by wild-type RanGAP in Drosophila
4324Kusano, AS, C.; Ganetzky, B., Proceedings of the National Academy of Sciences of the United States of America, 99:6866-6870. 2002-01-02 00:00:00.
Segregation Distorter (SD) is a meiotic drive system in Drosophila that causes preferential transmission of the SD chromosome from SD/SD+ males owing to the induced dysfunction of SD+ spermatids. The key distorter locus, Sid, is a dominant neomorphic allele encoding a truncated, but enzymatically active, RanGAP (RanGTPase-activating protein) whose nuclear mislocalization underlies distortion by disrupting the Ran signaling pathway. Here, we show that even wild-type RanGAP can cause segregation distortion when it is overexpressed in the male germ line or when the gene dosage of a particular modifier locus is increased. Both manipulations result in substantial nuclear accumulation of RanGAP. Distortion can be suppressed by overexpression of Ran or Ran guanine nucleotide exchange factor (RanGEF) in the male germ line, indicating that the primary consequence of nuclear mislocalization of RanGAP is reduction of intranuclear RanGTP levels. These results prove that segregation distortion does not depend on any unique properties of the mutant RanGAP encoded by Sid and provide a unifying explanation for the occurrence of distortion in a variety of experimental situations.
Meiotic drive alters sperm competitive ability in stalk-eyed flies
4336Wilkinson, GSF, C. L., Proceedings of the Royal Society B-Biological Sciences, 268:2559-2564. 2001-01-14 00:00:00.
Meiotic drive results when sperm carrying a driving chromosome preferentially survive development. Meiotic drive should therefore influence sperm competition because drive males produce fewer sperm than non-drive males. Whether meiotic drive also influences the competitive ability of sperm after ejaculation is unknown. Here we report the results from reciprocal crosses that are designed for estimating the sperm precedence of male stalk-eyed flies (Cyrtodiopsis whitei) with or without X-linked meiotic drive. We find that nearly half of all sex-ratio males, as compared with 14 % of non-sex-ratio males, fail to produce young in a reciprocal cross. Furthermore, the proportion of progeny sired by a sex-ratio male in a female jointly inseminated by a non-sex-ratio male was less than expected from the number of sperm transferred. These effects are not due to differential sperm storage by females because, after a single mating with a sex-ratio male, all females stored sperm and because two sex-ratio males share paternity after jointly mating with a female. In addition to demonstrating a new mechanism of sperm competition, these results provide insight into the maintenance of sex-ratio polymorphisms. Sex-ratio males have less than one-half the fertility of non-sex-ratio males, as is required in order for frequency-dependent selection on males to produce a stable sex-ratio polymorphism.
Sex-ratio segregation distortion associated with reproductive isolation in Drosophila
4333Tao, YH, D. L.; Laurie, C. C., Proceedings of the National Academy of Sciences of the United States of America, 98:13183-13188. 2001-01-11 00:00:00.
Sex-ratio distortion is the most common form of non-Mendelian segregation observed in natural populations. It may occur even more frequently than direct observations suggest, because the dysgenic population consequences of a biased sex ratio are expected to result in the rapid evolution of suppressors, resulting in suppressed or "cryptic" segregation distortion. Here we report evidence for cryptic sex-ratio distortion that was discovered by introgressing segments of the genome of Drosophila mauritiana into the genome of Drosophila simulans. The autosomal suppressor of sex-ratio distortion, which is also associated with a reduction in hybrid male fertility, has been genetically localized to a region smaller than 80-kb pairs in chromosome 3.
Outcrossed sex allows a selfish gene to invade yeast populations
4329Goddard, MRG, D.; Burt, A., Proceedings of the Royal Society B-Biological Sciences, 268:2537-2542. 2001-01-07 00:00:00.
Homing endonuclease genes (HEGs) in eukaryotes are optional genes that have no obvious effect on host phenotype except for causing chromosomes not containing a cop), of the gene to be cut, thus causing them to be inherited at a greater than Mendelian rate via gene conversion. These genes are therefore expected to increase in frequency in outcrossed populations, but not in obligately selfed populations. In order to test this idea, we compared the dynamics of the VDE HEG in six replicate outcrossed and inbred populations of yeast (Saccharomyces cerevisiae). VDE increased in frequency from 0.21 to 0.55 in four outcrossed generations, but showed no change in frequency in the inbred populations. The absence of change in the inbred populations indicates that any effect of VDE on mitotic replication rates is less than 1%. The data from the outcrossed populations best fit a model in which 82% of individuals are derived from outcrossing and VDE is inherited by 74% of the meiotic products from heterozygotes (as compared with 50% for Mendelian genes), These results empirically demonstrate how a host mating system plays a key role in determining the population dynamics of a selfish gene.
Nonrandom segregation during meiosis: the unfairness of females
4328de Villena, FPMS, C., Mammalian Genome, 12:331-339. 2001-01-06 00:00:00.
Most geneticists assume that chromosome segregation during meiosis is Mendelian (i.e., each allele at each locus is represented equally in the gametes). The great majority of reports that discuss non-Mendelian transmission have focused on systems of gametic selection, such as the mouse t-haplotype and Segregation distorter in Drosophila, or on systems in which post-fertilization selection takes place, Because the segregation of chromosomes in such systems is Mendelian and unequal representation of alleles among offspring is achieved through gamete dysfunction or embryonic death, there is a common perception that true disturbances in the randomness of chromosome segregation are rare and of limited biological significance. In this review we summarize data on nonrandom segregation in a wide variety of genetic systems. Despite apparent differences between some systems, the basic requirements for nonrandom segregation can be deduced from their shared characteristics: i) asymmetrical meiotic division(s); ii) functional asymmetry of the meiotic spindle poles: and iii) functional heterozygosity at a locus that mediates attachment of a chromosome to the spindle. The frequency with which all three of these requirements al e fulfilled in natural populations is an known, but our analyses indicate that nonrandom segregation occurs with sufficient frequency during female meiosis, and in exceptional cases of male meiosis, that it has important biological, clinical, and evolutionary consequences.
Transmission ratio distortion due to the bl gene in table beet
4327Austin, DG, I. L., Journal of the American Society for Horticultural Science, 126:340-343. 2001-01-05 00:00:00.
The bl gene conditions a blotchy phenotype (irregular sectors of red and white root color) in table beet (Beta vulgaris ssp, vulgaris). Segregation of the bl gene was found to be consistent with a single recessive gene, however, some evidence for a departure from a single gene model was observed when blbl plants were used as females. Tn this report, segregation of the bl gene was examined in greater detail in 10 F-2 populations derived from crosses of red blotchy-rooted females (genotype blbl, denoted blotchy) with red-rooted males (BlBl, denoted red,), and 10 Fz populations derived from the reciprocal cross. Tn blbl x BlBl crosses, the proportion of red-rooted progeny was greater than 0.75 in seven of the crosses, and was significantly greater (P = 0.005) in three crosses. A test for heterogeneity was significant, indicating that the proportion of red-rooted progeny differed significantly in these 10 crosses. In BlBl x blbl crosses, the proportion of red-rooted progeny was <0.75 in seven of the crosses and there were no significant departures from the expected 3:1 ratio in any of the individual crosses. However, a pooled estimate of the segregation ratio showed a significant (P < 0.01) departure from the 3:1 ratio (pooled estimate = 0.71.), These data demonstrate transmission ratio distortion at the bl locus when blbl plants are used as both females and males in matings with wild type plants, but the degree of distortion is greater when blbl plants are used as females. Ratio distortion in such crosses may be due to a variety of factors, including increased transmission of the bl gene through female or male gametes depending on the direction of the cross, reduced fitness of maternally derived blbl progeny, epigenetic phenomena, increased fitness of paternally derived blbl progeny, or linkage of the bl gene to viability genes.
Co-existence of hosts and sex ratio distorters in structured populations
4343Hatcher, MJD, A. M.; Tofts, C., Evolutionary Ecology Research, 2:185-205. 2000-01-21 00:00:00.
Vertically transmitted parasites occur in several invertebrate species, and alter host reproduction by a variety of mechanisms, including sex ratio distortion via feminization. Efficient feminizers are predicted to drive homogenous host populations extinct due to the absence of males. However, group (interdemic) selection may enable host-parasite co-existence through extinction-colonization turnover of local subpopulations. Here we analyse the effects of feminizers on host metapopulations, in relation to the underlying mechanism of host sex determination. We examine host metapopulations with (a) fixed probabilistic sex ratio control, (b) female heterogamety (WZ/ZZ) and (c) male heterogamety (XX/XY) with and without YY viability. Under some circumstances, host and parasite can co-exist in metapopulations despite deterministic instability of local populations, in which case the parasite persists at lower frequency than predicted for homogenous populations. However, co-existence is sensitive to host sex determining mechanism. Long-term co-existence is unlikely in chromosomal systems, where sex ratio selection and novel mating type combinations result in the loss of female-determining alleles from infected host subpopulations. The consequent loss of uninfected females precludes stochastic parasite exclusion and thus prevents local population recovery. Hence, host-feminizer co-existence via interdemic selection requires intrinsic patch recovery in addition to recolonization from neighbouring subpopulations. We conclude that metapopulation structure can only buffer host populations against parasite-mediated extinction if female-determining alleles are retained in the host population.
Non-Mendelian segregation of sex chromosomes in heterospecific Drosophila males
4341Dermitzakis, ETM, J. P.; Waldrip, H. M.; Clark, A. G., Genetics, 154:687-694. 2000-01-19 00:00:00.
Interspecific hybrids and backcrossed organisms generally suffer from reduced viability and/or fertility. To identify and genetically map these defects, we introgressed regions of the Drosophila sechellia genome into the D. simulans genome. A female-biased sex ratio was observed in 24 of the 221 recombinant inbred lines, and subsequent tests attributed the skew to failure of Y-bearing sperm to fertilize the eggs. Apparently these introgressed lines fail to suppl ess a normally silent meiotic drive system. Using molecular markers we mapped two regions of the Drosophila genome that appear to exhibit differences between D. simulans and D. sechellia in their regulation of sex chromosome segregation distortion. The data indicate that the sex ratio phenotype results from an epistatic interaction between at least two factors. We discuss whether this observation is relevant to the meiotic drive theory of hybrid male sterility.
A genetic test to determine the origin of maternal transmission ratio distortion: Meiotic drive at the mouse Om locus
4340de Villena, FPMdlC-E, E.; Briscoe, T. L.; Sapienza, C., Genetics, 154:333-342. 2000-01-18 00:00:00.
We have shown previously that the progeny of crosses between heterozygous females and C57BL/G males show transmission ratio distortion at the Om locus on mouse chromosome 11. This result has been replicated in several independent experiments. Here we show that the distortion maps to a single locus on chromosome 11, closely linked to Om, and that gene conversion is not implicated in the origin of this phenomenon. To further investigate the origin of the transmission ratio distortion we generated a test using the well-known effect of recombination on maternal meiotic drive. The genetic test presented here discriminates between unequal segregation of alleles during meiosis and lethality, based on the analysis of genotype at both the distorted locus and the centromere of the same chromosome. We used this test to determine the cause of the transmission ratio distortion observed at the Om locus. Our results indicate that transmission ratio distortion at Om is due to unequal segregation of alleles to the polar body at the second meiotic division. Because die presence of segregation distortion at Om also depends on rile genotype of the sire, our results confirm that the sperm can influence segregation of maternal chromosomes to the second polar body.
Heritability of the maternal meiotic drive system linked to Om and high-resolution mapping of the Responder locus in mouse
4339de Villena, FPMdlC-E, E.; Williams, J. W.; Malette, J. M.; Rosa, M.; Sapienza, C., Genetics, 155:283-289. 2000-01-17 00:00:00.
Matings between (C57BL/6 X DDK)F-1 females and C57BL/6 males result in a significant excess of offspring inheriting maternal DDK alleles in the central region of mouse chromosome 11 due to meiotic drive at the second meiotic division. We have shown previously that the locus subject to selection is in the vicinity of D11Mit66, a marker closely linked to the Om locus that controls the preimplantation embryolethal phenotype known as the "DDK syndrome." We have also shown that observation of meiotic drive in this system depends upon tl-le genotype of the sire. Here we show that females that are heterozygous at Om retain the meiotic drive phenotype and define a 0.32-cM candidate interval for the Responder locus in this drive system. In addition, analysis of the inheritance of alleles at Om among the offspring of F-1 intercrosses indicates that the effect of the sire is determined by the sperm genotype at Om or a locus linked to Om.
Sex-ratio meiotic drive in Drosophila simulans is related to equational nondisjunction of the Y chromosome
4338Cazemajor, MJ, D.; Montchamp-Moreau, C., Genetics, 154:229-236. 2000-01-16 00:00:00.
The sex-ratio trait, an example of naturally occurring X-linked meiotic drive, has been reported in a dozen Drosophila species. Males carrying a sex-ratio X chromosome produce an excess of female offspring caused by a deficiency of Y-bearing sperm. In Drosophila simulans, such males produce similar to 70-90% female offspring, and 15-30% of the male offspring are sterile. Here, we investigate the cytological basis of the drive in this species. We show that the sex-ratio trait is associated with nondisjunction of Y chromatids in meiosis II. Fluorescence in situ hybridization (FISH) using sex-chromosome-specific probes provides dir-ect evidence that the drive is caused by the failure of the resulting spermatids to develop into functional sperm. XYY progeny were not observed, indicating that few or no YY spermatids escape failure. The recovery of XO males among the progeny of sex-ratio males shows that some nullo-XY spermatids become functional sperm and likely explains the male sterility. A review of the cytological data. in other species shows that aberrant behavior of the Y chromosome may be a common basis of sex-ratio meiotic drive in Drosophila and the signal that triggers differential spermiogenesis failure.
Spore-killing meiotic drive factors in a natural population of the fungus Podospora anserina
4348van der Gaag, MD, A. J. M.; Oosterhof, J.; Slakhorst, M.; Thijssen, Jagm; Hoekstra, R. F., Genetics, 156:593-605. 2000-01-06 00:00:00.
In fungi, meiotic drive is observed as spore killing. In the secondarily homothallic ascomycete Podospora anserina it is characterized by the abortion of two of the four spores in the ascus. We have identified seven different types of meiotic drive elements (Spore killers). Among 99 isolates from nature, six of these meiotic drive elements occurred in a local population. Spore killers comprise 23% of the natural population of P. anserina in Wageningen, The Netherlands, sampled from 1991 to 1997. One Spore-killer type was also found in a French strain dating from 1937. All other isolates found so far are sensitive to spore killing. All seven Spore killer types differ in the percentage of asci that show killing and in their mutual interactions. Interactions among Spore killer types showed either mutual resistance or dominant epistasis. Most killer elements could be assigned to linkage group III but are not tightly linked to the centromere.
Chromosomally-induced meiotic drive in Drosophila males: Checkpoint or fallout?
4347Tomkiel, JE, Genetica, 109:95-103. 2000-01-05 00:00:00.
In male Drosophila melanogaster, anomalies in sex chromosome pairing at meiosis often lead to complete or partial sperm dysfunction. This observation has led to the suggestion that defects in either the efficiency or configuration of chromosome pairing at metaphase trigger a checkpoint mechanism that leads to the elimination of meiotic products. Here, we discuss this model in consideration of recent observations on the conservation of metaphase checkpoint components in male meiosis, and on the phenotype of new alleles of the male-specific meiotic mutant teflon. Based on these observations, we propose an alternative hypothesis for the cause of sperm dysfunction in cases of chromosomal sterility and drive. We suggest that disruption of the prophase compartmentalization of sex chromatin, rather than abnormal pairing at metaphase, may be the causative defect. Such disruption may occur as a result of perturbations in sex chromosome pairing, or by translocations involving autosomal and sex chromatin. We discuss how this hypothesis may account for previously described examples chromosomal causes of meiotic drive and sterility in Drosophila.
Physical mapping of male fertility and meiotic drive quantitative trait loci in the mouse t complex using chromosome deficiencies
4345Planchart, AY, Y.; Schimenti, J. C., Genetics, 155:803-812. 2000-01-03 00:00:00.
The t complex spans 20 cM of the proximal region of mouse chromosome 17. A variant form, the t haplotype (t), exists at significant frequencies in wild mouse populations and is characterized by the presence of inversions that suppress recombination with Mild-type (+) chromosomes. Transmission ratio distortion and sterility are associated with t and affect males only. It is hypothesized that these phenomena are caused by trans-acting distorter/sterility factors that interact with a responder locus (Tcr(t)) and that the distorter and sterility factors are the same because homozygosity of the distorters causes male sterility. One factor, Tcd1, was previously shown to be amorphic using a chromosome deletion. To overcome limitations imposed by recombination suppression, we used a series of deletions within the t complex in trans to t chromosomes to characterize the Tcd1 region. The find that the distorter activity of Tcd1 is distinct from a linked sterility factor, originally called tcs1. YACs mapped with respect to deletion breakpoints localize tcs1 to a 1.1-Mb interval flanked by D17Aus9 and Tctex1. We present evidence for the existence of multiple proximal t complex regions that exhibit distorter activity. These studies demonstrate the utility of chromosome deletions for complex trait analysis.
A male-biased primary sex ratio and larval mortality in Eucheira socialis (Lepidoptera : Pieridae)
4363Underwood, DLAS, A. M., Evolutionary Ecology Research, 1:703-717. 1999-01-21 00:00:00.
We investigated the sex ratio and sex-biased mortality in the Mexican pierid butterfly, Eucheira socialis westwoodi. We studied two populations between 1990 and 1997 along Mexico Highway 40, which runs from Mazatlan, Sinaloa to Durango, Durango, Populations occurring between km 64 and 101 and between km 163 and 213 were designated 'eastern' and 'western', respectively We determined the primary sex ratio of egg masses from these populations in 1992, 1995, 1996 and 1997, The primary sex ratio varied from 68.0 to 75.5% male and from 63.7 to 79.3% male in the eastern and western populations, respectively. The frequency of significantly male-biased full sib groups was between 55 and 100% in the east and between 67 and 94% in the west. For all years, in both populations, the primary sex ratio was significantly different from 1:1. Lf the probability of a given zygote being male is the same across sibships, the distribution of the primary sex ratio should be binomial. For years where at least 10 egg masses were collected, the distribution of primary sex ratio was significantly different from a binomial in all years in the east and two of three years in the west. We studied larval and pupal mortality in these populations in 1990, 1991 and 1997. Larval mortality was consistently disproportionately male, varying from 83 to 100% male. Pupal mortality tended to be female-biased. The operational sex ratio varied from 65 to 71% male in the east and from 70 to 76% male in the west.
Meiotic drive and evolution of female choice
4361Reinhold, KE, L.; Misof, B.; Kurtz, J., Proceedings of the Royal Society B-Biological Sciences, 266:1341-1345. 1999-01-19 00:00:00.
As a special version of the good-genes hypothesis, it was recently proposed that females could benefit from choosing drive-resistant males in a meiotic drive system. Here, we examine with a three-locus, six-allele population genetic model whether female choice for drive resistance can evolve. An allele leading to female preference for drive-resistant males was introduced at low frequency into a population polymorphic for meiotic drive and drive resistance. Our simulations show that female choice of drive-resistant males is disadvantageous when resistance is Y-linked. This disadvantage occurs because, at equilibrium, drive-resistant males have lower reproductive success than drive-susceptible males. Thus, female choice of drive-susceptible males can evolve when resistance is Y-linked. When resistance is autosomal, selection on female choice for drive resistance is less strong and depends on the frequency of choice: female preference of resistant males is favoured when choice is rare and disadvantageous when choice is frequent, leading to a stable equilibrium at a low frequency of the choice allele. Independent of the location of drive resistance alleles, males with the non-driving allele always have above average reproductive success. Female choice is therefore beneficial when choosy females prefer males with the non-driving allele.
