Keywords: Other mammals
Feral rabbit numbers are booming, so do myxomatosis and calicivirus still work, and what’s next for biocontrol?
35522Belinda Smith, ABC News, 2026-03-12 09:20:38.
If you've noticed more feral rabbits around than usual, you're right. Much of Australia is experiencing a bunny boom, driven by consecutive years of good breeding conditions. But with an estimated 200 million feral European rabbits (Oryctolagus cuniculus) currently hopping around the continent, you might also have wondered if the viruses that kept their numbers down in the past — myxoma virus and a calicivirus that causes rabbit haemorrhagic disease — still work. Heidi Kleinert, national feral rabbit management coordinator at the Centre for Invasive Species Solutions, says ideally Australia needs to develop and release a new biocontrol every 10 to 15 years to keep rabbit numbers as low as possible. "It takes time to find another effective virus that we know is targeted specifically to rabbits, and we know is proven and tested and has approval from government organisations," Ms Kleinert says. "Across Australia, we're seeing more rabbits in peri-urban and urban areas. That's why we need that continuous pipeline of biological control, because in these areas we can't use bait and toxins close to domestic housing and domestic pets." So how do myxoma and rabbit haemorrhagic disease viruses work, and what goes into finding the next bunny biocontrol weapon?
Discovery of a Genetic Toxin-Antidote System in Vertebrates
35490Duilio Mazzoni Zerbinato A Silva, Morgan Skinner, Takaya Totsuka, et al., bioRxiv, 2026-03-06 10:25:21.
Toxin-antidote (TA) systems are selfish genetic elements that bias their own inheritance by coupling a toxin that kills daughter cells or offspring with an antidote that specifically rescues those with the TA. TAs are a widespread phenomenon, observed in bacteria, fungi, plants, and invertebrate animals, but have not yet been described in vertebrates. Here we report the first known vertebrate TA system that sabotages mammalian embryogenesis. The HSR locus on mouse chromosome 1 is a selfish genetic element that biases its transmission through the female germline. When HSR heterozygous females are crossed with wild-type males, wild-type embryos show high mortality, leading to preferential survival of embryos with HSR. The mechanism underlying embryo killing was unknown. We find that HSR kills wild-type post implantation embryos by depositing a toxin (SP100) that induces significant DNA damage. Embryos with HSR also inherit the toxin but survive by expressing an antidote (SP110) that blocks the effects of the toxin. Our findings reveal a previously unrecognized genetic cheating strategy in vertebrates and demonstrate its impact on mammalian reproduction.
Comparison of single-cell sequencing technologies for allele-specific expression analysis in rabbit spermatids
35482Elena Smertina, Madi Rutherford, Brendan Hosking, et al., Genomics, 2026-03-05 08:26:37.
Gene drives are transmission distorters that can transmit specific alleles to >90% of the progeny, e.g., the naturally occurring t-haplotype in mice. For invasive pest species, there is interest in co-opting naturally occurring gene drives. It is unknown whether similar natural gene drives exist in the European rabbit, one of the most detrimental pest species in Australia. Here, we analysed the allele-specific expression (ASE) in rabbit spermatids to identify candidate genes for future investigation in genetic biocontrol applications. We utilised short-read and long-read technologies and performed a comparative analysis. Illumina sequencing was deemed unsuitable, whereas both long-read sequencing platforms demonstrated a similar performance. The SPINK2 gene that plays an important role in fertility, consistently showed ASE towards one of the alleles in all samples. Furthermore, two kinases were found to display a bimodal allele expression. Future work is warranted to assess suitability of these genes for genetic biocontrol applications.
New genetic-editing technique to alter the traits and fates of wild populations
31454Lori Dajose, CalTech, 2024-09-03 21:38:08.
