Scholarly Literature

This is a database of scholarly literature that concentrates currently on natural and engineered selfish genetic elements (gene drives).  The latest are shown here.
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Modeling the dynamics of a non-limited and a self-limited gene drive system in structured Aedes aegypti populations

4175
Legros, 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.

Diversity and abundance of the abnormal chromosome 10 meiotic drive complex in Zea mays

4174
Kanizay, LBP, T.; Lowry, E. G.; Hufford, M. B.; Peterson, D. G.; Ross-Ibarra, J.; Dawe, R. K.,  Heredity,  110:570-577. 2013-01-12 00:00:00.
Maize Abnormal chromosome 10 (Ab10) contains a classic meiotic drive system that exploits the asymmetry of meiosis to preferentially transmit itself and other chromosomes containing specialized heterochromatic regions called knobs. The structure and diversity of the Ab10 meiotic drive haplotype is poorly understood. We developed a bacterial artificial chromosome (BAC) library from an Ab10 line and used the data to develop sequence-based markers, focusing on the proximal portion of the haplotype that shows partial homology to normal chromosome 10. These molecular and additional cytological data demonstrate that two previously identified Ab10 variants (Ab10-I and Ab10-II) share a common origin. Dominant PCR markers were used with fluorescence in situ hybridization to assay 160 diverse teosinte and maize landrace populations from across the Americas, resulting in the identification of a previously unknown but prevalent form of Ab10 (Ab10-III). We find that Ab10 occurs in at least 75% of teosinte populations at a mean frequency of 15%. Ab10 was also found in 13% of the maize landraces, but does not appear to be fixed in any wild or cultivated population. Quantitative analyses suggest that the abundance and distribution of Ab10 is governed by a complex combination of intrinsic fitness effects as well as extrinsic environmental variability.

Transmission ratio distortion: review of concept and implications for genetic association studies

4173
Huang, 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

4172
Gell, 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.

Guidance on the environmental risk assessment of genetically modified animals.

4171
EFSA GMO Panel (EFSA Panel on Genetically Modified Organisms),  EFSA Journal,  11:3200. 2013-01-09 00:00:00.
This document provides guidance for the environmental risk assessment (ERA) of living genetically modified (GM) animals, namely fish, insects and mammals and birds, to be placed on the European Union (EU) market in accordance with Regulation (EC) No 1829/2003 or Directive 2001/18/EC. It provides guidance for assessing potential effects of GM animals on animal and human health and the environment and the rationales for data requirements for a comprehensive ERA. The ERA should be carried out on a case-by-case basis, following a step-by-step assessment approach. This document describes the six sequential steps for the ERA of GM animals, as indicated in Directive 2001/18/EC: (1) problem formulation including hazard and exposure identification; (2) hazard characterisation; (3) exposure characterisation; (4) risk characterisation; (5) risk management strategies; and (6) an overall risk evaluation. The Scientific Panel on Genetically Modified Organisms of the European Food Safety Authority follows Annex II of Directive 2001/18/EC, considering specific areas of risk to be addressed by applicants and risk assessors during the ERA of GM fish, GM insects and GM mammals and birds. Each specific area of risk is considered in a structured and systematic way following the aforementioned six steps. In addition, this Guidance Document describes several generic cross-cutting considerations (e.g. choice of comparators, use of non-GM surrogates, experimental design and statistics, long-term effects, uncertainty analysis) that need to be accounted for throughout the whole ERA.

Mechanism of meiotic drive in mammals

4170
Chmatal, LF, K.; Schultz, R. M.; Lampson, M. A.,  Molecular Biology of the Cell,  24:3775. 2013-01-08 00:00:00.
Meiotic drive is a phenomenon responsible for an unequal representation of alleles or whole chromosomes among gametes as a result of the mechanics of meiotic division (Sandler et Novitski 1957). When it drives segregation of Robertsonian translocations (Rb), a common chromosomal rearrangement in mammals, in oocytes these translocations are either preferentially maintained in the egg or preferentially expelled to the polar body during meiosis I (MI), thus being either transmitted or excluded from the next generation. Because Rb translocations are formed by fusion of two acrocentric chromosomes creating one metacentric chromosome, subsequent accumulation and fixation of these fusions over time leads to a change in karyotype (Castaglia 1982, Villena et Sapienza 2001). Despite the importance of this phenomenon for evolution and speciation, the underlying mechanisms of meiotic drive are unknown. We tested a model of meiotic drive based on three elements: (1) an asymmetric trivalent that forms in MI when a metacentric fusion pairs with the two homologous acrocentric chromosomes, (2) preferential orientation of the trivalent on an asymmetric spindle, and (3) orientation of the asymmetric spindle with one side preferentially facing the cortex. We find reduced levels of kinetochore proteins in fusion centromeres compared to the homologous acrocentric centromeres, suggesting that the trivalent asymmetry is based on differential centromere strength. We also find that stability of MI spindle microtubules is influenced by proximity to the cortex, leading to asymmetric spindles with more stable microtubules oriented towards the cortex. These MTs preferentially bind the fusion centromere, which orients the metacentric Rb fusion chromosome towards the cortex for eventual segregation to the polar body.Together, our data provide evidence for a model to explain the biased segregation of Rb translocations in mammalian oocytes.