Transmission ratio distortion in females on chromosome 10p11-p15
4360Paterson, ADP, A., American Journal of Medical Genetics, 88:657-661. 1999-01-18 00:00:00.
A number of recent reports of linkage of markers on chromosome 10p to schizophrenia, and evidence for linkage in one study to bipolar affective disorder, provide encouragement for psychiatric genetics, after nonreplication of linkage findings at other chromosomal regions, The same region on chromosome 10 also demonstrates evidence for linkage to obesity, female alcoholism, and female type 1 diabetes. However, evidence for linkage can be confounded by the biological phenomenon of transmission ratio distortion. Transmission ratio distortion (also termed segregation distortion or meiotic drive) results in non-Mendelian segregation of alleles to live born offspring, and has not been investigated at the majority of loci for complex traits. We examined evidence for transmission ratio distortion using 40 Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees across chromosome 10 using CEPH genotype data. Evidence for linkage of females to D10S211 was found (multipoint non-parametric linkage Z score [NPL] = 1.84, P = 0.040), while there was no linkage of this marker to male sex, The observation of possible transmission ratio distortion in females on chromosome 10p requires additional study, and may impact on the interpretation of positive linkage findings in this region. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:657-661, 1999. (C) 1999 Wiley-Liss, Inc.
Truncated RanGAP encoded by the Segregation Distorter locus of Drosophila
4359Merrill, CB, L.; Kusano, A.; Ganetzky, B., Science, 283:1742-1745. 1999-01-17 00:00:00.
Segregation Distorter (SD) in Drosophila melanogaster is a naturally occurring meiotic drive system in which the SD chromosome is transmitted from SD/SD+ males in vast: excess over its homolog owing to the induced dysfunction of SD+-bearing spermatids. The Sd Locus is the key distorting gene responsible for this phenotype. A genomic fragment from the Sd region conferred full distorting activity when introduced into the appropriate genetic background by germline transformation. The only functional product encoded by this fragment is a truncated version of the RanGAP nuclear transport protein. These results demonstrate that this mutant RanGAP is the functional Sd product.
Recurrent invasion and extinction of a selfish gene
4353Goddard, MRB, A., Proceedings of the National Academy of Sciences of the United States of America, 96:13880-13885. 1999-01-11 00:00:00.
Homing endonuclease genes show super-Mendelian inheritance, which allows them to spread in populations even when they are of no benefit to the host organism. To test the idea that regular horizontal transmission is necessary for the long-term persistence of these genes, we surveyed 20 species of yeasts for the omega-homing endonuclease gene and associated group I intron. The status of omega could be categorized into three states (functional, nonfunctional, or absent), and status was not clustered on the host phylogeny. Moreover, the phylogeny of w differed significantly from that of the host, strong evidence of horizontal transmission. Further analyses indicate that horizontal transmission is more common than transposition, and that it occurs preferentially between closely related species. Parsimony analysis and coalescent theory suggest that there have been 15 horizontal transmission events in the ancestry of our yeast species, through simulations indicate that this value is probably an underestimate. Overall, the data support a cyclical model of invasion, degeneration, and loss, followed by reinvasion, and each of these transitions is estimated to occur about once every 2 million years. The data are thus consistent with the idea that frequent horizontal transmission is necessary for the long-term persistence of homing endonuclease genes, and further, that this requirement limits these genes to organisms with easily accessible germ lines. The data also show that mitochondrial DNA sequences are transferred intact between yeast species; if other genes do not show such high levels of horizontal transmission, it would be due to lack of selection, rather than lack of opportunity.
Are Drosophila SR drive chromosomes always balanced?
4351Carvalho, ABV, S. C., Heredity, 83:221-228. 1999-01-09 00:00:00.
SR chromosomes are the best-known case of sex chromosome meiotic drive. These X chromosomes cause the production of female-biased progenies in several Drosophila species; Due to their meiotic drive advantage, they are expected to spread and become fixed, resulting in population extinction due to the lack of males. However, this apparently does not occur: SR chromosomes are maintained in balanced polymorphisms, resulting from the equilibrium between their meiotic drive advantage and deleterious fitness effects. In this paper we review the current explanations for their deleterious effects and we argue that it is highly improbable that all newly emerged SR are sufficiently deleterious to avoid fixation. Unbalanced SR almost certainly arise and go unnoticed because of three possible outcomes: (i) fixation followed by extinction of the population or species; (ii) fixation followed by the emergence and fixation of drive suppressors, restoring the normal 1:1 sexual proportion; or (iii) transformation into balanced SR due to partial suppression. If these outcomes really occur, then extant cases of sex-chromosome meiotic drive such as SR, causing small deviations on the population sexual proportion are only the tip of the iceberg and strong sexual proportion shifts (possibly followed by extinction) are a more common feature of species evolution than is usually assumed.
Evolution of driving X chromosomes and resistance factors in experimental populations of Drosophila simulans
4350Capillon, CA, A., Evolution, 53:506-517. 1999-01-08 00:00:00.
Sex-ratio drive is a particular case of meiotic drive, described in several Drosophila species, that causes males bearing driving X chromosome to produce a large excess of females in their progeny. In Drosophila simulans, driving X chromosomes and resistance factors located on the Y chromosome and on the autosomes have been previously reported. In this paper, we report the study of the dynamics of sex-ratio factors in experimental populations. We followed the evolution in frequency of driving X chromosomes in the absence of resistance factors and the evolution of resistance factors in the presence of driving X chromosomes. The driving X chromosome was lost, contrarily to theoretical expectations that predict its rapid invasion. Autosomal resistances increased in frequency, and resistant Y chromosomes invaded the population very quickly, as predicted by theoretical models. Fitness measurements showed that the loss of the driving X chromosome was due to a strong deleterious effect that was expressed only when distorting males were in competition with standard males. However, the spread of autosomal resistances reduced this deleterious effect. Implications for the maintenance of polymorphism in natural populations are discussed.
Segregation distortion in a deme structured population: opposing demands of gene, individual and group selection
4364van Boven, MW, F. J., Journal of Evolutionary Biology, 12:80-93. 1999-01-02 00:00:00.
The evolution of segregation distortion is governed by the interplay of selection at different levels. Despite their systematic advantage at the gamete level, none of the well-known segregation distorters spreads to fixation since they induce severe negative fitness effects at the individual level. In a deme-structured population, selection at the population level also plays a role. By means of a population genetical model, we analyse the various factors that determine the success of a segregation distorter in a metapopulation, Our focus is on the question of how the success of a distorter allele is affected by its segregation ratio and its fitness effects at the individual level. The analysis reveals that distorter alleles with high segregation ratios are the best invaders and reach the highest frequencies within single demes. However, the productivity of a deme harbouring a distorter with a high segregation ratio may be significantly reduced. As a consequence, an efficient distorter will be underrepresented in the migrant pool and, moreover, it may increase the probability of deme extinction. In other words, efficient distorters with high segregation ratios may well succumb to their own success. Therefore, distorters with intermediate segregation ratios may reach the highest frequency in the metapopulation as a result of the opposing forces of gamete, individual and group selection. We discuss the implications of this conclusion for the t complex of the house mouse.
Meiotic drive favors Robertsonian metacentric chromosomes in the common shrew (Sorex araneus, Insectivora, Mammalia)
4380Wyttenbach, AB, P.; Hausser, J., Cytogenetics and Cell Genetics, 83:199-206. 1998-01-18 00:00:00.
Meiotic drive has attracted much interest because it concerns the robustness of Mendelian segregation and its genetic and evolutionary stability. We studied chromosomal meiotic drive in the common shrew (Sorex araneus, Insectivora, Mammalia), which exhibits one of the most remarkable chromosomal polymorphisms within mammalian species. The open question of the evolutionary success of metacentric chromosomes (Robertsonian fusions) versus acrocentrics in the common shrew prompted us to test whether a segregation distortion in favor of metacentrics is present in female and/or male meiosis. Performing crosses under controlled laboratory conditions with animals from natural populations, we found a clear trend toward a segregation distortion in favor of metacentrics during male meiosis, two chromosome combinations (gm and ji) being significantly preferred over their acrocentric homologs. Apart for one Robertsonian fusion (hi), this trend was absent in female meiosis. We propose a model based on recombination events between twin acrocentrics to explain the difference in transmission ratios of the same metacentric in different sexes and unequal drive of particular metacentrics in the same sex. Pooled data for female and male meiosis revealed a trend toward stronger segregation distortion for larger metacentrics. This is partially in agreement with the frequency of metacentrics occurring in natural populations of a chromosome race showing a high degree of chromosomal polymorphism.
Male eye span in stalk-eyed flies indicates genetic quality by meiotic drive suppression
4379Wilkinson, GSP, D. C.; Crymes, L., Nature, 391:276-279. 1998-01-17 00:00:00.
In some species, females choose mates possessing ornaments that predict offspring survival(1-5). However, sexual selection by female preference for male genetic quality(6-8) remains controversial because conventional genetic mechanisms maintain insufficient variation in male quality to account for costly preference and ornament evolution(9,10). Here we show that females prefer ornaments that indicate genetic quality generated by transmission conflict between the sex chromosomes, By comparing sex-ratio distributions in stalk-eyed fly (Cyrtodiopsis) progeny we found that female-biased sex ratios occur in species exhibiting eye-stalk sexual dimorphism(11,12) and female preferences for long eye span(13,14). Female-biased sex ratios result from meiotic drive(15), the preferential transmission of a 'selfish' X-chromosome. Artificial selection for 22 generations on male eye-stalk length in sexually dimorphic C. dalmanni produced longer eye-stalks and male-biased progeny sex ratios in replicate lines. Because male-biased progeny sex ratios occur when a drive-resistant Y chromosome pairs with a driving X chromosome(15), long eye span is genetically linked to meiotic drive: suppression. Male eye span therefore signals genetic quality by influencing the reproductive value of offspring(16).
Male sterility and meiotic drive associated with sex chromosome rearrangements in Drosophila: Role of X-Y pairing
4375McKee, BDW, K.; Merrill, C.; Ren, X. J., Genetics, 149:143-155. 1998-01-13 00:00:00.
In Drosophila melanogaster, deletions of the pericentromeric X heterochromatin cause X-Y nondisjunction, reduced male fertility and distorted sperm recovery ratios (meiotic drive) in combination with a normal Y chromosome and interact with Y-autosome translocations (T(Y;A)) to cause complete male sterility. The pericentromeric heterochromatin has been shown to contain the male-specific X-Y meiotic pairing sites, which consist mostly of a 240-bp repeated sequence in the intergenic spacers (IGS) of the rDNA repeats. The experiments in this paper address the relationship between X-Y pairing failure and the meiotic drive and sterility effects of Xh deletions. X-linked insertions either of complete rDNA repeats or of rDNA fragments that contain the IGS were found to suppress X-Y nondisjunction and meiotic drive in Xh(-)/Y males, and to restore fertility to Xh(-)/T(Y;A) males for eight of nine tested Y-autosome translocations. rDNA fragments devoid of IGS repeats proved incapable of suppressing either meiotic drive or chromosomal sterility. These results indicate that the various spermatogenic disruptions associated with X heterochromatic deletions are all consequences of X-Y pairing failure. We interpret these findings in terms of a novel model in which misalignment of chromosomes triggers a checkpoint that acts by disabling the spermatids that derive from affected spermatocytes.
Segregation distortion in myotonic dystrophy
4374Magee, ACH, A. E., Journal of Medical Genetics, 35:1045-1046. 1998-01-12 00:00:00.
Myotonic dystrophy (DM) is an autosomal dominant disease which, in the typical pedigree, shows a three generation anticipation cascade. This results in infertility and congenital myotonic dystrophy (CDM) with the disappearance of DM in that pedigree. The concept of segregation distortion, where there is preferential transmission of the larger allele at the DM locus, has been put forward to explain partially the maintenance of DIM in the population. In a survey of DM in Northern Ireland, 59 pedigrees were ascertained. Sibships where the status of all the members had been identified were examined to determine the transmission of the DM expansion from affected parents to their offspring. Where the transmitting parent was male, 58.3% of the offspring were affected, and in the case of a female transmitting parent, 68.7% were affected. Studies on meiotic drive in DIM have shown increased transmission of the larger allele at the DM locus in non-DIM heterozygotes for CTGn. This study provides further evidence that the DM expansion tends to be transmitted preferentially.
Identification of the t complex-encoded cytoplasmic dynein light chain Tctex1 in inner arm I1 supports the involvement of flagellar dyneins in meiotic drive
4370Harrison, AO-C, P.; King, S. M., Journal of Cell Biology, 140:1137-1147. 1998-01-08 00:00:00.
The cytoplasmic dynein light chain Tctex1 is a candidate for one of the distorter products involved in the non-Mendelian transmission of mouse t haplotypes. It has been unclear, however, how the t-specific mutations in this protein, which is found associated with cytoplasmic dynein in many tissues, could result in a male germ cell-specific phenotype. Here, we demonstrate that Tctex1 is not only a cytoplasmic dynein component, but is also present both in mouse sperm and Chlamydomonas flagella. Genetic and biochemical dissection of the Chlamydomonas flagellum reveal that Tctex1 is a previously undescribed component of inner dynein arm Il. Combined with the recent identification of another putative t complex distorter, Tctex2, within the outer dynein arm, these results support the hypothesis that transmission ratio distortion (meiotic drive) of mouse t haplotypes involves dysfunction of both flagellar inner and outer dynein arms but does not require the cytoplasmic isozyme.
Wolbachia as a possible means of driving genes into populations
4368Curtis, CFS, S. P., Parasitology, 116:S111-S115. 1998-01-06 00:00:00.
Cytoplasmic incompatibility consists of sterility in cross matings, the crossing type being maternally inherited. It can be explained by the action of Wolbachia symbionts which are transmitted through the egg cytoplasm and leave an imprint on the sperm which prevents it fertilizing unless it is 'rescued' by the action of the same type of Wolbachia in the egg. Thus matings between infected males and uninfected females are sterile, but the reciprocal matings are fertile. Hence uninfected females are at risk of failing to transmit their uninfected cytoplasm if they cross mate, but infected females are at no such risk. Therefore natural selection favours the infected state and in two wild insect populations the infection has been observed spreading. If a gene for inability to transmit malaria could be introduced into Wolbachia and if this could be introduced into Anopheles (where these symbionts appear not to occur naturally), release of a limited number of such insects should trigger a process of displacement of malaria vectors, by the non-vector type. A simple model is used to demonstrate the limitations to this process which would be introduced by immigration.
Localization of the genes controlling B chromosome transmission rate in maize (Zea mays ssp. mays, Poaceae)
4367Chiavarino, AMR, M.; Rosi, P.; Poggio, L.; Naranjo, C. A., American Journal of Botany, 85:1581-1585. 1998-01-05 00:00:00.
In previous papers we found that the frequency of B chromosomes in native races of maize varies considerably in different populations. Moreover, we found genotypes that control high and low transmission rates (TR) of B chromosomes in the Pisingallo race. In the present work crosses were made to determine whether the genes controlling B-TR are located on the normal chromosome set (As) or on the B chromosomes (Bs). We made female f.0B X male m.2B crosses between and within high (H) and low (L) B-TR groups. The Bs were transmitted on the male side in all cases. The mean B-TR from the progeny of f.0B (H) X m.2B (H) and f.0B (H) X m.2B (L) crosses was significantly higher than that from f.0B (L) X m.2B (L) and f.0B (L) X m.2B (H) crosses. The results show that the B-TR of the crosses corresponds to the H or L B-TR of the 0B female parents irrespective of the Bs of the male parent. This indicates that B-TR is genetically controlled by the 0B female parent and that these genes are located on the A chromosomes.
Putting the brake on drive: meiotic drive of t haplotypes in natural populations of mice
4365Ardlie, KG, Trends in Genetics, 14:189-193. 1998-01-03 00:00:00.
Mouse t haplotypes are a 'selfish' form of chromosome 17 that show non-mendelian transmission from heterozygous +/t males. The considerable transmission bias in favour of t haplotypes should result in very high frequencies of these chromosomes in natural populations, but they seldom occur at the high frequencies expected. Recent research on this and other meiotic drive systems has shown bow a variety of mechanisms have evolved to suppress drive, and to re-establish mendelian segregation.
Polymorphism for Y-linked suppressors of sex-ratio in two natural populations of Drosophila mediopunctata
4383Carvalho, ABV, S. C.; Klaczko, L. B., Genetics, 146:891-902. 1997-01-21 00:00:00.
In several Drosophila species there is a trait known as ''sex-ratio'': males carrying certain X chromosomes (called ''SR'') produce female biased progenies due to X-Y meiotic drive. In Drosophila mediopunctata this trait has a variable expression due to Y-linked suppressors of sex-ratio expression, among other factors. There are two types of Y chromosomes (suppressor and nonsuppressor) and two types of SR chromosomes (suppressible and unsuppressible). Sex-ratio expression is suppressed in males with the SRsuppressible/Y-suppressor genotype, whereas the remaining three genotypes produce female biased progenies. Now we have found that similar to 10-20% of the Y chromosomes from two natural populations 1500 km apart are suppressors of sex-ratio expression. Preliminary estimates indicate that Y-suppressor has a meiotic drive advantage of 6% over Y-nonsuppressor. This Y polymorphism for a nonneutral trait is unexpected under current population genetics theory. We propose that this polymorphism is stabilized by an equilibrium between meiotic drive and natural selection, resulting from interactions in the population dynamics of X and Y alleles. Numerical simulations showed that this mechanism may stabilize nonneutral Y polymorphisms such as we have found in D. mediopunctata.
Identification of a male meiosis-specific gene, Tcte2, which is differentially spliced in species that form sterile hybrids with laboratory mice and deleted in t chromosomes showing meiotic drive
4382Braidotti, GB, D. P., Developmental Biology, 186:85-99. 1997-01-20 00:00:00.
Tcte2 (t complex testes expressed 2) is a male meiosis-specific gene that maps to band 3.3 of mouse chromosome 17. Two distinct male fertility defects, hybrid sterility and transmission ratio distortion, have previously been mapped to this region. Hybrid sterility arises in crosses between different mouse species and the F1 generation males have defects in the first meiotic division and are sterile. Transmission ratio distortion is shown by males heterozygous for the t haplotype form of chromosome 17 and is a type of meiotic drive in which male gametes function unequally at fertilization. The Tcte2 gene expresses a coding mRNA and a number of putative non-ORF transcripts in meiosis I. A deletion of the 5' part of the locus abolishes Tcte2 expression on the t haplotype form of chromosome 17. Additionally, the series of putative non-ORF RNAs at the Tcte2 locus are differentially spliced in species that show hybrid sterility when crossed to laboratory mice. The identification of polymorphisms in t haplotypes and in different mouse species allows alleles of Tcte2 to be proposed as candidates for loci which contribute to both meiotic drive and hybrid sterility phenotypes. While theoretical considerations have previously been used to propose that speciation and meiotic drive involve alleles of the same genes, Tcte2 is the first cloned candidate gene to support this link at a molecular level. (C) 1997 Academic Press.
The sex-ratio trait in Drosophila simulans: Geographical distribution of distortion and resistance
4381Atlan, AM, H.; Landre, C.; Montchamp-Moreau, C., Evolution, 51:1886-1895. 1997-01-19 00:00:00.