Gene drives are a common technology used to insert a novel gene into a population—for example, to make mosquitos resistant to malaria. They can also be used to modify existing genes, such as making herbicide-resistant weeds susceptible to herbicides once again or even to suppress invasive populations. However, gene drives often face social concerns and regulatory challenges because they involve the spread of transgenes (genes that have been transferred and integrated into an organism's DNA) to high frequency. The new technique, called an Allele Sail, uses the CRISPR/Cas9 genome-editing technology to introduce a targeted "editor" into a population at low frequency. This editor itself does not increase in frequency as organisms reproduce, however, any organism that mates with an editor-carrying organism will become altered at the genomic position targeted by the editor, passing the altered version (called an allele) of the gene down to its own offspring. In this way, the technique mimics the natural genetic process of passing down genes and mutations, and can be used in a wider range of species than traditional gene drive approaches. "Imagine you have a big room of bouncing balls, most of them white but a few are red," says Bruce Hay, professor of biology and biological engineering. "Any time a red ball—the editor—bumps into a white ball, it turns the white ball pink—the edit. As the balls bounce around, over time, more and more of them turn pink."
Revolutionizing Livestock Biosecurity: Using CRISPR Technology to Combat the New World Screwworm
28963Dr. Jessica Nelson, Medriva, 2024-03-05 13:07:55.
The New World screwworm, a persistent parasite responsible for significant damage to the global livestock industry, may soon meet its match. Researchers at Uruguay's National Institute of Agricultural Research (INIA) have developed a gene drive using CRISPR technology to combat this destructive pest. By manipulating the reproductive process of the screwworm fly, INIA scientists aim to cause a population crash, thereby reducing the parasite's devastating impact on the livestock industry. CRISPR gene drive technology offers a potentially more efficient and powerful solution compared to previous methods, such as the sterile insect technique (SIT) used by the US. Unlike traditional techniques, CRISPR gene drives aim to spread fertility-damaging genes throughout the screwworm population, causing a significant decrease in their numbers. The process works by making female screwworms sterile. The ultimate goal is to release gene-edited male screwworm flies into the wild. These males will mate with females, passing on the gene drive and leading to a population crash of the screwworm fly. This innovative approach has shown promise in caged trials and is currently being tested further in the INIA labs.
Invasive Feral Cats Could Be Wiped Out Using Genetic Modification
28632Jess Thomson, Newsweek, 2023-12-04 10:38:32.
Hordes of feral cats terrorizing native species in Australia could be combatted using a special type of genetic engineering, scientists have suggested. The cats, which came to Australia via European colonizers, regularly kill native mammals, birds, and reptiles, including woylies, quolls, and even penguins. The feral cats now number over six million, and are responsible for the extinction of at least 28 species across the country, threatening countless more. This has spurred numerous control measures to be announced, including poison, trapping, and cat curfews. "Gene drives literally 'drive' modified genes through a species by ensuring they are inherited from generation to generation, eventually resulting in the whole species having engineered genetic traits," Andrew D. Maynard, a professor of Advanced Technology Transitions at Arizona State University, told Newsweek. "It's a technique that is specific to species that mate and reproduce sexually, and works by ensuring that engineered genetic traits are inherited by every single offspring resulting from mating."
What are gene drives, and how can they help eradicate invasive species in Australia?
28563Dr. Ellen Cottingham, ABC News (Australia Broadcasting Corporation), 2023-11-29 13:52:33.
The impact of feral cats and other invasive species is felt across Australia. Not only do they threaten native species, but they can also spread diseases to humans and livestock. Invasive species are estimated to cost Australia an eye-watering $25 billion annually, while the global cost is a staggering $423 billion. Feral cats are everywhere — the nation is home to up to 6.3 million of them, and they are responsible for killing millions of native mammals, reptiles, and birds each day. Minister for the Environment and Water Tanya Plibersek recently declared "war on feral cats", announcing plans involving cat curfews, desexing regulations, and caps on cat numbers in homes. But what can we do about the millions of feral cats already wreaking havoc across Australia? And what about other pests such as foxes, rabbits, cane toads, carp, pigs, deer, or goats? One technique with the potential to help fight not just cats but all invasive species is called a "gene drive".