The design and in vivo evaluation of engineered I-OnuI-based enzymes for HEG gene drive

4169
Chan, 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

4168
Chan, 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

4167
Branco, 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

4166
Bastide, 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.

Germline excision of transgenes in Aedes aegypti by homing endonucleases

4165
Aryan, AA, M. A. E.; Myles, K. M.; Adelman, Z. N.,  Scientific Reports,  3:1603. 2013-01-03 00:00:00.
Aedes (Ae.) aegypti is the primary vector for dengue viruses (serotypes1-4) and chikungunya virus. Homing endonucleases (HEs) are ancient selfish elements that catalyze double-stranded DNA breaks (DSB) in a highly specific manner. In this report, we show that the HEs Y2-I-AniI, I-CreI and I-SceI are all capable of catalyzing the excision of genomic segments from the Ae. aegypti genome in a heritable manner. Y2-I-AniI demonstrated the highest efficiency at two independent genomic targets, with 20-40% of Y2-I-AniI-treated individuals producing offspring that had lost the target transgene. HE-induced DSBs were found to be repaired via the single-strand annealing (SSA) and non-homologous end-joining (NHEJ) pathways in a manner dependent on the availability of direct repeat sequences in the transgene. These results support the development of HE-based gene editing and gene drive strategies in Ae. aegypti, and confirm the utility of HEs in the manipulation and modification of transgenes in this important vector.

A Synthetic Gene Drive System for Local, Reversible Modification and Suppression of Insect Populations

4164
Akbari, OSM, K. D.; Marshall, J. M.; Huang, H. X.; Ward, C. M.; Hay, B. A.,  Current Biology,  23:671-677. 2013-01-02 00:00:00.
Replacement of wild insect populations with genetically modified individuals unable to transmit disease provides a self-perpetuating method of disease prevention but requires a gene drive mechanism to spread these traits to high frequency [1-3]. Drive mechanisms requiring that transgenes exceed a threshold frequency in order to spread are attractive because they bring about local but not global replacement, and transgenes can be eliminated through dilution of the population with wild-type individuals [4-6]. These features are likely to be important in many social and regulatory contexts [7-10]. Here we describe the first creation of a synthetic threshold-dependent gene drive system, designated maternal-effect lethal underdominance (UDMEL), in which two maternally expressed toxins, located on separate chromosomes, are each linked with a zygotic antidote able to rescue maternal-effect lethality of the other toxin. We demonstrate threshold-dependent replacement in single- and two-locus configurations in Drosophila. Models suggest that transgene spread can often be limited to local environments. They also show that in a population in which single-locus UDMEL has been carried out, repeated release of wild-type males can result in population suppression, a novel method of genetic population manipulation.

Ethical issues in field trials of genetically modified disease-resistant mosquitoes

13538
D. B. Resnik,  Developing World Bioethics,  14:37-46. 2012-07-29 19:12:07.
Mosquito-borne diseases take a tremendous toll on human populations, especially in developing nations. In the last decade, scientists have developed mosquitoes that have been genetically modified to prevent transmission of mosquito-borne diseases, and field trials have been conducted. Some mosquitoes have been rendered infertile, some have been equipped with a vaccine they transmit to humans, and some have been designed to resist diseases.

The contribution of female meiotic drive to the evolution of neo-sex chromosomes

4197
Yoshida, 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

4196
Traulsen, 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

4195
Shin, 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

4194
Price, 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

4193
Meyer, 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.

Confinement of gene drive systems to local populations: A comparative analysis

4192
Marshall, JMH, B. A.,  Journal of Theoretical Biology,  294:153-171. 2012-01-10 00:00:00.
Mosquito-borne diseases such as malaria and dengue fever pose a major health problem through much of the world. One approach to disease prevention involves the use of selfish genetic elements to drive disease-refractory genes into wild mosquito populations. Recently engineered synthetic drive systems have provided encouragement for this strategy; but at the same time have been greeted with caution over the concern that transgenes may spread into countries and communities without: their consent. Consequently, there is also interest in gene drive systems that, while strong enough to bring about local population replacement, are unable to establish themselves beyond a partially isolated release site, at least during the testing phase. Here, we develop simple deterministic and stochastic models to compare the confinement properties of a variety of gene drive systems. Our results highlight several systems with desirable features for confinement-a high migration rate required to become established in neighboring populations, and low-frequency persistence in neighboring populations for moderate migration rates. Single-allele underdominance and single-locus engineered underdominance have the strongest confinement properties, but are difficult to engineer and require a high introduction frequency, respectively. Toxin-antidote systems such as Semele. Merea and two-locus engineered underdominance show promising confinement properties and require lower introduction frequencies. Killer-rescue is self-limiting in time, but is able to disperse to significant levels in neighboring populations. We discuss the significance of these results in the context of a phased release of transgenic mosquitoes, and the need for characterization of local ecology prior to a release. (C) 2011 Elsevier Ltd. All rights reserved.

General principles of single-construct chromosomal gene drive

4191
Marshall, JMH, B. A.,  Evolution,  66:2150-2166. 2012-01-09 00:00:00.
Gene drive systems are genetic elements capable of spreading into a population even if they confer a fitness cost to their host. We consider a class of drive systems consisting of a chromosomally located, linked cluster of genes, the presence of which renders specific classes of offspring arising from specific parental crosses unviable. Under permissive conditions, a number of these elements are capable of distorting the offspring ratio in their favor. We use a population genetic framework to derive conditions under which these elements spread to fixation in a population or induce a population crash. Many of these systems can be engineered using combinations of toxin and antidote genes, analogous to Medea, which consists of a maternal toxin and zygotic antidote. The majority of toxinantidote drive systems require a critical frequency to be exceeded before they spread into a population. Of particular interest, a Z-linked Medea construct with a recessive antidote is expected to induce an all-male population crash for release frequencies above 50%. We suggest molecular tools that may be used to build these systems, and discuss their relevance to the control of a variety of insect pest species, including mosquito vectors of diseases such as malaria and dengue fever.

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