The sex-ratio trait we describe here in Drosophila simulans results from X-linked meiotic drive. Males bearing a driving X chromosome can produce a large excess of females (about 90%) in their progeny. This is, however, rarely the case in the wild, where resistance factors, including autosomal suppressors and insensitive Y chromosomes, prevent the expression of the driver. In this study, we searched for drive and resistance factors in strains of Drosophila simulans collected all over the world. Driving X chromosomes were found in all populations whenever a good sample size was available. Their frequency may reach up to 60%. However, the presence of driving X chromosomes never results in an excess of females, due to the systematic co-occurrence of resistance factors. The highest frequencies of driving X chromosomes were observed in islands, while populations from East and Central Africa (the supposed center of origin of the species) showed the highest level of resistance. The geographical pattern of drive and resistance factors, as well as the results of crosses between strains from different geographical areas, suggest that the sex-ratio system described here has a unique and ancient origin in the species.
Non-Mendelian transmission at the Machado-Joseph disease locus in normal females: Preferential transmission of alleles with smaller CAG repeats
4389Rubinsztein, DCL, J., Journal of Medical Genetics, 34:234-236. 1997-01-07 00:00:00.
Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a neurodegenerative disorder which is associated with a CAG repeat expansion in the MJD1 gene on chromosome 14q32.1. A recent study reported an excess of transmission of disease chromosomes relative to normal chromosomes from affected fathers, while this phenomenon was not observed in female meioses. These data were compatible with meiotic drive. We investigated the transmission of alleles with larger versus smaller CAG repeat numbers in the MJD1 gene in normal heterozygotes from the 40 CEPH families. Our data suggest that there was no segregation distortion in male meioses, while the smaller CAG allele was inherited in 57% of female meioses (p<0.016). The pattern of inheritance of smaller versus larger CAG alleles at this significantly different when female meioses were compared (p=0.0139). While previous data suggest that meiotic drive may be a feature of certain human diseases, including the trinucleotide diseases MJD, myotonic dystrophy, and dentatorubral-pallidoluysian atrophy, these data are compatible with meiotic drive also occurring among non-disease associated CAG sizes.
Sex chromosome meiotic drive in stalk-eyed flies
4388Presgraves, DCS, E.; Wilkinson, G. S., Genetics, 147:1169-1180. 1997-01-06 00:00:00.
Meiotically driven sex chromosomes can quickly spread to fixation and cause population extinction unless balanced by selection or suppressed by genetic modifiers. We report results of genetic analyses that demonstrate that extreme female-biased sex ratios in two sister species of stalk-eyed flies, Cyrtodiopsis dalmanni and C. whitei, are due to a meiotic drive element on the X chromosome (X-d). Relatively high frequencies of X-d in C. dalmanni and C. whitei (13-17% and 29%, respectively) cause female-biased sex ratios in natural populations of both species. Sex ratio distortion is associated with spermatid degeneration in male carriers of X-d. Variation in sex ratios is caused by Y-linked and autosomal factors that decrease the intensity of meiotic drive. Y-linked polymorphism for resistance to drive exists in C. dalmanni in which a resistant Y chromosome reduces the intensity and reverses the direction of meiotic drive. When paired with X-d, modifying Y chromosomes (Y-m) cause the transmission of predominantly Y-bearing sperm, and on average, production of 63% male progeny. The absence of sex ratio distortion in closely related monomorphic outgroup species suggests that this meiotic drive system may predate the origin of C. whitei and C. dalmanni. We discuss factors likely to be involved in the persistence of these sex linked polymorphisms and consider the impact of X-d on the operational sex ratio and the intensity of sexual selection in these extremely sexually dimorphic flies.
Variation in Y chromosome meiotic drive in Aedes aegypti (Diptera: Culicidae): a potential genetic approach to mosquito control
4387OwusuDaaku, KOW, R. J.; Butler, R. D., Bulletin of Entomological Research, 87:617-623. 1997-01-05 00:00:00.
Reciprocal crosses between strains of Aedes aegypti (Linnaeus) from different geographical areas have revealed an unexpectedly complex pattern of holandrically inherited male biased sex ratios in F2. The variation has been interpreted in terms of a web of X-Y interactions in F1, in which the Y chromosome may or may not show meiotic drive against the X chromosome with which it is paired. The pattern of inheritance is not in agreement with a single form of Y chromosome, driving with different degrees of intensity against Xs of different sensitivity, but indicates different forms of driving Y chromosome. A rule has emerged that if F1 males from any cross give rise to a male distorted sex ratio in their progeny (F2), the males from the reciprocal cross give rise to a normal sex ratio. All eleven newly colonized strains from Ghana showed Y meiotic drive against the Xs of five strains, one of American and four of Australian origin, although one of the eleven showed a greater degree of drive than the other ten against the same sensitive strains. The variation observed is discussed in relation to previous studies on meiotic drive by the MD haplotype, and to the possible exploitation of sex ratio distortion in controlling this potentially dangerous insect.
Selected lines of Aedes aegypti with persistently distorted sex ratios
4386OwusuDaaku, KOW, R. J.; Butler, R. D., Heredity, 79:388-393. 1997-01-04 00:00:00.
A breeding scheme to isolate X chromosomes sensitive to drive by the T8 (Trinidad) Y chromosome of Aedes aegypti (the MD haplotype) is reported. Crosses with an Australian strain Th.I (Thursday Island) revealed not only sensitive and resistant X chromosomes but also some with the capacity to drive against the T8 Y chromosome. Four strains were created in which sex ratio was male-distorted (28-36 per cent female) for 10 generations, with no regression towards sexual parity. The proportion of females varied significantly between generations in each of the four strains. Further selection produced strains with normal sex ratios, capable of generating fewer than 15 per cent female on outcrossing to T8 males.
Meiotic drive at the myotonic dystrophy and the cone-rod dystrophy loci on chromosome 19q13.3
4384Inglehearn, CFG, C. Y., American Journal of Human Genetics, 60:1562-1563. 1997-01-02 00:00:00.
The apparently conflicting observations of a high new mutation rate at the myotonic dystrophy (DM) locus on chromosome 19q13.3 and of a founder effect for DM chromosomes led researchers to invoke the influence of meiotic drive at this locus. Two studies (Carey et al. 1994; Gennarelli et al. 1994) suggested such an effect in male meioses, whereas one study (Shaw et al. 1995) found evidence for segregation distortion in female meioses. In the October 1996 issue of the Journal, Leeflang et al. demonstrated convincing evidence that, if such an effect exists in male meioses, it must operate postejaculation, presumably influencing sperm motilityor sperm survival. In so doing, the authors also reviewed the literature both supporting and opposing the influence of the action of meiotic drive at the DM locus. However, they appear to have missed a report from our laboratory (Evans et al. 1994) of a similar observation for dominant cone-rod dystrophy (CORD2), a form of retinal degeneration that also maps to chromosome 19q. The data from the study of the CORD2 locus suggest segregation distortion in female meioses. The most recent locus refinement for CORD2 (Bellingham et al., in press) places it in an interval 0.8-2.4 Mb distal to the DM locus, on the metric FISH map of Gordon et al. (1995). Is it not possible that the close proximity of these two loci, both of which apparently have such an unusual pattern of inheritance, is more than a coincidence?
Competition between segregation distorters: Coexistence of ”superior” and ”inferior” haplotypes at the t complex
4402vanBoven, MW, F. J.; Heg, D.; Huisman, J., Evolution, 50:2488-2498. 1996-01-20 00:00:00.
By means of population genetical models, we investigate the competition between sex-specific segregation distorters. Although the models are quite general, they are motivated by a specific example, the t complex of the house mouse. Some variants at this gene complex, the t haplotypes. distort Mendelian segregation in heterozygous males in their favor. The selective advantage at the gamete level is counterbalanced by strong negative fitness effects at the individual level (male sterility or even lethality in both sexes). A plethora of different t haplotypes has been found, both in the field and in the lab. Up to now, however, models have focused on the equilibrium frequency of a single t haplotype. In contrast, we explicitly model the competition between several t haplotypes, A deterministic model for a large, well-mixed population predicts a surprisingly high degree of polymorphism. Haplotypes with seemingly inferior fitness characteristics may easily coexist with ''superior'' haplotypes. For instance, a lethal haplotype with a low segregation ratio may stably coexist with a sterile haplotype with a high segregation ratio, Stable coexistence is even possible for haplotypes with a segregation disadvantage. A simple stochastic model shows that the same principles apply in the context of a structured metapopulation. Although counterintuitive at first sight, all our results can be explained by the fact that segregation distorters have an inherent advantage when they are rare. We conclude that fitness comparisons are not sufficient to predict the outcome of competition when selective forces are acting at different levels.
Genetic control of B chromosome transmission rate in Zea mays ssp mays (Poaceae)
4401Rosato, MC, A. M.; Naranjo, C. A.; Puertas, M. J.; Poggio, L., American Journal of Botany, 83:1107-1112. 1996-01-19 00:00:00.
We selected genotypes of high and low B chromosome transmission rate (TR) in a native race of maize (Pisingallo) from northwest Argentina. We made 20 female 0B x male 1B and 20 f.1B x m.0B crosses. The former (G0m) showed a large variation of B TR, with a mean of TR +/- SE = 0.52 +/- 0.06, ranging from 0.17 to 0.98. In the latter (G0f) the mean was TR = 0.47 +/- 0.02 ranging from 0.31 to 0.58. Plants showing the highest and the lowest TR were selected to constitute the progenitors of the G1 generations. We made 19 f.0B x m.2B crosses, studying 24-30 plants per cross. The TR of the high (H) and low (L) lines in G1m (G1mH and G1mL) significantly differed (TRH = 0.65 +/- 0.03, TRL = 0.40 +/- 0.01), indicating that the H and L lines are different groups. The large variation in male TR suggests that preferential fertilization of gametes carrying B chromosomes does not always occur. We also selected plants showing high and low TR in the progenies of f.1B x m.0B crosses (G0f), and made 24 f.1B x m.0B crosses, studying 23-30 plants per cross. The TRs of the H and L lines in G1f (G1fH and G1fL) were significantly different (TRH = 0.48 +/- 0.025, TRL = 0.40 +/- 0.02). The TRs in G0f and G1fL were significantly different (TR = 0.47 +/- 0.02 and 0.40 +/- 0.02, respectively), while this was not the case between G0f and G1fH. Our results demonstrate the existence of genotypes controlling B TR in this native population of maize.
Measuring meiotic drive
4400Robbins, LGP, G.; Bonaccorsi, S.; Pimpinelli, S., Genetics, 142:645-647. 1996-01-18 00:00:00.
LAURENCE HURST’S (1996) letter re-examines our data on the effect of Stellate copy number on the meiotic parameters of Mystal- (= su(ste)-) males (PALUMBO et al. 1994). In our analysis, we found a tight correlation of fertility and disjunction with Stellate copy number, with both being normal at low copy numbers. In contrast, we found only a weak correlation of meiotic drive and Stellate copy number, with substantial sperm lethality projected to exist even at Stellate copy number = 0. We argue that the absence of crystal, not the presence of Stellate, is the proximate cause of drive in crystal males. HURST argues that the data support the hypothesis (HURST 1992) that Stellate causes drive.
Meiotic drive in fungi: Chromosomal elements that cause fratricide and distort genetic ratios
4399Raju, NB, Journal of Genetics, 75:287-296. 1996-01-17 00:00:00.
Fungal Spore killers (Sk), studied most extensively in Neurospora and to a lesser extent in Podospora, Gibberella and Cochliobolus, cause the death of ascospores (= meiospores) that do not contain the killer (Sk(K)) element. When a Spore killer is heterozygous (Sk(K) x Sk(S)) in Neurospora, every ascus (= meiocyte) contains four normal-sized, black, viable ascospores (Sk(K)), and four ascospores that are tiny, unpigmented and unviable (Sk(S)). Killing of sensitive nuclei is expressed postmeiotically, and results in gross distortion of segregation ratios for Sk-linked genes. A sensitive nucleus that would otherwise die is rescued if a killer nucleus is also enclosed in the same ascospore. In Neurospora, Sk is centromere-linked (linkage group III), and when heterozygous, shows a recombination block in a 30-map-unit region spanning the centromere of linkage group III. There is no ascospore death or recombination block in killer x killer or sensitive x sensitive crosses. Spore killers are Fairly common in Gibberella fujikuroi and Neurospora sitophila but extremely rare in N. intermedia, and have not yet been found among natural isolates of N. crassa.
Epistatic control of non-mendelian inheritance in mouse interspecific crosses
4398Montagutelli, XT, R.; Nadeau, J. H., Genetics, 143:1739-1752. 1996-01-16 00:00:00.
Strong deviation of allele frequencies from Mendelian inheritance favoring Mus spretus-derived alleles has been described previously for X-linked loci in four mouse interspecific crosses. We reanalyzed data for three of these crosses focusing on the location of the gene(s) controlling deviation on the X-chromosome and the genetic basis for incomplete deviation. At least two loci control deviation on the X chromosome, one near Xist (the candidate gene controlling X inactivation) and the other more centromerically located. In all three crosses, strong epistasis was found between loci near Xist and marker loci on the central portion of chromosome 2. The mechanism for this deviation from Mendelian expectations is not yet known but it is probably based on lethality of embryos carrying particular combinations of alleles rather than true segregation distortion during oogenesis in F-1 hybrid females.
Further evidence consistent with Stellate’s involvement in meiotic drive
4394Hurst, LD, Genetics, 142:641-643. 1996-01-12 00:00:00.
STELLATE is an X-linked multicopy gene found in Drosophila melanogaster and is one of the most bizarre gene arrays yet described (for details see HARDY et al. 1984; LIVAK 1984, 1990; DANILEVSKAYA et al. 1991; BAW~REVA et al. 1992; SHEVELYOV 1992; PALUMBO et al. 1994). The activity of Stellate is restricted to spermatogenesis. However, the transcription and translation of Stellate is inhibited in most males by a Y-linked multicopy gene, Suppressor of Stellate (Su(Ste)) alias crystal (q) . If Stellate is not suppressed, then the protein product (homologous to the beta subunit of casein kinase 11) is produced at levels dependent upon the copy number of Stellate. If Stellate copy number is relatively low, then linear crystals form and the males are of reduced, but nonzero, fertility. In high copy number (up to 200), however, the protein forms a star-shaped crystal in sperm, and the males are typically sterile. An understanding of this system is hence potentially of importance for the study of both intra- and inter-specific sterility and hence of HALDANE’S Rule
Segregation distortion of the CTG repeats at the myotonic dystrophy locus
4392Chakraborty, RS, D. N.; Deka, R.; Yu, L. M.; Shriver, M. D.; Ferrell, R. E., American Journal of Human Genetics, 59:109-118. 1996-01-10 00:00:00.
Myotonic dystrophy (DM), an autosomal dominant neuromuscular disease, is caused by a CTG-repeat expansion, with affected individuals having greater than or equal to 50 repeats of this trinucleotide, at the DMPK locus of human chromosome 19q13.3. Severely affected individuals die early in life; the milder form of this disease reduces reproductive ability. Alleles in the normal range of CTG repeats are not as unstable as the (CTG)(greater than or equal to 50) alleles. In the DM families, anticipation and parental bias of allelic expansions have been noted. However, data on mechanism of maintenance of DM in populations are conflicting. We present a maximum-likelihood model for examining segregation distortion of CTG-repeat alleles in normal families. Analyzing 726 meiotic events in 95 nuclear families from the CEPH panel pedigrees, we find evidence of preferential transmission of larger alleles (of size less than or equal to 29 repeats) from females (the probability of transmission of larger alleles is .565 +/- 0.03, different from .5 at P approximate to .028). There is no evidence of segregation distortion during male meiosis. We propose a hypothesis that preferential transmission of larger CTG-repeat alleles during female meiosis can compensate for mutational contraction of repeats within the normal allelic size range, and reduced viability and fertility of affected individuals. Thus, the pool of premutant alleles at the DM locus can be maintained in populations, which can subsequently mutate to the full mutation status to give rise to DM.
The inheritance of B chromosomes in Allium schoenoprasum L
4391Bougourd, SMP, A. B., Chromosome Research, 4:151-158. 1996-01-09 00:00:00.
The inheritance of B chromosomes has been investigated in Allium schoenoprasum from the River Wye, Powys; controlled crosses between plants of known B chromosome constitution were carried out, and the numbers of Bs present in the progenies scored. There was considerable heterogeneity in B chromosome transmission rates across the range of B chromosome numbers, through both the male and female lines, and in crosses involving odd and even numbers of Bs. The mean B number of the progeny was lower than the Mendelian expectation in 41 of the 57 crosses, significantly so in about a third of cases. No progeny had a mean B number significantly higher than expected. The mean transmission rate per B was not significantly different between parents with different numbers of Bs, in either the male or female line, or between plants carrying odd or even numbers of Bs. Transmission through the male line (0.43) was higher than through the female line (0.35), but not significantly so. The overall mean transmission rate per B (0.4), estimated from all crosses, was significantly lower than the expected rate of 0.5. This study provides conclusive evidence that B chromosomes in A. schoenoprasum from the River Wye lack an effective accumulation mechanism and, furthermore, show significant losses during transmission to the progeny of controlled crosses.
Low frequency of mouse t haplotypes in wild populations is not explained by modifiers of meiotic drive
4390Ardlie, KGS, L. M., Genetics, 144:1787-1797. 1996-01-08 00:00:00.
t haplotypes are naturally occurring forms of mouse chromosome 17 that show non-Mendelian transmission from heterozygous +/t males. In laboratory studies, transmission ratios of greater than or equal to 0.90 or higher are typically observed. With transmission ratios of this level, theoretical analyses predict high frequencies of t haplotypes (similar to 75%) in wild populations. In contrast, empirical frequencies of only 15-25% are typically found. This has led to the suggestion that modifiers of drive may play a role in reducing t frequencies. We have measured transmission ratio distortion (TRD) levels in wild +/t mice to examine this hypothesis. TRD was very high in both litters collected from wild-caught pregnant females, and in wild litters bred in the laboratory (mean = 0.9). Contrary to the results of other studies, we found no difference in TRD levels between semilethal and lethal t haplotypes nor between litters conceived from cycling or postpartum estrus. We found three litters with aberrantly low TRDs that were all multiply sired, although the role this might play in natural populations is unknown. These findings show a general absence of modifiers of drive in natural populations and suggest that other factors are responsible for the low observed frequencies of wild t haplotypes.
Sex-ratio distortion in Drosophila simulans – cooccurrence of a meiotic drive and a suppressor of drive
4406Mercot, HA, A.; Jacques, M.; Montchampmoreau, C., Journal of Evolutionary Biology, 8:283-300. 1995-01-04 00:00:00.
A sex-ratio distortion factor was found at high frequency in D. simulans strains from Seychelles and New Caledonia. This factor is poorly or not expressed within those strains which are resistant to it. Its presence was detected by crossing females from New Caledonia or the Seychelles with males from a different geographic origin. Most of the Fl males obtained produced an excess of females (up to 99%) in their progeny. The two strains are infected with Wolbachia, but these micro-organismms are not involved in the sex-ratio distortion. The sex-ratio factor is shown to be an X-linked meiotic driver; nuclear resistance factor(s) act by suppressing the drive. It is likely that the same X-located driver invaded the two populations, which subsequently developed resistance factor(s) against it.
Meiotic drive an Myotonic Dystrophy – Reply
4404Carey, NJ, K.; Nokelainen, P.; Peltonen, L.; Savontaus, M. L.; Juvonen, V.; Anvret, M.; Grandell, U.; Chotai, K.; Robertson, E.; Middletonprice, H.; Malcolm, S., Nature Genetics, 10:133-133. 1995-01-02 00:00:00.