Optimizing the delivery of self-disseminating vaccines in fluctuating wildlife populations
27639C. Schreiner, A. Basinski, C. Remien and S. Nuismer, PLOS Neglected Tropical Diseases, 17:e0011018. 2023-08-18 07:45:43.
Author summary Pathogens such as Ebola, rabies, and Lassa virus that usually infect wildlife can jump to the human population. In the worst case, this can lead to outbreaks or pandemics such as happened in 2014 with Ebola and 2019 with SARS-CoV-2. One approach to mitigate the threat of pathogens spilling into the human population is to proactively vaccinate wildlife harboring these pathogens before the pathogens infect humans. With traditional vaccines, administering enough vaccines to the wildlife population to limit pathogen spread is challenging. To address this challenge, recent technological advances have allowed the development of vaccines that allow some degree of spread of the vaccine from animal to animal. However, for a vaccination campaign using these self-disseminating vaccines to be implemented successfully, we need to know when vaccines should be administered. We used mathematical models to explore how the reservoir host’s population ecology and properties of the vaccine affect the success of a vaccination campaign. Our results demonstrate that the timing of vaccine delivery relative to seasonal reproduction can make or break the success of vaccination programs. The effectiveness of self-disseminating vaccines is optimized by introducing vaccine after the peak of seasonal reproduction when the number of animals available for vaccination is highest.
Genome and Transcriptome Analyses Facilitate Genetic Control of Wohlfahrtia magnifica, a Myiasis-Causing Flesh Fly
27427Z. Jia, S. Hasi, D. Zhan, B. Hou, C. Vogl and P. A. Burger, Insects, 14. 2023-07-10 08:53:12.
Myiasis caused by Wohlfahrtia magnifica is a widespread parasitic infestation in mammals. The infested host suffers from damage as the developing larvae feed on its tissues. For the control of myiasis infestation, genetic methods have been shown to be effective and promising as an alternative to insecticides. Combining genome, isoform sequencing (Iso-Seq), and RNA sequencing (RNA-seq) data, we isolated and characterized two sex-determination genes, W. magnifica transformer (Wmtra) and W. magnifica transformer2 (Wmtra2), whose orthologs in a number of insect pests have been utilized to develop genetic control approaches. Wmtra transcripts are sex-specifically spliced; only the female transcript encodes a full-length functional protein, while the male transcript encodes a truncated and non-functional polypeptide due to the presence of the male-specific exon containing multiple in-frame stop codons. The existence of five predicted TRA/TRA2 binding sites in the male-specific exon and the surrounding intron of Wmtra, as well as the presence of an RNA-recognition motif in WmTRA2 may suggest the auto-regulation of Wmtra by its own protein interacting with WmTRA2. This results in the skipping of the male-specific exon and translation of the full-length functional protein only in females. Our comparative study in dipteran species showed that both the WmTRA and WmTRA2 proteins exhibit a high degree of similarity to their orthologs in the myiasis-causing blow flies. Additionally, transcriptome profiling performed between adult females and adult males reported 657 upregulated and 365 downregulated genes. Functional analysis showed that among upregulated genes those related to meiosis and mitosis Gene Ontology (GO) terms were enriched, while, among downregulated genes, those related to muscle cell development and aerobic metabolic processes were enriched. Among the female-biased gene set, we detected five candidate genes, vasa (vas), nanos (nanos), bicoid (bcd), Bicaudal C (BicC), and innexin5 (inx5). The promoters of these genes may be able to upregulate Cas9 expression in the germline in Cas9-based homing gene drive systems as established in some flies and mosquitoes. The isolation and characterization of these genes is an important step toward the development of genetic control programs against W. magnifica infestation.