Myotonic dystrophy (DM) is a trinucleotide disorder and in sub-clinical individuals there is considerable variation in the length of the CTG repeat. Two groups have recently analysed the patterns of segregation of different sized alleles at this locus and both report an excess of the longer version of the allele in the progeny of sub-clinical individuals1•2• This excess they claim to be due to meiotic drive1•2• Our re-analysis of these two studies indic
Ascoycete spore killers: Chromosomal elements that distort genetic ratios among the products of meiosis
4417Raju, NB, Mycologia, 86:461-473. 1994-01-15 00:00:00.
Spore killers (Sk), studied most extensively in Neurospora, are also known in Podospora, Gibberella and Cochliobolus. Spore killers are no doubt present in natural populations of other fungi. Criteria are outlined here for recognizing their presence and distinguishing them from other causes of ascospore death. Killing occurs when one parent carries the killer element (Sk(K)) and the other carries the sensitive counterpart (Sk(S)). When heterozygous, every ascus contains four normal-sized, viable ascospores and four ascospores that are tiny, undeveloped, and inviable. Spore killers are expressed postmeiotically causing the death of ascospores that do not receive the killer element and resulting in gross distortion of allele ratios for Sk-linked genes. There is little or no ascospore death in homozygous killer x killer or sensitive x sensitive crosses. Sk(K) is centromere-linked in linkage group III of Neurospora crassa and N. intermedia. When Sk is heterozygous, crossing over is blocked in a 30 map unit region that spans the centromere. A sensitive nucleus that would otherwise die is rescued, unchanged, if a killer nucleus is also included in the same ascospore. This has been shown for a developmental giant-ascospore mutant of N, crassa and for the naturally heterokaryotic ascospores of N. tetrasperma and Podospora anserina. As with other segregation-distorters in animals and plants, fungal Spore killers have been found only among strains from nature. Spore killers are fairly common in N. sitophila and Gibberella fujikuroi, but none have been found among natural isolates of N. crassa. In N. intermedia, most strains are sensitive to killing and killers are extremely rare. Some neutral strains are found in nature. These neither kill nor are killed. Resistance to killing is conferred by loci linked to the Sk region. The significance of fungal Spore killers for the individual organism and for populations is discussed.
Characterization of 2 Segregation Distorter revertants: Evidence that the tandem duplication is necessary for SD activity in Drosophila melanogaster
4416Palopoli, MFD, P.; Wu, C. I., Genetics, 136:209-215. 1994-01-14 00:00:00.
Segregation Distorter (SD) is a naturally occurring system of meiotic drive in Drosophila melanogaster. Males heterozygous for an SD second chromosome and a normal homolog (SD+) transmit predominantly SD-bearing sperm. To accomplish this, the Segregation distorter (Sd) locus induces the dysfunction of those spermatids that receive the SD+ chromosome. Recently, P. A. Powers and B. Ganetzky isolated overlapping DNA clones spanning the region of DNA known to contain the Sd gene and identified a 5-kb tandem duplication that is present on all SD chromosomes examined, but is apparently absent from wild-type chromosomes. Here we report a molecular analysis of two spontaneous revertants from an Australian SD chromosome (SD-Arm28). Both of these revertants have lost the 5-kb tandem duplication along with the ability to distort transmission; the critical observation, however, is that they retain the DNA haplotype in the flanking regions (both proximally and distally) that is characteristic of the original SD-Arm28. We propose unequal sister chromatid exchange between the tandem repeats as the only plausible explanation for loss of a repeat while retaining flanking markers. This provides direct evidence that the tandem duplication is indeed necessary for the Sd phenotype. Further, we examined testes-specific levels of both RNA and protein for the nearby Topoisomerase 2 gene. Neither revealed a consistent difference between SD and SD+ strains. We also measured testes-specific levels of RNA using the tandem duplication itself as probe. Our results suggest that there is strong up-regulation of one or several 2.0-2.3-kb transcripts from the duplicated region in the testes of an SD strain. Whether it is this overexpression of transcripts that causes segregation distortion remains to be investigated.
Functional identification of the Segregation Distorter locus of Drosophila melanogaster by germline transformation
4415McLean, JRM, C. J.; Powers, P. A.; Ganetzky, B., Genetics, 137:201-209. 1994-01-13 00:00:00.
Segregation Distorter (SD) is a meiotic drive system in D. melanogaster that results in the failure of SD/SD+ males to transmit SD+ homologs owing to the induced dysfunction of spermatids carrying the normal chromosome. Segregation distorter (Sd), the gene primarily responsible for this distorted transmission, is associated with a novel 12-kb restriction fragment containing a tandem duplication of a 5-kb wild-type segment of genomic DNA. When introduced into appropriate genetic backgrounds by germline transformation, this 12-kb fragment causes full levels of distortion and directs the expression of an Sd-specific 4-kb transcript. Transformants that have lost part of this segment are unable to cause distortion and do not express the 4-kb transcript. These results identify the tandem duplication as Sd.
Selfish DNA as method of pest control
4414Hastings, IM, Philosophical Transactions of the Royal Society B-Biological Sciences, 344:313-324. 1994-01-12 00:00:00.
The inheritance of most genes is tightly controlled, governed by the rules of mendelian inheritance if nuclear or uniparental inheritance if cytoplasmic. A few notable genes and cytoplasmic genomes have escaped this regulation. Such genes may spread by increasing their own rate of transmission despite reducing host fitness and may be regarded as 'selfish'. Their population genetics are described and it appears they may impose a significant genetic load on the host population. Modern molecular techniques may enable similar loads to be imposed on pest species either by transferring selfish genes between species, or by linking deleterious genes to a selfish locus. Alternatively, 'modifier' genes that eliminate the virulent, or disease vectorial capacity, of the pest population may be introduced by linkage to a selfish locus. Selfish elements present in multiple copies may be preferable to single-copy elements as the former are capable of a larger reduction in host fitness. The practical application of these agents depends on five factors: (i) the rate of 'reversion' to a non-selfish form; (ii) the evolution of host repressor systems; (iii) their effect on host fitness, which determines their rate of invasion; (iv) the mechanism regulating host population size in the field; and (v) their ease of manipulation in the laboratory. The first two factors are the most uncertain in most systems, but should be amenable to experimental analysis. It is proposed that the development of such techniques may result in powerful new methods of population control which may be applied to both agricultural pests and disease vectors.
Meiotic drive at the myotonic dystrophy locus
4413Gennarelli, MD, B.; Baiget, M.; Martorell, L.; Novelli, G., Journal of Medical Genetics, 31:980-980. 1994-01-11 00:00:00.
The mutation underlying myotonic dystrophy (DM, MIM* 160900) is the expansion of a CTG trinucleotide repeat sequence at the 3' untranslated region of a protein kinase gene (MT-PK).' The kinetics of this process is influenced by the sex of the transmitting parent and size of the parental allele.2 Congenital DM (CDM) occurs almost always with maternal transmission. Only two patients with CDM have proven paternal inheritance.5' Maternal transmission is considered to be the result of a large intergenerational increase of the CTG repeat size,7 while repeat length contractions are more likely inherited if the mutated allele is of paternal origin.8 However, the range of expansions is wider for alleles transmitted by fathers with fewer than 100 repeats (range 41 to 95).9 This has suggested a male bias in the generation of new contracted or expanded DM alleles.'° Carey et all' described an unusual segregation of the MT-PK alleles with a CTG number > 19 in healthy persons heterozygous for repeats in the wild type size range, and suggested the possibility of meiotic drive at the DM locus
Y-linked suppressors of the sex-ratio trait in Drosophila mediopunctata
4412Decarvalho, ABK, L. B., Heredity, 73:573-579. 1994-01-10 00:00:00.
X-linked meiotic drive causing female-biased progenies is known to occur in nine Drosophila species and is called 'sex-ratio'. In D. mediopunctata this trait is associated with the X:21 chromosome inversion and has variable expression. We describe here a powerful Y-linked suppressor system of sex-ratio expression in this species. There are two types of Y chromosomes (suppressor and nonsuppressor) and two types of X:21 chromosomes (suppressible and unsuppressible). Sex-ratio expression is suppressed in males with the 21 (suppressible)/Y-suppressor genotype, whereas the remaining three genotypes produce female-biased progenies.
The evolution of lethals in the t-haplotype system of the mouse
4411Charlesworth, B, Proceedings of the Royal Society B-Biological Sciences, 258:101-107. 1994-01-09 00:00:00.
The evolution of lethal haplotypes in the t-haplotype segregation distortion system of Mus is examined by mathematical and computer models. The models assume that there is reproductive compensation for the loss of lethal embryos, such that the net reproductive success of a female is not reduced in proportion to the frequency of lethal offspring which she produces. The initial population consists of a mixture of wildtype and homozygous male-sterile t-haplotypes. The failure of sterile males to reproduce may cause a higher fitness cost to mothers heterozygous for t-haplotypes than does elimination of a recessive lethal. Under certain conditions, a recessive lethal will spread and come to a polymorphic equilibrium. Wildtype, lethal and non-lethal haplotypes are all present at this equilibrium. Ifa second lethal mutation arises on a non-lethal t-haplotype in such an equilibrium population, it will increase in frequency and eventually displace the non-lethal t-haplotypes. A third lethal t-haplotype introduced at a low frequency into an equilibrium with two lethals can sometimes be selected for, although this is less likely if compensation is strong. The theoretical predictions are compared with data on natural populations.
The Segregation Distorter (SD) complex and the accumulation of deleterious genes in laboratory strains of Drosophila melanogaster
4423Dominguez, AS, E.; Albornoz, J.; Gutierrez, A., Theoretical and Applied Genetics, 87:479-486. 1993-01-21 00:00:00.
Segregation Distorter (SD) associated with the second chromosome of D. melanogaster is found in nature at equilibrium frequencies lower than 5%. We report extremely high frequencies of SD (30-50%) in two selected strains, established in 1976, and show it to be responsible for the accumulation of deleterious genes in chromosome II. Samples of chromosomes extracted over a 4-year period were characterized with respect to distortion, sensitivity, lethality, sterility, and inversions. SD chromosomes were inversion-free as they have been shown to be in the Mediterranean area. The cosmopolitan inversion In(2L)t was found associated with SD+ chromosomes. Lines polymorphic for SD have accumulated linked lethal and female-sterile genes approaching a near balanced system. It is proposed that deleterious genes linked in coupling to SD were accumulated by the balancing effect of distortion, while drift and restricted recombination account for the accumulation of deleterious genes linked in repulsion by a mechanism similar to Muller's ratchet. Our results should not be viewed as a particular case as SD chromosomes associated with detrimental genes and inversions are present in almost all populations around the world. The system could evolve in the way we describe whenever equilibrium conditions are broken down in small populations and lead to an increase in SD frequency.
Autosomal suppressors of sex-ratio in Drosophila mediopunctata
4422Decarvalho, ABK, L. B., Heredity, 71:546-551. 1993-01-20 00:00:00.
The sex-ratio trait has been described as the production of progenies with excess of females due to X-linked meiotic drive in the parental males. This trait has a variable expression in Drosophila mediopunctata. We describe here the existence and chromosomal localization of autosomal suppressors of sex-ratio in this species. There are at least four such genes (one on each major autosome) and the strongest effect.is localized on chromosome IV. These genes possibly result from the operation of 'Fisher's Principle'; a mechanism of Natural Selection leading to a 1:1 sex ratio.
Didymium iridis reproductive systems: Additions and meiotic drive
4421Clark, JL, J. C., Mycologia, 85:764-768. 1993-01-19 00:00:00.
Three heterothallic Mexican isolates (Mex 1, Mex 2, and Mex 3) of Didymium iridis belong to the reproductively isolated A5 mating series of this morphospecies. This was unexpected in that the sole previous A5 isolate was from Georgia and the Mexican isolates were collected in southern Mexico adjacent to the Central American Al series region. The Mexican isolates were also unusual in that mating alleles did not generally segregate in a normal 1:1 ratio. The A5(3) or A5(4) mating types, when present in a plasmodium, caused the partial or total elimination of the other mating allele during growth or sporulation. Isolates from Guatemala (Gua 2) and Panama (Pan 8) were found to belong to the Central American Al mating series. Each of these isolates was collected as a haploid selfed plasmodium which contained a single mating type respectively designated A1(13) and A1(14). Four nonheterothallic isolates from California (Ca 8), Guatemala (Gua 1), Japan (jap 1) and South Africa (SA 2) were also investigated.
Deletion analysis of the selfish B-chromosome, Paternal Sex-Ratio (PSR), in the parasitic wasp Nasonia vitripennis
4420Beukeboom, LWW, J. H., Genetics, 133:637-648. 1993-01-18 00:00:00.
Paternal Sex Ratio (PSR) is a ''selfish'' B chromosome in the parasitoid wasp Nasonia vitripennis. It is transmitted via sperm, but causes supercondensation and destruction of the paternal chromosomes in early fertilized eggs. Because this wasp has haplodiploid sex determination, the effect of PSR is to convert diploid (female) eggs into haploid (male) eggs that carry PSR. Characterizing its genetic structure is a first step toward understanding mechanisms of PSR action. The chromosome is largely heterochromatic and contains several tandemly repeated DNA sequences that are not present on the autosomes. A deletion analysis of PSR was performed to investigate organization of repeats and location of functional domains causing paternal chromosome destruction. Deletion profiles using probes to PSR-specific repetitive DNA indicate that most repeats are organized in blocks on the chromosome. This study shows that the functional domains of PSR can be deleted, resulting in nonfunctional PSR chromosomes that are transmitted to daughters. A functional domain may be linked with the psr22 repeat, but function may also depend on abundance of PSR-specific repeats on the chromosome. It is hypothesized that the repeats act as a ''sink'' for a product required for proper paternal chromosome processing. Almost all deletion chromosomes remained either functional of nonfunctional in subsequent generations following their creation. One chromosome was exceptional in that it reverted from nonfunctionality to functionality in one lineage. Transmission rates of nonfunctional deletion chromosomes were high through haploid males, but low through diploid females.
Transmission and expression of the parasitic Paternal Sex-Ratio (PSR) chromosome
4419Beukeboom, LWW, J. H., Heredity, 70:437-443. 1993-01-17 00:00:00.
B-chromosomes are often considered genomic parasites. They are extra to the normal chromosomal complement, are unnecessary for survival of an individual, and are often inherited at higher than Mendelian rates. Paternal Sex Ratio (PSR) is an extreme example of a parasitic B-chromosome in the wasp Nasonia vitripennis. It is transmitted via sperm but then destroys the other paternal chromosomes in the early fertilized egg. PSR disrupts the normal haplodiploid sex determination system of this wasp by converting diploid (female) eggs into haploid eggs that develop into PSR-bearing males. Transmission and expression of PSR was measured in single pair crosses between carrier males and standard females. Presence of the chromosome was detected by probing offspring with PSR-specific repetitive DNA. Most (equal to or more than 90 per cent) PSR males produced all-male offspring. Overall transmission rates of PSR to fertilized eggs varied beween 0.94 and 1.0. Some males (up to 10 per cent) produced daughters at varying frequencies. Of 226 daughters tested, only one carried PSR (and this may have been a laboratory error) indicating that daughters result from failure of transmission rather than loss of expression. Transmission of PSR to males in families that included female offspring varied from 0 to 94 per cent. Incomplete transmission is most likely the result of loss of PSR in some spermatogonial cell lineages and indicates some mitotic instability. Implications of the results to the aetiology and population genetics of PSR are discussed.
The peculiar journey of a selfish chromosome: Mouse t-haplotypes and meiotic drive
4428Silver, LM, Trends in Genetics, 9:250-254. 1993-01-06 00:00:00.
Mouse t haplotypes are descendents of a variant form of chromosome 17 that evolved the ability to propagate itself at the expense of the wild-type homolog from heterozygous +/t males. Although once enigmatic, these widespread selfish chromosomes have revealed many of their secrets in response to a combined assault with molecular, genetic and phylogenetic techniques. This review summarizes the current understanding of t haplotypes and their raison d'etre.
Evolutionary dynamics of spore killers
4426Nauta, MJH, R. F., Genetics, 135:923-930. 1993-01-04 00:00:00.
Spore killing in ascomycetes is a special form of segregation distortion. When a strain with the Killer genotype is crossed to a Sensitive type, spore killing is expressed by asci with only half the number of ascospores as usual, all surviving ascospores being of the Killer type. Using population genetic modeling, this paper explores conditions for invasion of Spore killers and for polymorphism of Killers, Sensitives and Resistants (which neither kill, nor get killed), as found in natural populations. The models show that a population with only Killers and Sensitives can never be stable. The invasion of Killers and stable polymorphism only occur if Killers have some additional advantage during the process of spore killing. This may be due to the effects of local sib competition or some kind of ''heterozygous'' advantage in the stage of ascospore formation or in the short diploid stage of the life cycle. This form of segregation distortion appears to be essentially different from other, well-investigated forms, and more field data are needed for a better understanding of spore killing.
Cheaters sometimes prosper: Distortion of Mendelian segregation by meiotic drive
4425Lyttle, TW, Trends in Genetics, 9:205-210. 1993-01-03 00:00:00.
Two of Mendel's three laws were quickly discarded as information on the organization and transmission of genes accumulated at the beginning of this century, but bis law of segregation has shown remarkable staying power. In fact, within most of population genetic theory for sexual diploids is buried the tacit assumption that heterozygous alleles are represented in gametes in a 1:1 ratio. Nevertheless, there is a small, but important, group of genetic systems that subvert the law of segregation, and show 'meiotic drive.'
The evolution of unusual chromosomal systems in coccoids: Extraordinary sex-ratios revisited
4424Haig, D, Journal of Evolutionary Biology, 6:69-77. 1993-01-02 00:00:00.
Coccoids (scale insects) exhibit a wide variety of chromosomal systems. In many species, paternal chromosomes are eliminated from the male germline such that all of a male's sperm transmit an identical set of maternal chromosomes. In such species, an offspring's sex is determined by whether or not paternal chromosomes are inactivated in the egg's cytoplasm after fertilization. This paper presents a model of the evolution of paternal genome loss in coccoids from an ancestral system of XX-XO sex determination. The model is based on Hamilton's (1967) theory that different genetic elements within the genome have different unbeatable sex ratios. In this model (1) meiotic drive by the X chromosome in XO males causes female-biased sex ratios; (2) the maternal set of autosomes in males evolves effective sex linkage to exploit X-drive; and (3) genes expressed in mothers are selected to convert some of their XX daughters into sons. A similar model may explain the evolution of haplodiploidy.
Evolution of the mouse t-haplotype – Recent and worldwide introgression to Mus musculus
4433Morita, TK, H.; Murata, K.; Nozaki, M.; Delarbre, C.; Willison, K.; Satta, Y.; Sakaizumi, M.; Takahata, N.; Gachelin, G.; Matsushiro, A., Proceedings of the National Academy of Sciences of the United States of America, 89:6851-6855. 1992-01-11 00:00:00.
Mouse t haplotypes are variants of chromosome 17, consisting of four inversions. Despite the homozygous lethality and pleiotropic effect on embryonic development, sperm production, and recombination, they have widely spread in natural populations of the house mouse (10-40% in frequency) because of the meiotic drive advantage. We sequenced 14 Tcp-1 (t-complex polypeptide 1) genes from four t haplotypes, nine wild mice, and a rat as a reference. From a comparison of intron sequences of 610 base pairs, we dated the origin of t haplotypes to 2.9 +/- 0.7 million years ago, which predates the splitting of Mus musculus subspecies (almost-equal-to 1 million years ago). However, the Tcp-1 intron sequences of t haplotypes from different M. musculus subspecies from various parts of the world show no divergence, indicating the recent introgression (no earlier than 0.8 million years ago) of a single ancestral type. Nucleotide changes in coding regions are also consistent with this conclusion. Hence, polymorphisms among t haplotypes including lethality factors have accumulated during this short time period independently in each M. musculus subspecies.
Population genetics of a parasitic chromosome – Experimental analysis of PSR in subdivided populaltions
4431Beukeboom, LWW, J. H., Evolution, 46:1257-1268. 1992-01-09 00:00:00.
Nasonia vitripennis is a parasitoid wasp that harbors several non-Mendelian sex-ratio distorters. These include MSR (Maternal Sex Ratio), a cytoplasmic element that causes nearly all-female families, and PSR (Paternal Sex Ratio), a supernumerary chromosome that causes all-male families. As in other hymenoptera, N. vitripennis has haplodiploid sex determination. Normally, unfertilized (haploid) eggs develop into males and fertilized (diploid) eggs develop into females. The PSR chromosome violates this normal pattern; it is inherited through sperm, but then causes destruction of the paternal chromosomes (except itself, thus converting diploid fertilized eggs (normally females) into haploid eggs that develop into PSR-bearing males. PSR is an extreme example of "parasitic" or "selfish" DNA. Because N. vitripennis has a highly subdivided population structure in nature, population-level selection may be important in determining the dynamics of PSR in natural populations. A theoretical analysis shows that subdivided population structure reduces PSR frequency, whereas high fertilization proportion (such as produced by the MSR element) increases PSR frequency. Population experiments using two deme sizes (3- and 12-foundress groups) and strains producing two fertilization proportions [wild-type (LabII)-57-67% female, and MSR (MI)-90-93% female] confirm these predictions. PSR achieved frequencies over 0.90 in 12-foundress group MSR populations in contrast to 0.20-0.40 in wild-type 12-foundress populations. PSR was selected against in wild-type populations composed of three-foundress groups. In MSR populations with three-foundress groups, presence of PSR selected against the MSR cytoplasmic element, eventually leading to low frequencies of both PSR and MSR. Complicated dynamics may occur when these two sex-ratio distorters are both present in highly subdivided populations. The existence of PSR in natural populations may depend on the presence of MSR. Results indicate that population subdivision could be important in determining the frequency of sex ratio distorters in N. vitripennis.
Effects of deletions on mitotic stability of the Paternal Sex-Ratio (PSR) chromosome from Nasonia
4430Beukeboom, LWR, K. M.; Werren, J. H., Chromosoma, 102:20-26. 1992-01-08 00:00:00.
Paternal-Sex-Ratio (PSR) is a B chromosome that causes all-male offspring in the parasitoid wasp Nasonia vitripennis. It is only transmitted via sperm of carrier males and destroys the other paternal chromosomes during the first mitotic division of the fertilized egg. Because of haplodiploidy, the effect of PSR is to convert diploid (female) eggs into haploid eggs that develop into PSR-bearing males. The PSR chromosome was previously found to contain several families of repetitive DNA, which appear to be present in local blocks. PSR chromosomes with irradiation-induced deletions have decreased rates of transmission and increased variation in transmission. This study investigates whether these differences in transmission of deletion chromosomes are due to mitotic instability. Two deletion chromosomes (E306 and F316) and the wild-type PSR chromosome were examined. A cytogenetic assay of testes revealed that wild-type PSR males contained the chromosome in 98%-100% of their spermatocytes. Similar counts from carriers of two deletion chromosomes were lower and varied between individuals from 50%-100%. One F316 male did not contain the chromosome in any of its spermatocytes although the chromosome was present in somatic tissues based on hybridization to PSR-specific repetitive DNA. A molecular analysis of males found the wild-type PSR chromosome to be present in all somatic tissues. Tissue specific differences in the presence or PSR were found in several males from the two deletion lines. The results show that deletions can result in mosaicism due to increased mitotic instability of PSR. Such individuals sometimes partially or completely fail to transmit the chromosome. Patterns of mosaicism of 13 chromosomes in other organisms are discussed.
Genetic scrambling as a defense against meiotic drive
4443Haig, DG, A., Journal of Theoretical Biology, 153:531-558. 1991-01-21 00:00:00.
Genetic recombination has important consequences, including the familiar rules of Mendelian genetics. Here we present a new argument for the evolutionary function of recombination based on the hypothesis that meiotic drive systems continually arise to threaten the fairness of meiosis. These drive systems act at the expense of the fitness of the organism as a whole for the benefit of the genes involved. We show that genes increasing crossing over are favoured, in the process of breaking up drive systems and reducing the fitness loss to organisms.
Meiotic drive in Lucilia cuprina and chromosomal evolution
4441Foster, GGW, M. J., American Naturalist, 137:403-415. 1991-01-19 00:00:00.
In females heterozygous for pericentric inversions that alter the relative lengths of the long and short arms of a chromosome, crossing-over within the inversion can lead to unequal segregation at anaphase II, favoring the homologue with the more centrally located centromere. It is suggested that this phenomenon may have played a role in the evolution of centromere position in certain species groups.
X-chromosome segregation distortion in Drosophila
4439Curtsinger, JW, American Naturalist, 137:344-348. 1991-01-17 00:00:00.
The sex-ratio trait exhibits both discrete and continuous variation in Drosophila pseudoobscura. The discrete variation is caused by X-chromosome meiotic drive. The evolutionary forces maintaining the meiotic-drive polymorphism include strong viability selection against homozygous females and virility selection in males. The relative importance of the two factors is unresolved. The evidence for a genetic component in the continuous sex-ratio variation comes from artificial-selection experiments, large-scale estimation of segregation ratios corrected for viability effects, and an examination of the rates of spermatid loss. Segregation ratio can be treated as a typical quantitative character subject to major and minor genetic modifiers.
Sex-ratio distortion caused by meiotic drive in mosquitos
4458Wood, RJN, M. E., American Naturalist, 137:379-391. 1991-01-16 00:00:00.
Meiotic-drive genes have been described in two species of mosquito, Aedes aegypti and Culex quinquefasciatus. In both species, a Y (M)-linked gene causes a change in sex ratio in favor of males. More is known about the Distorter gene (D) in A. aegypti, but the gene in C. quinquefasciatus appears to be similar. D is located on the right arm of the sex chromosome, is marked with the intercalary Giemsa C-band when present, and is linked closely to the sex locus or region. D undergoes meiotic drive only when in coupling with M, the male-determining gene, which does not recombine with the centromere. Sensitivity to the MD haplotype is controlled at m, the female-determining gene. Therefore, m is considered to be the responder. The m haplotype is polymorphic for sensitivity to MD (m(r1), m(r2), m(s1)-m(s6)). Sensitivity is influenced, in some strains, by a second sex-linked gene t (tolerance to Distorter). Another sex-linked gene, A, enhances the effect of D. Meiotic drive is associated with breaks on the sex chromosomes. First seen at diplotene, mainly at four discrete positions, 90% of these breaks occur on the X (m) chromosome. They usually appear on a chiasmic arm of the bivalent, with the result that most acentric fragments remain attached to the unbroken homologue by a chiasma. Examination of developing spermatozoa in Distorter males reveals extreme sperm depletion, a high degree of abnormality (e.g., multiple axonemes), and an increased DNA content up to the 4C level. Surprisingly, however, the effective fertility of these males is hardly reduced. Evidently, spermatozoa are produced in nondistorter males in vast excess. The Distorter gene has been found in populations from Africa, America, Australia, and Sri Lanka. Resistance to it is much more widespread. The presence of natural resistance argues against the use of D for population control, but its effect has been shown to be enhanced in the presence of certain translocations and the A gene, causing it to become effective in field cage trials, even in the presence of some resistance. There is also experimental support for using D to bring about changes in populations ("population replacement").
Why is Mendelian segregation so exact
4438Crow, JF, Bioessays, 13:305-312. 1991-01-16 00:00:00.
The precise 1:1 segregation of Mendelian heredity is ordinarily taken for granted, yet there are numerous examples of 'cheating' genes that perpetuate themselves in the population by biasing the Mendelian process in their favor. One example is the Segregation Distortion system of Drosophila melanogaster, in which the distorting gene causes its homologous chromosome to produce a nonfunctional sperm. This system depends on three closely linked components, whose molecular basis is beginning to be understood. The system is characterized by numerous modifiers changing the degree of distortion. Mathematical theory shows that unlinked modifiers that change the degree of distortion in the direction of Mendelism always increase in the population. This provides a mechanism for removing cheaters and preserving the honesty of the Mendelian gene-shuffle.
Male sex-ratio trait in Drosophila pseudoobscura: Frequency of autosomal aneuploid sperm
4437Cobbs, GJ, L.; Gordon, L., Genetics, 127:381-390. 1991-01-15 00:00:00.
Males with the SR X chromosome show the "sex-ratio" (sr) phenotype in which they produce almost entirely daughters. The few sons (about 1%) are invariably sterile X/O males and result entirely from nullo-XY sperm. The "male-sex-ratio" (msr) phenotype is a modified form of sr in which SR/Y males produce a higher frequency of sterile X/O sons. The msr trait is due to the presence of the SR X-chromosome in males which are also homozygous for one or more autosomes from the L116 strain. Here the frequency of nullo-3 and diplo-3 sperm from msr males was measured by crossing to a compound-3 strain and found to be 13.8% and 3.2%, respectively, of the total viable sperm. The sr males produced very low levels of nullo-3 sperm at a frequency not different from control X/Y males and a slightly elevated frequency of diplo-3 sperm over X/Y males. The msr males were found to have only 12% the fecundity of sr males and in matings to cause a high frequency of brown inviable eggs. These results indicate that high rates of autosomal aneuploidy are not restricted to chromosome 3 but also occur for chromosomes 2, 4 and 5. The overall frequency of autosomal aneuploid sperm is estimated to be approximately 50%. Microscopic studies of meiosis in testes from msr males indicates meiotic nondisjunction and meiotic chromosome loss are responsible for the msr phenotype. Last, microscopic studies of sperm cysts from msr males reveal high levels of spermiogenic failure.
The paternal-sex-ratio chromosome of Nasonia
4457Werren, JH, American Naturalist, 137:392-402. 1991-01-15 00:00:00.
Paternal sex ratio (PSR) is a supernumerary chromosome that is transmitted through sperm to fertilized eggs and then gains a transmission advantage by causing supercondensation of the paternal chromosomes (except itself). Because of haplodiploidy, this converts diploid females into haploid (PSR) males. PSR gains a transmission advantage because the unpaired chromosome has a higher frequency of transmission through male (mitotic) gametngenesis than through female (meiotic) gametogenesis. PSR increases in panmictic populations that produce more than 50% fertilized eggs. PSR frequency is typically reduced by population subdivision because of increased local competition among PSR males and reduced availability of females resulting from PSR action. Genetic and molecular studies of PSR have recently begun. PSR is highly heterochromatic and contains large tandem arrays of repetitive DNA unique to it. PSR apparently acts by "imprinting" the set of paternal chromosomes, resulting in their supercondensation during mitosis. Deletion studies are under way to characterize the genetic basis of PSR action and "protection" from its own action.
Sex ratio polymorphism in Drosophila pseudoobscura
4436Beckenbach, AT, American Naturalist, 137:340-343. 1991-01-14 00:00:00.
I studied "sex-ratio" (SR) genotype frequencies in two populations of Drosophila pseudoobscura from southeastern Arizona: Bear Creek Canyon and Tucson. Wild-inseminated females were collected, their fecundities measured in the laboratory, and their SR genotypes inferred by cytological analysis of their progenies. A statistically significant fecundity deficiency was observed among SR/SR females from Bear Creek Canyon. The SR frequency in the Tucson population increased at a rate consistent with the operation of meiotic drive unopposed by selection.
Meiotic drive of t-haplotypes – chromosome segregation in mice with tertiary trisomy
4435Agulnik, AIA, S. I.; Ruvinsky, A. O., Genetical Research, 57:51-54. 1991-01-13 00:00:00.
The properties of the t haplotypes, specific mutant states of the proximal region of chromosomes 17 in the house mouse, are of continuing interest. One such property is increased transmission of the t haplotype by heterozygous t/+ males to offspring. Using the reciprocal translocation T(16; 17)43H we have constructed males with tertiary trisomy of chromosome 17 (+ T43/ + +/Rb7 +) carrying the Robertsonian translocation Rb(16.17)7Bnr. Only the progeny of these males which had inherited either T43/ + or Rb7 from their male parent were viable. The segregation patterns in the offspring of t-bearing trisomics were analysed on days 16-18 of embryonic development. It was found that, when the t12 haplotype is in the normal acrocentric (males + + T43/ + t12 + /Rb7 + +), its presence in the gamete + t12 + / + + T43 does not produce meiotic drive. However, when t6 is in Rb7, meiotic drive was observed: 80% of offspring carried the t haplotype. It is concluded that the meiotic drive is probably inhibited by the presence of a normal homologue of chromosome 17 in the same sperm. Possible mechanisms for the t haplotype effect are discussed.
Segregation distortion in Drosophila melanogaster: Genetic and molecular analysis
4455Temin, RGG, B.; Powers, P. A.; Lyttle, T. W.; Pimpinelli, S.; Dimitri, P.; Wu, C. I.; Hiraizumi, Y., American Naturalist, 137:287-331. 1991-01-13 00:00:00.
The Segregation Distorter (SD) complex in the centromeric region of chromosome 2 in Drosophila melanogaster is responsible for a naturally occurring and strong system of male meiotic drive. Earlier recombinational dissection and deletional analysis showed that the SD complex resolves into three major loci: the euchromatic Sd, or Segregation distorter gene at the base of the left arm of the chromosome (2L), and two heterochromatic genes: E(SD), the Enhancer of SD, and Rsp, the Responder, in the center of the left arm and the right arm (2R), respectively. Rsp exists in the major allelic forms, Rsp(s), for sensitive, and Rsp(i), for insensitive. Males that are heterozygous for an SD chromosome (SdE(SD)Rsp(i)) and a sensitive SD+ homologue (Sd+ E(SD)+ Rsp(s)) transmit predominantly or even exclusively the SD-bearing chromosome to the progeny. The distortion of the segregation ratio is traceable to failure in chromatin condensation and maturation of those spermatids that receive the Rsp(s) homologue during meiosis. Characterization of the properties of null alleles of Sd, E(SD), and Rsp that were generated by delection determined the precise cytological locations of the components and established the functional relationship of each to its wild-type counterpart, suggesting a model whereby a deleterious action of Sd, along with E(SD), on the Rsp(s) target sets in motion the events culminating in sperm dysfunction. Further genetic analysis of E(SD), a gene required for full expression of drive, showed that E(SD) in two doses can cause significant distortion even in the absence of Sd. This distortion is suppressible by a suppressor of SD action. Thus, E(SD) is more than a simple modifier of Sd; rather, it is an effector locus that, like Sd, can act at the Rsp(s) target. Cloning and molecular analysis of the Sd locus reveal that the alteration uniquely associated with Sd is a 5-kb tandem duplication within the polytene band 37D5, which is where Sd is known to map. The Sd-associated duplication appears to be part of a large gene about 100 kb in size. A 4.2-kb SD-specific transcript has been identified, and analyses of the cDNAs indicate a complex transcription pattern. Since Responder plays such a key role in segregation distortion, recent progress in analyzing this locus has been exciting. Studies of Rsp at the genetic, cytogenetic, and molecular levels have been mutually reinforcing and consistent in demonstrating that Rsp is an extended locus that is (1) subdivisible and (2) associated with a 120-bp repeated sequence of DNA that is rich in adenine-thymine pairs and whose copy number is correlated with the degree of sensitivity. In an exceptional situation, there are certain Sd Rsp(i)/Sd+ Rsp(s) males carrying particular modifiers in which the Rsp(i) chromosome can be transmitted at frequencies of less than 0.50 relative to the Rsp(s) chromosome, suggesting that the genetics of segregation ratios may involve even further complexities, which need to be unraveled.
Expression of meiotic drive elements Spore Killer-2 and Spore Killer-3 in asci of Neurospora tetrasperma
4454Raju, NBP, D. D., Genetics, 129:25-37. 1991-01-12 00:00:00.
It was shown previously that when a chromosomal Spore killer factor is heterozygous in Neurospora species with eight-spored asci, the four sensitive ascospores in each ascus die and the four survivors are all killers. Sk-2K and Sk-3K are nonrecombining haplotypes that segregate with the centromere of linkage group III. No killing occurs when either one of these killers is homozygous, but each is sensitive to killing by the other in crosses of Sk-2K x Sk-3K. In the present study, Sk-2K and Sk-3K were transferred by recurrent backcrosses from the eight-spored species Neurospora crassa into Neurospora tetrasperma, a pseudohomothallic species which normally makes asci with four large spores, each heterokaryotic for mating type and for any other centromere-linked genes that are heterozygous in the cross. The action of Sk-2K and Sk-3K in N. tetrasperma is that predicted from their behavior in eight-spored species. A sensitive nucleus is protected from killing if it is enclosed in the same ascospore with a killer nucleus. Crosses of Sk-2K x Sk-2S, Sk-3K x Sk-3S, and Sk-2K X Sk-3K all produce four-spored asci that are wild type in appearance, with the ascospores heterokaryotic and viable. The Eight-spore gene E, which shows variable penetrance, was used to obtain N. tetrasperma asci in which two to eight spores are small and homokaryotic. When killer and sensitive alleles are segregating in the presence of E, only those ascospores that contain a killer allele survive. Half of the small ascospores are killed. In crosses of Sk-2K x Sk-3K (with E heterozygous), effectively all small ascospores are killed. The ability of N. tetrasperma to carry killer elements in cryptic condition suggests a possible role for Spore killers in the origin of pseudohomothallism, with adoption of the four-spored mode restoring ascospore viability of crosses in which killing would otherwise occur.
Meiotic drive of t haplotypes: chromosome segregation in mice with tertiary trisomy
4434Agulnik, AIA, Sergei I.; Ruvinsky, Anatoly O., Genetics Research, 57:51. 1991-01-12 00:00:00.
The properties of the / haplotypes, specific mutant states of the proximal region of chromosomes17 in the house mouse, are of continuing interest. One such property is increased transmission ofthe / haplotype by heterozygous // + males to offspring. Using the reciprocal translocationT(16; 17)43H we have constructed males with tertiary trisomy of chromosome 17( + T43/+ +/Rb7 + ) carrying the Robertsonian translocation Rb(16.17)7Bnr. Only the progeny ofthese males which had inherited either T43/ + or Rb7 from their male parent were viable. Thesegregation patterns in the offspring of /-bearing trisomics were analysed on days 16-18 ofembryonic development. It was found that, when the tn haplotype is in the normal acrocentric(c?c?+ + T43/ + //2+/Rb7 + +), its presence in the gamete +/" + /+ + T43 does not producemeiotic drive. However, when t6 is in Rb7, meiotic drive was observed: 80 % of offspring carriedthe / haplotype. It is concluded that the meiotic drive is probably inhibited by the presence of anormal homologue of chromosome 17 in the same sperm. Possible mechanisms for the t haplotypeeffect are discussed
On the components of Segregation Distortion in Drosophila melanogaster 5: Molecular analysis of the SD locus
4453Powers, PAG, B., Genetics, 129:133-144. 1991-01-11 00:00:00.
Segregation Distorter (SD) is a naturally occurring meiotic drive system comprising at least three distinct loci: Sd, Rsp and E(SD). Heterozygous SD/SD+ males transmit the SD chromosome in vast excess over the normal homolog. The distorted transmission involves the induced dysfunction of the spermatids that receive the SD+ chromosome. In the 220-kb region of DNA that contains the Sd gene, we identified a 5-kb tandem duplication that is uniquely associated with all SD chromosomes, absent in SD+ chromosomes, and detectably altered in Sd revertants. On northern blots, genomic probes from the tandem duplication detect an SD-specific 4-kb transcript in addition to several smaller transcripts present in both SD and SD+. Seven classes of cDNAs derived from these transcripts have been isolated. All of these cDNAs share extensive sequence identity at their 3' ends but differ at their 5' ends. Sequence analysis indicates that these cDNAs potentially encode four distinct, but related, polypeptides. Introduction of the tandem duplication into SD+ flies by germline transformation did not confer the dominant gain-of-function Sd phenotype. This result, taken together with our analysis of the Sd cDNAs, suggests that the duplication is part of a much larger gene that encodes several different polypeptides.