Unravelling transmission ratio distortion across the bovine genome: identification of candidate regions for reproduction defects
26542S. Id-Lahoucine, J. Casellas, A. Suárez-Vega, P. A. S. Fonseca, F. S. Schenkel, M. Sargolzaei and A. Cánovas, BMC Genomics, 24:383. 2023-07-08 08:21:35.
Our results revealed the importance of implementing different TRD parameterizations to capture all types of distortions and to determine the corresponding inheritance pattern. Novel candidate genomic regions containing lethal alleles and genes with functional and biological consequences on fertility and pre‑ and post‑natal viability were also identified, providing opportunities for improving breeding success in cattle
A framework for identifying fertility gene targets for mammalian pest control
25416C. C. Anna, A. Alana, E. Rey, E. Kevin, K. Sebastian, D. Ludovic, C. Jackson, E. C. Samuel, W. M. Philipp and J. G. Neil, bioRxiv, 2023.05.30.542751. 2023-06-01 07:38:46.
Fertility-targeted gene drives have been proposed as an ethical genetic approach for managing wild populations of vertebrate pests for public health and conservation benefit. This manuscript introduces a framework to identify and evaluate target gene suitability based on biological gene function, gene expression, and results from mouse knockout models. This framework identified 16 genes essential for male fertility and 12 genes important for female fertility that may be feasible targets for mammalian gene drives and other non-drive genetic pest control technology. Further, a comparative genomics analysis demonstrates the conservation of the identified genes across several globally significant invasive mammals. In addition to providing important considerations for identifying candidate genes, our framework and the genes identified in this study may have utility in developing additional pest control tools such as wildlife contraceptives.Competing Interest StatementThe authors have declared no competing interest.
Oxitec Launches New Technology Program to Develop a Friendly™ Solution for the World’s Most Damaging Cattle Tick
25292Oxitec Ltd, Oxitec Press Release, 2023-05-24 07:45:30.
Oxitec Ltd, the leading developer of insect-based biological solutions to control pests that transmit disease, destroy crops and harm livestock, today announced the launch of development of a targeted, biological Friendly™ solution for the world’s most devastating cattle pest, the Asian blue tick, or Rhipicephalus microplus. In a feasibility project funded by the Bill & Melinda Gates Foundation, Oxitec’s team validated the key methods for development of a Friendly™ R. microplus, and found that, for management of this dangerous tick, this biological approach is anticipated to provide a highly effective alternative to chemical pesticides. The Foundation has now committed $4.8 million to an early development phase to start to build the Friendly™ R. microplus solution, Oxitec’s first targeting a non-insect pest.
Social justice environmental activists move to block gene editing to control invasive species and promote biodiversity. Here’s why they’re misguided
24701S. Smyth, Genetic Literacy Project, 2023-02-07 12:46:02.
Control of invasive species has been extremely difficult with eradication virtually impossible. To control invasive plant species, chemicals are commonly used while in some instances removal of plants by hand, as Shiva advocates, is undertaken. Efforts to control invasive animals include poisoning and shooting. Needless to say, these ‘control techniques’ are inefficient and often harmful to the applicators. Advances in genetics potentially offer new solutions, using gene editing technology to create sterile populations. Sterility is a natural trait in mammals, which can be induced into invasive animals as a means of population control. Invasive pests can be captured, gene-edited to confer sterility in future generations and then released back into the wild. The offspring will gradually without the use of chemicals or hand labor contribute to reduced populations. Applying gene editing technologies is not an instantaneous solution, but they may be part of a long-term strategy.
Bypassing Mendel’s First Law: Transmission Ratio Distortion in Mammals
24587G. Friocourt, A. Perrin, P. A. Saunders, E. Nikalayevich, C. Voisset, C. Coutton, G. Martinez and F. Morel, International Journal Molecular Sciences, 24. 2023-01-13 10:43:58.