X-Y pairing, meiotic drive and ribosomal DNA in Drosophila melanogaster males
4452McKee, BD, American Naturalist, 137:332-339. 1991-01-10 00:00:00.
One of the genotypic features responsible for sex-chromosome meiotic drive and sterility in Drosophila melanogaster males has now been defined clearly. Separation of a significant fraction of X euchromatin from the X pairing site causes either meiotic drive or sterility, depending on whether the separation occurs alone or in combination with rearrangements involving the Y chromosome. The relationship between X-chromosome integrity and the late-spermatid developmental breakdowns responsible for meiotic drive and sterility is still not understood. X-Y pairing is important for some aspect of spermatogenesis in addition to its role in X-Y disjunction. Transcriptional inactivation and meiotic timing are two possibilities that are worth exploring, and there are likely to be others. With molecular probes for genes active in spermatogenesis becoming available, ideas such as the pairing dependence of transcriptional inactivation should become amenable to direct tests. It is hoped that an increased use of molecular methods will shed new light on this fascinating genetic problem.
The Genetic Basis of Transmission-Ratio Distortion and Male Sterility Due to the t Complex
4449Lyon, MF, American Naturalist, 137:349-358. 1991-01-07 00:00:00.
The abnormal transmission ratios observed in male mice heterozygous for a complete t haplotype have been shown by breeding studies to be due to three or more distorter genes acting on a responder gene. The action of the t form of the responder is relatively resistant to this harmful action. When the distorters are homozygous, their harmful action is more severe. The t form of the responder is then affected, and the males are sterile. The distorter and responder genes are distributed over a region occupying the proximal third of mouse chromosome 17. Crossover suppression between t and wild-type bapiotypes in this region is due to the presence of inversions and is thought to be selectively advantageous in locking the genetic factors together. The recessive lethals carried by many t haplotypes are also thought to be advantageous in removing the sterile males from the population. Transmission ratio is also affected by genetic background, and there is evidence of differences among t haplotypes either in the responder or in cis-acting effects of distorters.
Behavioral reduction in the transmission of deleterious t-haplotypes by wild house mice
4446Lenington, SH, I. L., The American Naturalist, 137:366-378. 1991-01-04 00:00:00.
About 25% of wild house mice are heterozygous (+/t) for a variable recessive haplotype of the T locus. Although t haplotypes are highly deleterious when homozygous, they are maintained in wild mouse populations because they are associated with transmission-ratio distortion in heterozygous males, which may transmit their t haplotype to 90%-100% of their progeny. In a study of factors affecting variation in male transmission ratio in matings between wild-caught +/t males and +/+ females, we found (1) that male transmission ratio is considerably lower in litters produced as a result of postpartum-estrus matings than in litters produced as a result of cycling-estrus matings, (2) that the frequency of postpartum-estrus litters is much higher when +/t males mate with females caught from the same location as themselves than when they mate with females caught elsewhere, and (3) that, as a result of findings I and 2, the male transmission ratio is considerably lower in within-population matings than in betweenpopulation matings. These data suggest that the frequency of t haplotypes within populations may be correlated with the migration rate and that t haplotypes may be found in high frequencies only in populations for which the migration rate is high.
Sex-ratio meiotic drive in Drosophila testacea
4462James, ACJ, J., Genetics, 126:651-656. 1990-01-20 00:00:00.
We document the occurrence of "sex ratio" meiotic drive in natural populations of Drosophila testacea. "Sex ratio" males sire greater than 95% female offspring. Genetic analysis reveals that this effect is due to a meiotically driven X chromosome, as in other species of Drosophila in which "sex ratio" has been found. In contrast to other drosophilids, the "sex ratio" and standard chromosomes of D. testacea do not differ in gene arrangement, implying that the effect may be due to a single genetic factor in this species. In all likelihood, the "sex ratio" condition has evolved independently in D. testacea and in the Drosophila obscura species group, as the loci responsible for the effect occur on different chromosomal elements. An important ecological consequence of "sex ratio" is that natural populations of D. testacea exhibit a strong female bias. Because D. testacea mates, oviposits, and feeds as adults and larvae on mushrooms, this species provides an excellent opportunity to study the selective factors in nature that prevent "sex ratio" chromosomes from increasing to fixation and causing the extinction of the species.
Rapid spread of transposable P elements in experimental populations of Drosophila melanogaster.
6265A. G. Good, G. A. Meister, H. W. Brock, T. A. Grigliatti and D. A. Hickey, Genetics, 1223:387-396. 1989-05-08 16:20:58.
The invasion of P elements in natural populations of Drosophila melanogaster was modeled by establishing laboratory populations with 1 %, 5% and 10% P genomes and monitoring the populations for 20 generations. In one experiment, the ability of flies to either induce or suppress gonadal sterility in different generations was correlated with the amount of P element DNA. In a second experiment, the percentage of genomes that contained P elements, and the distribution of P elements among individual flies was monitored. The ability to induce gonadal dysgenesis increased rapidly each generation. However, the increase in P cytotype lagged behind by five to ten generations. The total amount of P element DNA and the frequency of flies containing P elements increased each generation. The number of P elements within individual genomes decreased initially, but then increased. Finally, the distribution of P elements within the genomes of individuals from later generations varied considerably, and this pattern differed from the parental P strain. These results suggest that the interaction between the assortment and recombination of chromosomal segments, and multiplicative transposition could result in the rapid spread of P elements in natural populations
Genetics-driving genes and chromosomes
4463Charlesworth, B, Nature, 332:394-395. 1988-01-21 00:00:00.
Thereare several genetic and chromosomal systems in which Mendel's first law - the equal probability of transmission of maternal and paternal alternative alleles or homologues - is violated. This phenomenon was named 'meiotic drive' in 1957 by Sandler and Novitski, who drew attention to the fact that it operates as an evolutionary force which can cause an increase in the population frequency of the allele or chromosome which is favoured in transmission, even if it confers a disadvantage on its carriers in terms of fitness at the level of the individual
Methods for replacement of malaria vector populations
4464Curtis, CFG, P. M., American Journal of Tropical Medicine and Hygiene, 91:43-48. 1988-01-02 00:00:00.
The prospects are reviewed of replacement of malaria vector populations by harmless mosquito populations by means of: (i) ecologically competitive non-vector species; (ii) natural selection due to the harmfulness of being infected; (iii) selection for insecticide resistance genes; (iv) meiotic drive; (v) negative heterosis; and (vi) hybrid dysgenesis. Serious difficulties exist with all of these approaches. At present 'dilution', i.e. release of insects carrying the desired genes without any system for forcing population replacement is the only available method. It avoids the disadvantage that, in constructing elaborate genetic 'packages', factors for low fitness may be irreversibly incorporated into them. It is debatable whether release of males only or both sexes should be attempted.
Thte genetic basis of resistance and sensitivity to the meiotic drive gene D in the mosquito Aedes aegypti L.
4469Wood, RJO, N. A., Genetica, 72:69-79. 1987-01-07 00:00:00.
A study has been made on the genetic basis of meiotic drive at the Distorter (D) locus which, in coupling with the male-determining gene (or region) M on the Y chromosome, causes production of excess male progeny. Its effect is regulated by the sensitivity/resistance of the X chromosome. This study demonstrates that there are two major loci controlling resistance/sensitivity to MD: (1) the m gene (or region) on the X chromosome (allelic with M) which may be either m R or m S (resistant or sensitive), (2) the t (tolerance) gene (or genes) which recombines with m and, if present, largely counteracts the effect of m S . There is also evidence that MD itself is capable of limited adaptation.; ; The conclusions were derived from using MD males of the T30 or ACCRA strains (from Trinidad and Ghana respectively). The work involved the use of the CHIPEI and RED strains with sensitive X chromosomes, the latter also carrying the t (tolerance) gene which is linked to re (red eye) and m (the sex-determining locus or region) but recombines with both. The implications of these findings for using MD as a method of population control are discussed.
Abnormal salivary gland puff associated with meiotic drive in mosquitos (Diptera, Culicidae)
4468Sweeny, TLG, P.; Barr, A. R., Journal of Medical Entomology, 24:623-627. 1987-01-06 00:00:00.
A meiotic drive factor, distorter (d), has been described previously for Culex pipiens L. mosquitoes. Males homozygous for the gene (Md/md) produce few female offspring owing to breakage of the female-determining dyad of chromosome 1 (the sex chromosome) during the first meiotic division of spermatogenesis. Orcein squash preparations of polytene salivary gland chromosomes of the distorter strain revealed a chromosome break and other abnormalities at zone 10C3, the location of a large puff that has been reported to be associated with sex determination in C. pipiens. In the polytene chromosomes, d apparently disrupts normal expansion and contraction of the puff. Zone 10C3 probably is also the breakpoint of the female-determining dyad. Zone 10C3 on the male-determining dyad seems to be resistant to the action of d, whereas zone 10C3 on the female-determining dyad is vulnerable to the destructive action of d. Possibly the break in the female-determining dyad occurs directly at m, the gene locus for "femaleness" in C. pipiens, in which case d may be a mutated form of m.
Control of meiotic drive of B-chromosomes in the mealybug, Pseudococcus affinis (obscurus)
4467Nur, UB, B. L. H., Genetics, 115:499-510. 1987-01-05 00:00:00.
Isofemale lines of Pseudococcus affznis (MASKELL) differ in their ability to maintain B chromosomes (Bs) due to the presence of genotypes that affect the rate of transmission (k) of the Bs. The nature of these genotypes was analyzed by comparing ks of males carrying the same B and the same paternal genome (which is heterochromatic), but differing in their maternal genome. In males from line L-60, which maintained the B at a frequency of over 4.0 Bs per individual, the mean k varied between 0.7 and 0.95 in different experiments. Over the same period, the mean k of males with a maternal genome from one of two lines in which the B was rapidly lost (L-1 19), increased from 0.5 to 0.9, and that of the other line (L-230) decreased gradually from 0.6 to less than 0.1. The ks appear not to be correlated with the geographical or parental origin of the B. The observed changes in k are attributed at least in part to changes in the frequency of genotypes (alleles) which can drastically reduce the transmission of the B and, when present in high frequency, can lead to its rapid loss. The frequency distribution of the ks of sons of F, females from the cross L-230 X L-60 suggests that the two lines differ at two unlinked loci with additive effects on k. The genome of L-119 also caused the B to undergo nondisjunction in about 10% of the primary spermatocytes. A comparison between the ks of the males tested and those of males from a natural population suggests that in that population the B is “parasitic” and that the frequency of transmission-reducing genotypes is low.
X-4 Translocation and meiotic drive in Drosophila melanogaster males: Role of sex chromosome pairing
4466McKee, B, Genetics, 116:409-413. 1987-01-04 00:00:00.
Males carrying certain X-4 translocations exhibit strongly skewed sperm recovery ratios. The Xp4D half of the translocation disjoins regularly from the Y chromosome and the 4‘XD half disjoins regularly from the normal 4. Yet the smaller member of each bivalent is recovered in excess of its pairing partner, apparently due to differential gametic lethality. Chromosome recovery probabilities are multiplicative; the viability of each genotype is the product of the recovery probability of its component chromosomes. Meiotic drive can also be caused by deficiency for X heterochromatin. In( I)scQLscBR males show the same size dependent chromosome recoveries and multiplicative recovery probabilities found in T(1;4)Bs males. Meiotic drive in Zn(I)scQLscBR males has been shown to be due to X-Y pairing failure. Although pairing is regular in the T(X;4) males, the striking phenotypic parallels suggest a common explanation. The experiments described below show that the two phenomena are, in fact, one and the same. X-4 translocations are shown to have the same effect on recovery of independently assorting chromosomes as does Zn(I)scqLscgR. Addition of pairing sites to the 4pXD half of the translocation eliminates drive. A common explanation-failure of the distal euchromatic portion of the X chromosome to participate in XY meiotic pairing-is suggested as the cause for drive. The effect of X chromosome breakpoint on X-4 translocation induced meiotic drive is investigated. It is found that translocations with breakpoints distal to 13C on the salivary map do not cause drive while translocations broken proximal to 13C cause drive. The level of drive is related to the position of the breakpoint-the more proximal the breakpoint the greater the drive.
Meiotic drive in the sex-chromosome system of the varying lemming, Dicrostonyx torquatus Pall (Rodentia, Microtinae)
4465Gileva, EA, Heredity, 59:383-389. 1987-01-03 00:00:00.
In the varying lemming, numerous fertile XY females occur regularly due to the X-linked mutation (X*). Their frequency both in natural populations and laboratory colonies turned out to be about twice higher than that expected under random segregation of heterochromosomes in both sexes. It has been shown in experiments that an excess of XY females resulted from a preferential segregation of the Y chromosome in males. Segregation distortion is not produced by selective embryonal mortality. Meiotic drive of the Y chromosome also causes a significant decrease of sex ratio. Although in the varying lemming meiotic drive is rather weak (the segregation ratio of the Y being 0·54–0·59), it seems to contribute essentially to the evolutionary spread and the maintenance of the X* mutation in populations. The example of Dicrostonyx and probably of other microtines also demonstrates the possible role of meiotic drive in the regulation of the population sex ratio in mammals.
Detection of Rsp and modifier variation in the meiotic drive system Segregation Distorter (SD) of Drosophila melanogaster
4470Lyttle, TWB, J. G.; Ganetzky, B., Genetics, 114:183-202. 1986-01-08 00:00:00.
Identification of allelic variability at the two major loci (Sd and Rsp) that interact to cause sperm dysfunction in Segregation distorter (SD) males of D. melanogaster has been hampered by the difficulty in separating the elements recombinationally. In addition, small differences in the strength of Sd alleles or sensitivities of Rsp alleles to Sd are difficult to measure against background genetic or environmental variation. Viability effects of the markers used to score progeny classes may also introduce a bias. Removal of Sd and E(SD) from their second chromosome location to create a Dp(2;Y)Sd E(SD) chromosome eliminates these problems, since any combination of Rsp alleles can be easily tested without resorting to recombinational techniques. Further, since these pairs of Rsp alleles are compared in their response to Dp Sd E(SD) in the same individual males, background variation and viability effects can be easily removed to allow finescale resolution of Rsp differences. Tests of all possible pairwise combination of six laboratory chromosomes in this way revealed at least three and possibly four different Rsp allelic classes. In addition, the hierarchical nature of the tests further allowed for determination of the presence of linked suppressors or enhancers of Sd activity. A sample of 11 second chromosomes selected from a group recently isolated from a natural population was also unambiguously ordered as to Rsp allelic status using this approach. The resultant pattern was similar to that obtained for the laboratory chromosomes, except for the not unexpected observation that the natural population apparently harbored more drive suppressors. The pattern of results obtained from these pairwise combinations of Rsp alleles supports the notion that there are no dominance interactions within the group, but that each responds more or less independently to Sd in giving sperm dysfunction.
Tthe genetic control of meiotic drive acting on the B-chromosome of Myrmeleotettix maculatus (Orthoptera, Aacrididae)
4473Shaw, MWH, G. M., Heredity, 54:187-194. 1985-01-11 00:00:00.
Crosses between populations with and without B-chromosomes were made, and backcrossed to the non B parent for two generations. No polygenic differences in male or female meiotic transmission were found, but a modifier of meiotic drive segregated in the experiment, drastically reducing female transmission rate. We tentatively interpret this as evidence of a coevolutionary race between the B-chromosome and the A genome.
Genotypes suppressing meiotic drive of a B-chromosome in the mealybug, Pseudococcus obscurus
4471Nur, UB, B. L. H., Genetics, 110:73-92. 1985-01-09 00:00:00.
The rate of transmission (k) of a supernumerary B chromosome in male mealybugs is shown tq depend strongly on the chromosome set of materpal origin. When both parents came from an isofemale line in which the frequency of the B chromosome increased rapidly and stabilized at a mean of more than 4.0 B chromosomes per individual, was 0,92 and 0.95 in two series of crosses. However, when the female parent came from one of two isofemale lines in which the frequency of the B chromosome decreased from 2.0 to 0 in a few generations, R ranged from 0.53 to 0.78. The high ks, which represent a strong meiotic drive, are apparently responsible for the observed increase in the frequency of the B chromosome in several lines from a mean of about 0.5 to more than 4.0 in about 20 generations. The rapid loss of the B chromosome in other lines is attributed to genetic factors which caused the reduction in the rate of transmission qf the B chromosome.
Sex-chromosome meiotic drive in Drosophila melanogaster males
4474McKee, B, Genetics, 106:403-422. 1984-01-12 00:00:00.
In Drosophila melanogaster males, deficiency for X heterochromatin causes high X-Y nondisjunction and skewed sex chromosome segregation ratios (meiotic drive). Y and XY classes are recovered poorly because of sperm dysfunction. In this study it was found that X heterochromatic deficiencies disrupt recovery not only of the Y chromosome but also of the X and autosomes, that; both heterochromatic and euchromatic regions of chromosomes are affected and that the "sensitivity" of a chromosome to meiotic drive is a function of its length. Two models to explain these results are considered. One is a competitive model that proposes that all chromosomes must compete for a scarce chromosome-binding material in Xh- males. The failure to observe competitive interactions among chromosome recovery probabilities rules out this model. The second is a pairing model which holds that normal spermiogenesis requires X-Y pairing at special heterochromatic pairing sites. Unsaturated pairing sites become gametic lethals. This model fails to account for autosomal sensitivity to meiotic drive. It is also contradicted by evidence that saturation of Y-pairing sites fails to suppress meiotic drive in Xh- males and that extra X-pairing sites in an otherwise normal male do not induce drive. It is argued that meiotic drive results from separation of X euchromatin from X heterochromatin.
The fate of autosomeal modifiers of the sex-ratio trait in Drosophila and other sex-linked meiotic drive systems.
4475Wu, CI, Theoretical Population Biology, 24:107-120. 1983-01-13 00:00:00.
A model is proposed to analyze the behavior of autosomal suppressor modifiers of "Sex-Ratio" meiotic drive in drosophila. These modifiers, if neutral in fitness, are expected to increase because they tend to be associated with the rare sex (males). However, selection operating on the sex-linked drive locus will sometimes act against autosomal modifiers as well because the two loci are always in gametic phase disequilibrium. Conditions under which modifiers will not increase are presented in terms of the relative fitness of the sex-linked drive locus. To prevent the increase of modifiers, the fitness of Sex-Ratio males relative to Standard males has to be no greater than 0.3 and there has to be overdominance in females. This model integrates findings from the search for modifiers and results from the measurement of fitness.
Meiotic drive at the D(MD) locus and fertility in the mosquito, Aedes aegypti (L)
4479Youngson, JW, H. M.; Wood, R. J., Genetica, 54:335-340. 1981-01-17 00:00:00.
The Distorter gene D in Aedes aegypti shows meiotic drive when associated with the male determining M gene, causing sex ratio distortion in favour of males. The fertility of Distorter (MD /ms) and normal (M/m-) males has been compared after mating them to a series of 20 females at daily intervals. ; Males of each genotype inseminated up to 13 fe. males (mean 8.0 - 9.0). The major difference was in the significantly greater number of inviable eggs produced by females mated to Distorter males. It is postulated that these eggs were fertilised by abnormal spermatozoa. Females mated to Distorter males also produced significantly greater numbers of shrivelled i.e. unfertilised eggs, indicating a lower density of effective spermatozoa.; The difference in percentage hatch from the two matings was small, indicating that spermatozoa were produced in superabundance so that the overall fertility of Distorter males was not greatly reduced.
Experimental population-genetics of meiotic drive systems .3: Neutralization of sex-ratio distortion in Drosophila through sex-chromosome aneuploidy
4477Lyttle, TW, Genetics, 98:317-334. 1981-01-15 00:00:00.
Laboratory populations of Drosophila melanogaster were challenged by; pseudo-Y drive, which mimics true Y-chromosome meiotic drive through the; incorporation of Segregation Distorter (SD) in a T(Y;2) complex. This causes; extreme sex-ratio distrotion and can ultimately lead to population extinction.; Populations normally respond by the gradual accumulation of drive suppressors,; and this reduction in strength of distortion allows the sex ratio to move; closer to the optimal value of 1:l. One population monitored, however, was; rapidly able to neutralize the effects of sex-ratio distortion by the accumulation; of sex-chromosome aneuploids (XXY, XYY) . This apparently occurs because; XX-bearing eggs, produced in relatively high numbers (-4%) by XXY; genotypes, become the main population source of females under strong Ychromosome; drive. Computer simulation for a discrete generation model incorporating; random mating with differences in fitness and segregation permits; several predictions that can be compared to the data. First, sex-chromosome; aneuploids should rapidly attain equilibrium, while stabilizing the population; at -60% males. This sex ratio should be roughly independent of the strength; of the meiotic drive. Moreover, conditions favoring the accumulation of drive; suppressors (e.g., weak distortion, slow population extinction) are insufficient; for maintaining aneuploidy, while conditions favoring aneuploidy (e.g., strong; distortion, low production of females) lead to population extinction before drive; suppressors can accumulate. Thus, the different mechanisms for neutralizing; sex-ratio distortion are complementary. In addition, Y drive and sex-chromosome; aneuploidy are potentially co-adaptive, since under some conditions; neither will survive alone. Finally, these results suggest the possibility that; genetic variants promoting sex-chromosome nondisjunction may have a selective; advantage in natural populations faced with sex-ratio distortion.
Combining the meiotic drive gene-D and the translocation T-1 in the mosquito, Aedes aegypti(L) .2: Recombination
4481Pearson, AMW, R. J., Genetica, 54:79-85. 1980-01-19 00:00:00.
Recombination on the sex-chromosome of Aedes aegypti has been studied in male genotypes incorporating the sex-linked translocation T1 and the meiotic drive gene D from three different strains (Trinidad, Bozo and Caracas).
Combining the meiotic drive gene-D and the translocation-T1 in the mosquito, Aedes aegypti (L) .1: Sex-ratio distortion and fertility
4480Pearson, AMW, R. J., Genetica, 51:203-210. 1980-01-18 00:00:00.
Sex-ratio distortion has been investigated in males carrying the Y(M)-linked meiotic-drive gene D, from three different strains (Bozo, Caracas and Trinidad), paired with Chipei X-chromosomes highly sensitive to D. The effect of D was tested on its own and also associated with a 1-3 translocation (designated TI). The fertility of males homozygous and heterozygous for the translocation, with and without D, was also investigated
Experimental population-genetics of meiotic drive systems .2: Accumulation of genetic modifiers of Segregation Distorter (SD) in laboratory populations
4482Lyttle, TW, Genetics, 91:339-357. 1979-01-20 00:00:00.
The accumulation of modifiers of the meiotic-drive locus Segregation; Distorter (SD) in Drosophila melanogaster was monitored by measuring the; changes in the mean and variance of drive strength (in terms of “make” value); that occur in laboratory populations when SD and SD+ chromosomes are in; direct competition. The particular SD lines used are T(Y;Z),SD translocations; showing pseudo-Y drive. Four sets of population cages were analyzed. Two sets; were monitored for changes in SD fitness and drive strength (presumed to be; positively correlated) and analyzed for the presence of autosomal dominant; or X-linked modifiers after long periods of time. The remaining two sets were; made up of cages either made isogenic or variable for background genetic; material, and these were used to test whether the rate of accumulation of; modifiers was dependent on initial genetic variability.-Contrary to previous; studies in which most suppression of SD action could apparently be attributed; to a few dominantly acting modifiers of large effect, the conclusion here is; that laboratory populations that are initially free of such major dominant loci; evolve to suppress SD action by accumulating polygenic, recessive modifiers,; each of small effect, and that much of the required genetic variability can be; generated a!e novo by mutation. Possible explanations for these seemingly incompatible results and the evolutionary implications for SD are considered.
Sex-ratio trait in Drosophila pseudoobscura – Fertility relations of males and meiotic drive.
4483Beckenbach, AT, American Naturalist, 112:97-117. 1978-01-21 00:00:00.
In the early analysis of the "sex-ratio" polymorphism (SR) of Drosophila pseudoobscura, complete meiotic drive was assumed, and study centered on the nature of the selective forces opposing its spread. Policansky and Ellison (1970) found that the mechanism of SR involved the degeneration of half the spermatids during spermatogenesis. They suggested that little or no drive may be expressed due to a fertility deficiency of SR males. Thus little or no selection is required to balance the drive. I report studies conducted to determine the conditions under which either of these alternatives might hold. Virgin females were mated once to either SR or ST (standard) males aged as virgins for 3 days, and their fecundities were determined by daily egg counts. No differences were found between the two groups in either daily egg production or egg-to-adult survival of the progenies. Only females maintained with males throughout the experiment were clearly superior in these parameters. No fertility differences between SR and ST males are unconditional. Fertilities of males aged for varying lengths of time as virgins were determined by mating them to as many virgin females as they would inseminate in a brief span of time. Time periods ranged from 3 to 8 h, depending on the ages of the males. Fertility of the SR males was lower than that of ST males of the same age for males aged 20-33 h from eclosion. Differences in 4-day-old males were not so clear. When 4-day-old males which had depleted their stores of sperm by repeated matings were retested after 12 h of rest, SR males again showed lower fertility than ST males. The fertility reduction of SR males occurs only during the first few days as adults or after repeated matings. The effect of different degrees of insemination on the pattern of production of fertile eggs was examined by mating virgin females to males which were either virgin (heavy insemination) or with seminal vesicles partially depleted by three previous matings (light insemination). No differences in either fecundity or hatchability between the groups were observed early in the reproductive period, but the hatchability of the eggs produced by the lightly inseminated females declined sooner than that of the heavily inseminated group. This response would minimize the populational consequences of fertility differences in males unless the females remate. It is suggested that the conditional fertility differences between SR and ST males are of little consequence until the females remate. Depending on the time of remating, there is potentially a wide range in the amount of meiotic drive expressed.
Transporting marker gene re (red eye) into a laboratory cage population of Aedes aegypti (Diptera Culicidae), using meiotic drive at MD locus
4486Wood, RJC, L. M.; Hamilton, A.; Whitelaw, A., Journal of Medical Entomology, 14:461-464. 1978-01-04 00:00:00.
An attempt has.been made to use the meiotic drive gene MD to transport a marker re (red eye) into a laboaratory population of the mosquito Aedes aegypti. The experiment produced an increase in re frequency, but also indicated that this gene has unexpectedly high fitness in the laboratory. The need for field estimates of fitness is indicated.
Sex ratio distortion caused by meiotic drive in a mosquito Culex pipiens
4485Sweeny, TLB, A. R., Genetics, 88:427-446. 1978-01-03 00:00:00.
A genetic factor, distorter (d), has been discovered that upsets the normal sex ratio of 1 : 1 and results in a large excess of males in Culex pipiens. The effect can be explained by a sex-linked, recessive gene. Males homozygous for the gene (Md/md) produce few female offspring; the effect is not due to postzygotic mortality. During the first meiotic division in spermatogenesis, the shortest chromosome pair, which, according to JOST and LAVEN (1971), is associated with sex determination, can be seen to be abnormal. In a high proportion of spermatocysts, one of the dyads of the shortest bivalent fragments, and the pieces are distributed irregularly to the daughter cells. It is believed that the female-determining chromosomes fragment. This would give rise to an excess of male-determining sperm. The possible usefulness of this factor for control or for experimental purposes is discussed.
Transporting marker gene re (red eye) into a laboratory cage population of Aedes-aegypti (Diptera Culicidae), using meiotic drive at MD locus
6233R. J. Wood, L. M. Cook, A. Hamilton and A. Whitelaw, Journal of Medical Entomology, 14:461-464. 1977-12-24 21:51:08.
An attempt has been made to use the meiotic drive gene MD to transport a marker re (redeye) into a laboratory population of the mosquito Aedes aegypti. The experiment produced an increase in re frequency, but also indicated that this gene has unexpectedly high fitness in the laboratory. The need for field estimates of fitness is indicated.
Resistance to meiotic drive at MD locus in an Indian wild population of Aedes aegypti
4488Suguna, SGW, R. J.; Curtis, C. F.; Whitelaw, A.; Kazmi, S. J., Genetical Research, 29:123-132. 1977-01-06 00:00:00.
Females from an Indian wild population of Aedes aegypti were crossed to males carrying the sex ratio distorter factor MB which shows meiotic drive. Progenies from ¥1 males were tested for sex ratio distortion, i.e. the chromosomes from the wild females were screened for their resistance to the action of M°. The distribution of sex ratio in the progenies of different ¥1 males indicated a polymorphism in the wild population for resistant and sensitive variants of the X chromosome. Seven discrete categories of X appear to exist, associated with sex ratios ranging from 50 % $ to less than 1'25 % $. The overall level of resistance varied slightly but significantly in different parts of a town. The results are discussed in relation to the use of sex ratio distortion for genetic control of mosquitoes.
Experimental population-genetics of meiotic drive systems .1: Pseudo-Y chromosomal drive as a means of eliminating cage populations of Drosophila melanogaster
4487Lyttle, TW, Genetics, 86:413-445. 1977-01-05 00:00:00.
The experimental population genetics of Y-chromosome drive in Drosophila; melanogasier is approximated by studying the behavior of T(Y;S),SD lines.; These exhibit “pseudo-Y” drive through the effective coupling of the Y chromosome; to the second chromosome meiotic drive locus, Segregation distorter; (SD). T(Y;S),SD males consequently produce only male offspring. When; such lines are allowed to compete against structurally normal SD+ flies in; population cages, T(Y;S),SD males increase in frequency according to the; dynamics of a simple haploid selection model until the cage population is; eliminated as a result of a deficiency in the number of adult females. Cage; population extinction generally occurs within about seven generatiomSeveral; conclusions can be drawn from these competition cage studies:; (1) Fitness estimates for the T(Y;Z),SD lines (relative to SD+) are generally; in the range of 2-4, and these values are corroborated by; independent estimates derived from studies of migration-selection; equilibrium.; (2) Fitness estimates are unaffected by cage replication, sample time, or; the starting frequency of T(Y;Z),SD males, indicating that data from; diverse cages can be legitimately pooled to give an overall fitness; estimate.; (3) Partitioning of the T(Y;S),SD fitnesses into components of viability,; fertility, and frequency of alternate segregation (Y + SD from; X+SD+) suggests that most of the T(Y;S),SD advantage derives; from the latter two components. Improvements in the system might; involve increasing both the viability and the alternate segregation to; increase the total fitness.; While pseudo-Y drive operates quite effectively against laboratory stocks,; it is less successful in eliminating wild-type populations which are already; segregating for suppressors of SD action. This observation suggests that further
Between family variation in sex-ratio in Trinidad (T-30) strain of Aedes-aegypti (L) indicating differences in sensitivity to meiotic drive gene MD
4494Wood, RJ, Genetica, 46:345-361. 1976-01-12 00:00:00.
Sex ratio in the Trinidad (T-30) strain of Aedes aegypti has remained constant at around 43%? during seventeen years of laboratory culture. The divergence from 50% is due to meiotic drive by the MD gene on the Y chromosome. The driving Y chromosome gives a much more distorted sex ratio (mean = 5.7%?) when coupled with the highly sensitive X chromosomes from strain 64. This was demonstrated in all of 98 families tested, indicating that all or most of the Y chromosomes in T-30 carry the MD gene. Consequently the low level of sex ratio distortion in T-30 must be due to resistance to MD.; ; Crosses made within T-30 demonstrated wide differences in sex ratio between families, depending on the sensitivity of the male parent's X chromosome to MD. However, sex ratios were not continuously variable but fell within fairly discrete categories. Thus, X chromosomes could be classified according to the modal sex ratios associated with them: ms3 (12.5%?), ms2 (32.5%?), ms1 (40%?), mr1 (47.5%?) mr2 (57.5%?).; ; The different sex ratio categories were more discrete in the families of sib matings than from random matings, suggesting the possibility of background modification of what is essentially a balanced polymorphism. Evidence is presented suggesting that the polymorphism could be due to interaction at two loci. A further X variant, ms4 (<10%?) characterised strain 64 but was absent from T-30.; ; A comparison of fertility between the different sex ratio categories in T-30 established that sex ratio distortion was not caused by differential mortality after fertilisation.
Population genetics of modifiers of meiotic drive.3. Equilibrium analysis of a gneral model for genetic control of segregation distortion
4493Thomson, GJF, M. W., Theoretical Population Biology, 10:8-25. 1976-01-11 00:00:00.
Prout, Bungaard and Bryant (1973, Theor. Popul. Biol. 4, 446–465) presented the first formal treatment of a model of meiotic drive involving a modifier locus which controls the intensity of drive. They studied the equilibrium behavior in the simplest model where it is assumed that drive is maximal when not suppressed. In that case there is one polymorphic equilibrium at which there is linkage disequilibrium. The equilibrium solutions in the general model of meiotic drive proposed by Prout, et al. are given in this paper together with a stability analysis. It is shown that up to three polymorphic equilibria may exist, two of which are in linkage disequilibrium and one in linkage equilibrium. These equilibria exhibit behavior qualitatively opposite to what is widely accepted as the usual for two locus systems and which is not seem in the simple case originally treated. The polymorphic equilibria with linkage disequilibrium may be stable for loose linkage and not for tight while that with linkage equilibrium is stable in an interval of relatively tight linkage values.
Evidence for autosomal meiotic drive in the butterfly Danaus chrysippus L.
4492Smith, DAS, Heredity, 36:139-142. 1976-01-10 00:00:00.
Danaus chrysippus (Danaidae) in East Africa is highly polymorphic for colour, the genetic control of which resides at three loci. The B locus has two alleles, B giving a nutbrown ground colour and bb orange on both fore and hindwings. The C locus determines forewing pattern: there are two alleles, C giving a wing uniformly coloured except for a black margin (form dorippus) and cc a large black apical area traversed by a row of white subapical spots (form ae&yptius = form chrysippus of my earlier papers). Heterozygotes (Cc) are basically dorippus but are often phenotypically distinct in showing the "aegyptius" subapical spots on the underside of the forewing. The B and C loci are closely linked (Smith, 1975a). The A locus has a recessive allele a the homozygous possessor of which has a large white patch on the hindwing (form alcippus when combined with the aegyptius forewing and form albinus with the dorippus forewing). The A locus probably assorts independently from the B and C loci (Clarke, Sheppard and Smith, 1973; Smith, 1975a). All-female broods commonly occur in D. chrysippus. These probably result when a Y-linked gene D causes meiotic drive for the Y chromosome so that it always enters the secondary oocyte at the first meiotic division in the female. Females from all-female broods usually themselves produce allfemale broods but a switch to bisexual broods can occur and seems to depend on the acquisition of a dominant autosomal suppressor gene S from the maternal male grandparent. The S locus is probably closely linked with the C locus (Smith, 1975b).
Cytogenetic analysis of meiotic drive in mosquito, Aedes aegypti
4491Newton, MEW, R. J.; Southern, D. I., Genetica, 46:297-318. 1976-01-09 00:00:00.
Meiotic drive in Aedes aegypti (L.) is shown by a Giemsa C-banding technique to be associated with. preferential isochromatid breakage of the X chromosome during male meiosis. These breaks remain open at least until anaphase-I and, since the range of cells affected is proportional to the sensitivity of the X chromosome to the Distorter gene, it is argued that they are directly related to the decreased number of spermatozoa found in distorting males. This reduction is considered to be attributable to the degeneration of more X- than Y-bearing spermatids but it is probable that some non-functional X-bearing spermatozoa are also produced. Chromosome breakage is almost completely confined to four sites, two adjacent to the centromere, one just proximal to the intercalary band and another about the centre of the unbanded arm. Although the first three of these lie within a region in which crossing-over does not take place, fragmentation occurs more frequently in a chiasmate arm than in one devoid of chromatid exchange.
Meiotic drive for B-chromosomes in primary oocytes of Myrmeleotettix maculatus (Orthoptera-Acrididae)
4489Hewitt, GM, Chromosoma, 56:381-391. 1976-01-07 00:00:00.
Using a modified technique which allowed observation of chromosome orientation in the primary oocyte of grasshoppers at the onset of anaphase, it has been possible to establish that the B-chromosome is distributed preferentially on the egg side of the metaphase plate rather than the polar body side. The frequency of this preferential orientation matches very closely the level of preferential transmission determined from breeding experiments using individuals from the same population. The spindle is asymmetrical in the primary oocyte of this species, and a possible explanation of the meiotic drive is proposed as a result of the conical shape of nucleoplasm surrounding this spindle. The autosomal chiasma frequency of these females is generally lower than comparable males and is increased by the presence of B chromosomes; but the chiasma frequencies of the sexes respond differently to the addition of 1 and 2 B-chromosomes.
Sex-chromosome meiotic drive systems in Drosophila melanogaster .1: Abnormal spermatid development in males with a heterochromatin-deficient X-chromosome (sc4sc8)
4496Peacock, WJM, G. L. G.; Goodchild, D. J., Genetics, 79:613-634. 1975-01-14 00:00:00.
The meiotic drive characteristics of the In(1)sc4Lsc8R/Y system have been examined by genetic analysis and by light and electron microscopy. sc4sc8/Y males show a direct correlation between nondisjunction frequency and meiotic drive. Temperature-shift experiments reveal that the temperature-sensitive period for nondisjunction is at meiosis, whereas that for meiotic drive has both meiotic and post-meiotic components. Cytological analyses in the light and electron microscopes reveal failures in spermiogenesis in the testes of sc4sc8 males. The extent of abnormal spermatid development increases as nondisjunction becomes more extreme.
Modifier theory of meiotic drive
4495Hartl, DL, Theoretical Population Biology, 7:168-174. 1975-01-13 00:00:00.
The evolutionary fate of rare modifiers of recessive lethal segregation distorters has been studied. Suppressors or partial suppressors will always increase in frequency. Enhancers will increase in frequency if linkage is sufficiently tight and be lost if linkage is sufficiently loose.
Sex-ration, meiotic drive, and group selectin in Drosophila pseudoobscura
4498Policansky, D, American Naturalist, 108:75-90. 1974-01-16 00:00:00.
Sex ratio (SR) is a widespread genetic condition of the X-chromosome in Drosophila species which causes males to produce progenies consisting almost entirely of females. Results of samples from natural populations of Drosophila pseudoobscura and results of some laboratory experiments indicate that SR males produce only about half as many sperm as normal (ST) males; because of this deficiency, SR males are able to fertilize only about half as many eggs as ST males. These results explain the observed equilibria of frequencies of SR in natural populations, and suggest that, at least in the case of D. pseudoobscura, male fertility may be partly limited by the number of sperm males can produce.
Population replacement in Culex fatigens by means of cytoplasmic incompatibility. Laboratory experiments with non-overlapping generations
6291C. F. Curtis and T. Adak, Bulletin of the World Health Organization, 51:249-255. 1974-01-08 19:45:42.