Mendel's law of segregation states that the two alleles at a diploid locus should be transmitted equally to the progeny. A genetic segregation distortion, also referred to as transmission ratio distortion (TRD), is a statistically significant deviation from this rule. TRD has been observed in several mammal species and may be due to different biological mechanisms occurring at diverse time points ranging from gamete formation to lethality at post-natal stages. In this review, we describe examples of TRD and their possible mechanisms in mammals based on current knowledge. We first focus on the differences between TRD in male and female gametogenesis in the house mouse, in which some of the most well studied TRD systems have been characterized. We then describe known TRD in other mammals, with a special focus on the farmed species and in the peculiar common shrew species. Finally, we discuss TRD in human diseases. Thus far, to our knowledge, this is the first time that such description is proposed. This review will help better comprehend the processes involved in TRD. A better understanding of these molecular mechanisms will imply a better comprehension of their impact on fertility and on genome evolution. In turn, this should allow for better genetic counseling and lead to better care for human families.
Meiotic defects in human oocytes: Potential causes and clinical implications
23677T. Wu, H. Gu, Y. Luo, L. Wang and Q. Sang, BioEssays, 2022-10-07 08:30:48.
Meiotic defects cause abnormal chromosome segregation leading to aneuploidy in mammalian oocytes. Chromosome segregation is particularly error-prone in human oocytes, but the mechanisms behind such errors remain unclear. To explain the frequent chromosome segregation errors, recent investigations have identified multiple meiotic defects and explained how these defects occur in female meiosis. In particular, we review the causes of cohesin exhaustion, leaky spindle assembly checkpoint (SAC), inherently unstable meiotic spindle, fragmented kinetochores or centromeres, abnormal aurora kinases (AURK), and clinical genetic variants in human oocytes. We mainly focus on meiotic defects in human oocytes, but also refer to the potential defects of female meiosis in mouse models.
Selfish evolution of placental hormones
23534G. Keegan and M. M. Patten, Evolution, Medicine, and Public Health, 10:391-397. 2022-09-10 05:50:19.
We hypothesize that some placental hormones—specifically those that arise by tandem duplication of genes for maternal hormones—may behave as gestational drivers, selfish genetic elements that encourage the spontaneous abortion of offspring that fail to inherit them. Such drivers are quite simple to evolve, requiring just three things: a decrease in expression or activity of some essential maternal hormone during pregnancy; a compensatory increase in expression or activity of the homologous hormone by the placenta; and genetic linkage between the two effects. Gestational drive may therefore be a common selection pressure experienced by any of the various hormones of mammalian pregnancy that have arisen by tandem gene duplication. We examine the evolution of chorionic gonadotropin in the human lineage in light of this hypothesis. Finally, we postulate that some of the difficulties of human pregnancy may be a consequence of the action of selfish genes.We show how placental hormones that have arisen via tandem gene duplication from maternally produced hormones may subsequently experience selection as selfish genetic elements and spread through populations despite causing reproductive inefficiency. We examine the implications of this hypothesis and point to some empirical tests.
Genetically-enhanced biocontrols can help fight large invasive mammals
23157Pensoft Publishers, Science Daily, 2022-07-08 09:49:27.
A team of researchers from the University of Adelaide developed a mathematical model able to simulate the impact of gene drives on mammal populations at a landscape scale. Published in the open-access NeoBiotajournal, their study is the first to estimate the time it would take to eradicate long-lived alien mammals. Using CRISPR-Cas9 technology, the simulated gene drive relies on "molecular scissors" inserted into the Y-chromosome that target and slice up the X-chromosome at the right time during meiosis, so that only Y-chromosome carrying sperms are functional and can successfully fertilize the egg. In this way, the drive carrying males should only produce sons that also carry the molecular scissors on their Y-chromosome. Over multiple generations, females will become rarer and produce fewer offspring; as a result, the population size will fall.
Scalability of genetic biocontrols for eradicating invasive alien mammals
23159A. Birand, P. Cassey, J. V. Ross, P. Q. Thomas and T. A. A. Prowse, NeoBiota, 74:93-103. 2022-07-07 09:59:20.
CRISPR-based gene drives offer novel solutions for controlling invasive alien species, which could ultimately extend eradication efforts to continental scales. Gene drives for suppressing invasive alien vertebrates are now under development. Using a landscape-scale individual-based model, we present the first estimates of times to eradication for long-lived alien mammals. We show that demography and life-history traits interact to determine the scalability of gene drives for vertebrate pest eradication. Notably, optimism around eradicating smaller-bodied pests (rodents and rabbits) with gene-drive technologies does not easily translate into eradication of larger-bodied alien species (cats and foxes).
Selfish centromeres and the wastefulness of human reproduction
23129L. D. Hurst, PLOS Biology, 20:e3001671. 2022-07-05 10:34:00.
Many human embryos die in utero owing to an excess or deficit of chromosomes, a phenomenon known as aneuploidy; this is largely a consequence of nondisjunction during maternal meiosis I. Asymmetries of this division render it vulnerable to selfish centromeres that promote their own transmission, these being thought to somehow underpin aneuploidy. In this essay, I suggest that these vulnerabilities provide only half the solution to the enigma. In mammals, as in utero and postnatal provisioning is continuous, the costs of early death are mitigated. With such reproductive compensation, selection can favour a centromere because it induces lethal aneuploidy: if, when taken towards the polar body, it instead kills the embryo via aneuploidy, it gains. The model is consistent with the observation that reduced dosage of a murine drive suppressor induces aneuploidy and with the fact that high aneuploidy rates in vertebrates are seen exclusively in mammals. I propose further tests of this idea. The wastefulness of human reproduction may be a price we pay for nurturing our offspring.
Do Australians support genetic technology to control feral animals?
23095E. Phiddian, COSMOS, 2022-07-02 07:43:33.
Synthetic biology and genetic technology could be a safer, more humane way of curbing invasive species. Feral cat populations, for instance, could be controlled by preventing them from breeding. But there’s no point trying a new technology it if it doesn’t have public support – so does synthetic biology pass the pub test? According to a report from the CSIRO, it just might. Their survey of nearly 4,000 Australians finds that most support the idea of using gene drives on feral cats.“This particular study builds on our public acceptability work over the last three to four years on synthetic biology solutions to significant national challenges,” says Dr Aditi Mankad, co-author of the report and a researcher at CSIRO Land & Water’s Sustainability Pathways Program.
Public perspectives towards using gene drive for invasive species management in Australia
23100A. Mankad, E. V. Hobman and L. Carter, CSIRO, 2022-06-30 07:55:31.
Many pest animal species live and reproduce in high numbers across Australia. This includes animal species, such as cane toads, feral cats, foxes, rodents, wild pigs, wild rabbits. These species significantly damage Australia’s agricultural industries, natural landscapes, and biodiversity. For example, feral cats kill an estimated 1.8 billion Australian animals every year. Feral animals can also carry livestock diseases and cause significant damage to land and native vegetation. This results in agricultural production losses of more than $800 million per year. Sites of cultural significance to Indigenous peoples are also at risk to pest incursions. Adding further complexity, current methods of pest control being used to manage local landscape, such as baiting, trapping and shooting, are labour-intensive and expensive. They also have animal welfare implications and are considered ineffective at scale. Genetic technologies that are developed using synthetic biology have the potential to reduce or in some cases eliminate populations of invasive pests in parts of Australia. But there are multiple social, cultural and institutional considerations to understand before genetic technologies could feasibly be integrated with current pest management practices.
Breeding out the feral cat problem
23097S. Schmidt, ECOS, 2022-06-30 07:48:16.
While feral cats have only existed as part of Australia’s ecosystem for the last 200 or so years, they’ve left a destructive mark on our landscape. They’ve contributed to a growing list of Australian native animals that have become threatened or extinct in that time. Today, feral cats (Felis catus) are rampant in all parts of Australia, covering 99% of Australia’s total land area. That includes ecosystems from deserts to forests and grasslands, and even many of our offshore islands. Though they might share their species name and genome with their domestic counterparts, that’s where their similarity ends, explains Biosecurity Research Director at CSIRO, Dr Raghu Sathyamurthy. “Feral cats are opportunistic predators. They’re one of the most significant threats to our native species including small mammals, birds and reptiles,” says Dr Sathyamurthy.