Bidirectional cytoplasmic incompatibility in the Culex pipiens complex appears to provide a mechanism for the replacement of a wild population by a strain refractory to filaria or a strain made partly sterile by a translocation. As a preliminary test of the feasibility of the replacement process, various ratios of strains with the cytoplasm of either Delhi or Paris, which are bidirectionally incompatible, were tested in laboratory cages. Where one strain was marked with the ruby-eye gene, this strain always declined in frequency in the next generation. In experiments in which the Paris strain was marked with a male-linked translocation complex, after 2-4 generations of breeding there was complete elimination of either the Paris or the Delhi type depending, as expected, on the relative frequencies of the two types with which the population began. In one experiment a type with Paris cytoplasm devoid of the translocation was found. This type increased in frequency in succeeding generations. The possible causes of origin of this type and its relevance to the practical use of the replacement principle are discussed.
Multiple meiotic drive systems in Drosophila melanogaster male
4499Miklos, GLGY, A. F.; Peacock, W. J., Genetics, 72:105-115. 1972-01-17 00:00:00.
The behaviour of two "meiotic drive" systems, Segregation-Distorter (SD) and the sex chromosome sc4sc8 has been examined in the same meiocyte. It has been found that the two systems interact in a specific way. When the distorting effects of SD and sc4sc8 are against each other, there is no detectable interaction. Each system is apparently oblivious to the presence of the other, gametes being produced according to independence expectations. However when the affected chromosomes are at the same meiotic pole an interaction occurs; the survival probability of the gamete containing both distorted chromosomal products is increased, rather than being decreased by the combined action of two systems.
Analysis of a general population genetic model of meiotic drive
4501Hartl, DL, Evolution, 24:538-545. 1970-01-19 00:00:00.
The purpose of this article is to present the detailed solution of a model of meiotic drive which Lewontin (1968) has suggested would be helpful in understanding the evo- lutionary dynamics of the t-alleles in the house mouse. Because mice tend to breed in small endogamous family units, however, the deterministic model is only a very rough approximation to what would be expected to occur in nature, and to gain better insight one is forced to undertake Monte Carlo simulation of small populations (Lewontin and Dunn, 1960; Lewontin, 1968).
Meiotic drive in natural populations of Drosophila melanogaster 9: Suppressors of segregation distorter in wild populations
4500Hartl, DL, Canadian Journal of Genetics and Cytology, 12:594-600. 1970-01-18 00:00:00.
A population of Drosophila melanogaster in Madison, Wisconsin, has been screened for suppressors of segregation distorter (SD), an autosomal meiotic drive element found in the same population. Three kinds of suppressors were tested for: (1) Y-linked suppressors, none were found, (2) X-linked suppressors, whose frequency was found to be 85%, and (3) autosomal dominant suppressors, which occur in 45% of autosome complements.The frequency of X-linked suppressors is comparable to that found in a Japanese population; autosomal suppressors are much more frequent in Madison than in Japan (Katoaka, 1967). The similarity in the frequency of sex-linked suppressors may result from the meiotic drive shown by the suppressor-X itself; the difference in the frequency of autosomal dominant suppressors is possibly related to a higher frequency of SD itself in the Madison population.
Extraordinary sex ratios
6186W. D. Hamilton, Science, 156:477-488. 1967-04-03 19:10:19.
The two sexes are usually produced in approximately equal numbers. Fisher (1) was the first to explain why, under natural selection, this should be so, irrespective of the particular mechanism of sex determination. His rather tersely expressed argument has been clarified by subsequent writers (2) and seems to be widely accepted. In bare outline, the factor of parental care being ignored, it may be given as follows: 1) Suppose male births are less common than female. 2) A newborn male then has better mating prospects than a newborn female, and therefore can expect to have more offspring. 3) Therefore parents genetically disposed to produce males tend to have more than average numbers of grandchildren born to them. 4) Therefore the genes for male-producing tendencies spread, and male births become commoner. 5) As the 1:1 sex ratio is approached, the advantage associated with producing males dies away. 6) The same reasoning holds if females are substituted for males throughout. Therefore 1:1 is the equilibrium ratio.
Genetic distortion of sex ratio in a mosquito Aedes aegypti
4505Hickey, WAC, G. B., Genetics, 53:1177-1196. 1966-01-03 00:00:00.
CRAIG, HICKEY and VANDEHEY (1960) reported that a hereditary factor transmitted by males was responsible for high male ratios in A. aegypti. This phenomenon was designated as male-producing or MP. Males from high maleproducing families produced a high proportion of males in their own progeny, regardless of the type of female to which they were crossed. This condition was not due to selective mortality, at least in postgametic stages. In 1960, nothing was known about the sex-determining mechanism in A. aegypti. In addition, the male-producing lines available for study were highly variable in expression. These factors hampered more precise analysis of the mechanism of inheritance of MP. The present work was initiated because new crosses with different strains gave more pronounced and predictable distortion of sex ratios. Earlier strains gave about 15 to 30% female, whereas present lines produce about 0 to 15% female. This paper presents an analysis of the mode of inheritance of MP. In addition, data suggesting the mechanism of action are included. Separate reports will be published elsewhere on ( 1 ) the distribution and behavior of MP in experimental populations and (2) the effect of environment on expression of MP. A more detailed account of some of this work is given by HICKEY (1965a, b). Nomenclature used ih these preliminary reports is superseded by that in the present work.
Meiotic drive in Drosophila involving chromosome breakage
4506Erickson, J, Genetics, 51:555-571. 1965-01-04 00:00:00.
In ordinary genetic systems the members of a pair of unlike alleles, or of a pair of unlike chromosomes, are recovered in equal numbers among the off spring, barring complications affecting viability. Contrary to this expectation, in a number of studies it has been found that one allele or chromosome is recovered in significantly more than 50 percent of the functional gametes. The time and mode of the action resulting in inequality varies; where these phenomena result from events of the meiotic process they are known as instances of meiotic drive (SANDLER and NOVITSKI 1957). The case described herein was isolated from a chronically irradiated population (NOVITSKI and HANKS 1961), and was referred to as “29G” previously (HANKS 1961; ERICKSON and HANKS 1961). HANKS (1964) has renamed the line “RD”, referring to a disruption in recovery of the Y chromosome. which gives rise to a high-female sex ratio in the off spring of RD males.
Aanalysis of case of meiotic drive in Drosophila melanogaster
4507Hanks, GD, Genetics, 50:123-130. 1964-01-05 00:00:00.
IN the past ten years there has been a renewed interest in the abnormal recovery of chromosomes after meiosis; see for example DUNN (1953); NOVITSKI and SANDLER (1957) ; SANDLER and NOVITSKI ( 1957) ; LINDSLEY and SANDLER (1958); NOVITSKI and HANKS (1961); and MAGUIRE (1963). When the two types of gametes from a heterozygote are recovered with unequal frequency because of a meiotic mechanism the force resulting is called meiotic drive (SANDLER and NOVITSKI 1957). Such a force is capable of altering allele frequencies in a population, and thus the evolutionary consequences are potentially important; this has been discussed in detail by DUNN (1953) and SANDLER and NOVITSKI (1957). The case analyzed here was found by testing chromosomes from population cages maintained by WALLACE atCold Spring Harbor which were subjected to low intensity radiation for over 200 generations (WALLACE 1956). Earlier studies have indicated that the case here analyzed does not produce its effect by zygotic mortality, is manifested only in the male, and is greatly altered by temperature changes during the period of meiosis in the male (NOVITSKI and HANKS 1961; ERICKSON and HANKS 1961). This paper presents the genetic analysis of this case showing the extent to which its effect may be modified by substituting different sex chromosomes and autosomes.
Applications of genetic technology to mosquito rearing
6098G. B. Craig, Bulletin of the World Health Organization, 29:89-97. 1963-01-02 16:40:36.
Since the development of insecticide-resistance and the consequent partial failure of the chemical approach to the control of disease vectors, interest in the biological approach has re-awakened. An aspect of the latter approach that is of great current interest is " autocidal control "-that is, the use of insects for their own destruction. This paper discusses the various ways in which genetic mechanisms can be used to bring about the destruction of harmful insects, with special reference to those of medical importance. The author considers that the prospects for the genetic control of vector species are good, but stresses that before genetic methods can be applied on a field scale certain requirements must be met. For example, genetic technology must be expanded, a firm background of genetic knowledge of vector species must be built up, a great deal more information about vector ecology, particularly population dynamics, must be acquired, and techniques for the mass production of vector insects under controlled conditions must be developed.
Meiotic drive in natural populations of Drosophila melanogaster .7. Conditional segregation distortion – a possible nonallelic conversion
4512Sandler, LH, Y., Genetics, 46:585-604. 1961-01-10 00:00:00.
Males, heterozygous for the Segregation-distorter (SD) allele (located in or near the centromeric heterochromatin of the right arm of chromosome 11) and a standard tester second chromosome, regularly produce a preponderance of functional SD-bearing sperm ( SANDLER, HIRAIZUMI and SANDLER 1959). Segregation in heterozygous SD females, on the other hand, is always normal. It has been found, however, that, for certain SD lines, if the SD-bearing chromosome is inherited from the female parent, then, in a fraction of F, male sibships, only one half of the heterozygous SD sons exhibit the phenomenon of segregationdistortion; in the other half of the sons, segregation is normal. In the following generation, all of the males exhibit abnormal ratios irrespective of whether or not their father showed an abnormal ratio. Those females that produce sons. only one half of which distort, are referred to as conditioned; the phenomenon is termed conditional distortion ( SANDLER and HIRAIZUMI 1959)
Meiotic drive in natural populations of Drosophila melanogaster .8. A heritable aging effect on phenomenon of segregation distortion
4511Sandler, LH, Y., Canadian Journal of Genetics and Cytology, 3:34-46. 1961-01-09 00:00:00.
Second chromosomes have been found in natural populations of Drosophila melanogaster that contain an abnormal centromere region which conditions a highly aberrant segregation ratio in heterozygous males (Sandler, Hiraizumi, and Sandler, 1959). In particular, when a chromosome carrying this abnormal region (symbolized SD for Segregation-distorter) is made heterozygous with a normal second chronlosome (routinely a standard tester chromosome marked by the recessives cn and bw) in males, and backcrossed to homozygous cn bw females, 90 per cent or more of the F1 receive the SD-bearing second chromosome. These abnormal segregation ratios are not accompanied by egg mortality. It has now, been found that as heterozygous SD males are aged, the segregation ratios become less abnormal. When, moreover, young sons of aged fathers are examined, it is found that they too exhibit less extreme segregation ratios. Indeed, changes in the segregation ratio induced by aging may persist in selected, males for at least five generations and possibly indefinitely. The evidence demonstrating a heritable aging effect and a consideration of certain other questions relevant to the aging phenomenon are presented below.
Analysis of irradiated Drosophila populations for meiotic drive
4510Novitski, EH, G. D., Nature, 190:989-990. 1961-01-08 00:00:00.
The existence of chromosomes or alleles that are represented in the gametes of a heterozygote with a frequency greater than the expected 50 percent is now well established for a variety of species. The immediate population result of introducing such a chromosome or allele must be a sharp increase in its frequency, alon with any other genes associated by linkage, independent of or, indeed, in spite of, their phenotypic effects. For this reason such phenomena have been referred to as cases of 'drive' and, more specifically, as 'meiotic drive' when the basis is found in some aberration of meiosis. Such instances would seem to provide an unparalleled opportunity for the study of population dynamics, for example, the efficacy of response of natural selection to unfavourable genes. It seemed worth while, therefore, to determine whether such chromosomes or alleles characterized by drive might be induced in the laboratory.
Time of temperature sensitivity of meiotic drive in Drosophila melanogaster
4508Erickson, JH, G. D., American Naturalist, 95:247-250. 1961-01-06 00:00:00.
In a line of Drosophila melanogaster demonstrating meiotic drive, it was found that the high recovery rate of the X-chromosome could be nearly nullified by temperature treatment. A series of experiments were carried out to determine at what stage of the life-cycle this treatment is effective. The effect is observed to occur during a part of the process of spermatogenesis, either during the primary spermatocyte stage or extending through this and the meiotic divisions which follow.
Inherited male-producing factor in Aedes aegypti
6096G. B. Craig, W. A. Hickey and R. C. Vandehey, Science, 132:1887-1889. 1960-12-23 14:59:02.
An inherited factor causes a predominance of males in certain strains and in progeny of single pairs of Aedes aegypti L. This factor appears to be transmitted only by males and is not due to differential mortality, at least in postgametic stages. Mass release of male-producing males might be used in control operations.
Meiotic drive in natural populations of Drosophila melanogaster .4: Instability at the Segregation Distorter locus
4515Sandler, LH, Y., Genetics, 45:1269-1287. 1960-01-13 00:00:00.
In a collection of flies from a natural population of Drosophila melanogaster, several second chromosomes have been isolated that contain, in the centromere region .of chromosome 11, a locus (named segregation-distorter and symbolized SO) that conditions, in heterozygous males, a highly abnormal segregation ratio in favor of the SD-bearing chromosome. Experiments bearing on the cytogenetic basis of the phenomenon of segregation-distortion and on the formal genetics of the SD locus have been reported by SANDLER, HIRAIZUMI, and SANDLER (1959). and by SANDLER and HIRAIZUMI ( 1959).
Meiotic drive in natural populations of Drosophila melanogaster .5. On the nature of the SD region
4514Sandler, LH, Y., Genetics, 45:1671-1689. 1960-01-12 00:00:00.
Second chromosomes were collected from nature which, when heterozygous with a normal chromosome 1 in males, are present in functional sperm much more often than the expected 50 percent. This phenomenon, named segregation distortion, was found to depend on a locus named Segregation-distorter (symbolized SD), which is located near the centromere (and probably in the right arm) of chromosome 1
Meiotic drive in natural populations of Drosophila melanogaster .1. The cytogenetic basis of segregation distortion
4517Sandler, LH, Y.; Sandler, I., Genetics, 44:233-250. 1959-01-15 00:00:00.
Meiotic drive has been defined as a force, potentially capable of altering gene frequencies in natural populations, which somehow depends upon the nature of the meiotic divisions; specifically, when the meiotic divisions are such that the two kinds of gametes from a heterozygote are produced in a ratio different from 1 : 1 ( SANDLER and NOVITSKI 195 7). There have been reported numerous cases which either are, or may be, examples of meiotic drive. These include cases in Drosophila ( GERSHENSON 1928; STURTEVANT and DOBZHANSKY 1936; NOVITSKI 1951 ; NOVITSKI and IRIS SANDLER 1957; LINDSLEY and SANDLER 1958), in maize (RHOADES 1942; LONGLEY 1945), in tobacco (CAMERON and MOAV 1957), and possibly in mice (DUNN 1953) and in man (DUNN 1953; SANDLER and NOVITSKI 1957). The purpose of this paper is to present a first account of the results of a series of studies designed to elucidate the cytogenetic basis of a case of meiotic drive which was discovered in a natural population of D. melanogaster. In this population there has been found a second chromosome locus, located in or near the proximal heterochromatin and called segregation-distorter (symbol, SO), which is recovered much more frequently than its normal allele among the progeny of heterozygous male parents. This phenomenon, to which the name segregation distortion has been applied, (1) has never been found to occur in females, (2) apparently requires synapsis (particularly in the region of the locus in question) in order to operate, and (3) comes about as a result of the failure of sperm carrying the normal allele to be formed or to function normally. The evidence bearing on these, and certain other points, and a cytogenetic model to account for the results are presented below.
Meiotic drive in natural populations of Drosophila melanogaster 2. Genetic variation at the Segregation Distorter locus
4516Sandler, LH, Y., Proceedings of the National Academy of Sciences of the United States of America, 45:1412-1422. 1959-01-14 00:00:00.
It has now been found that the proportion of heterozygous SD males resulting from any given cross which exhibits segregation-distortion, and the amount of distortion that any particular male shows (the k value), varies widely depending upon the precise source and history of the SD-bearing and the SD+-bearing chromosomes in the heterozygotes being tested. It is the purpose of this report to present a general account of the kinds of variations in the behavior of SD which have been observed. More fully documented reports of each phase of the work are currently in preparation, and will be presented elsewhere. For this reason, extended discussion of these variations and comparable systems in other organisms has been omitted.
Inheritance in Nicotiana tabacum XXVII. Pollen Killer, An alien genetic locus inducing abortion of microspores not carrying it
6116D. R. Cameron and R. M. Moav, Genetics, 42:326. 1957-01-02 19:37:02.
A cytogenetic study of experimental introgression from N. plumbaginifolia (pbg) into N. tabacum (tbc) has been pursued in this laboratory for several years (CLAUSEN 1952). In the hybrid derivatives it was observed that genically controlled pollen abortion was associated with the addition of a pbg chromosome to the tbc complement. This chromosome also carried the locus (Bs) determining resistance or probably immunity to black shank, a serious disease of commercial tobacco caused by Phytophthora parasitica var. nicotianae. (For description see CLAYTON and AICAIVRTRY 1950). Paradoxically, it developed that the pbg chromosome under study produced its effect on gametophytes in which it was not present. Thus, the male gametophytes containing a complete set of 24 tbc chromosomes degenerate while most of the functional pollen had the constitution 24 tbc + 1 pbg. This paper presents a description of the genetic aspects of the problem with some suggestions as to the possible method of action of the locus involved. Certain other phases of the larger investigation will be mentioned but only as they apply to the pollen lethal condition. The investigation was initiated by the late PROF. R. E. CLAUSEN who participated actively in the work presented here.
Studies of the genetic variability in populations of wild house mice .2. Analysis of eight additional alleles at locus – T
6113L. C. Dunn, Genetics, 42:299-311. 1957-01-02 19:27:44.
1 Eight additional lethal alleles at locus T are described, each derived from a wild heterozygote in one of six different wild populations. 2. The frequency of heterozygotes appears to be high in most wild populations, possibly as high as 50 percent. 3. In two of the populations in which several heterozygotes were found, the same allele was isolated from each heterozygote of the same population. One heterozygote was found in each of two subpopulations on the same farm. These two alleles have not been shown to be different. One wild heterozygote from another population transmitted two different alleles; probably one was a new mutant, giving rise to the possibility that more than one allele may occur in the same population, although the rule at present is to find but one type of variant allele per population. 4. All wild t alleles show the “male segregation ratio peculiarity” by which male heterozygotes transmit the t allele to a great majority (about 96 percent) of the offspring. This may be due to the effects of natural selection on factors favoring high transmission ratios. 5. t alleles from the wild fall into at least three groups, one with three viable alleles, and two groups of lethals. Lethals within the same group have not formed viable compounds when combined; lethals belonging to different groups do form viable compounds by complementary interaction and are thus shown to be nonidentical. 6. Since 29 alleles have now been detected at this locus, many of which are nonidentical, the locus is assumed to contain many sites of mutation and to have great potential complexity.
Sur la reproduction des souris anoures
6057N. Dobrovolskaia-Zavadskaia and N. Kobozieff, Comptes rendus des séances de la Société de biologie et de ses filiales, 97:116-119. 1927-06-15 15:44:03.
Nous ne connaissons que deux lignees de Souris sans queue, celle de Lang (1913), et cell de Duboscq (1922). L’elevange de Lang (lignee des Souris brachyures et anoures du preparateur Alfred Nageli) a donne 199 Souris normales, pour 173 brachyures et 9 anoures. Croisses entre ells et aveec des bachyures, les Souris anoures n’ont donne aucune reproduction. Dans la lignee du P Duboscq, provenant d’une femelle anoure A et de son frere normal, et comportant 25 petis en 8 portees, il y avait 8 anoures, don’t la plupart moururent jeunes.
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