Australians open to using genetic technology to manage feral cats
23086CSIRO, MIRAGE, 2022-06-30 07:20:05.
New genetic technologies could help address the rise of invasives through a number of ways, one of which is called gene drive. Gene drive can determine the sex of offspring, reducing the number of animals able to reproduce, and therefore over time driving down populations. Researchers from CSIRO surveyed more than 3,800 people across Australia to understand public perceptions of using gene drive on feral cats. The research found 86 per cent of people were at least moderately supportive for the local implementation of gene drive technology to manage invasive feral cat species in their local area.
Investigating CRISPR/Cas9 gene drive for production of disease-preventing prion gene alleles
22796A. R. Castle, S. Wohlgemuth, L. Arce and D. Westaway, PLoS One, 17:e0269342. 2022-06-07 09:14:53.
Prion diseases are a group of fatal neurodegenerative disorders that includes chronic wasting disease, which affects cervids and is highly transmissible. Given that chronic wasting disease prevalence exceeds 30% in some endemic areas of North America, and that eventual transmission to other mammalian species, potentially including humans, cannot be ruled out, novel control strategies beyond population management via hunting and/or culling must be investigated. Prion diseases depend upon post-translational conversion of the cellular prion protein, encoded by the Prnp gene, into a disease-associated conformation; ablation of cellular prion protein expression, which is generally well-tolerated, eliminates prion disease susceptibility entirely. Inspired by demonstrations of gene drive in caged mosquito species, we aimed to test whether a CRISPR/Cas9-based gene drive mechanism could, in principle, promote the spread of a null Prnp allele among mammalian populations. First, we showed that transient co-expression of Cas9 and Prnp-directed guide RNAs in RK13 cells generates indels within the Prnp open-reading frame, indicating that repair of Cas9-induced double-strand breaks by non-homologous end-joining had taken place. Second, we integrated a ~1.2 kb donor DNA sequence into the Prnp open-reading frame in N2a cells by homology-directed repair following Cas9-induced cleavages and confirmed that integration occurred precisely in most cases. Third, we demonstrated that electroporation of Cas9/guide RNA ribonucleoprotein complexes into fertilised mouse oocytes resulted in pups with a variety of disruptions to the Prnp open reading frame, with a new coisogenic line of Prnp-null mice obtained as part of this work. However, a technical challenge in obtaining expression of Cas9 in the male germline prevented implementation of a complete gene drive mechanism in mice.
Track New Zealand’s Bid to Take Back Nature
20169K. Peek, Scientific American, 2022-01-25 09:05:48.
A thousand years ago the islands that today form New Zealand were riotously wild. Birds, reptiles and invertebrates flourished in lush forests hundreds of miles from any other landmass. Māori settlers in the 1200s brought Polynesian rats for food, and together the humans and the rodents began to shift the ecological balance. Native species started to go extinct. Enter European ships, bearing new carnivores: more aggressive rat species, plus mice, stoats, and others. These ground-based predators hunted differently from the falcons and other aerial threats New Zealand wildlife had evolved with. Native birds that slept in burrows made easy prey for prowling mammals. Invasive predator populations exploded, devastating native wildlife. But in the past 60 years humans have intervened to help old New Zealand ecosystems claw their way back. First, a single five-acre (two-hectare) islet called Maria Island (Ruapuke in Māori) was declared rat-free by ecologists in 1964, five years after volunteers set poisoned bait. It was a special case. The white-faced storm petrels at risk there were especially charismatic—they appear to walk on water—and easily gained public support. The ample baiting effort also got particularly lucky with its placement, ecologists say. Nevertheless, the serendipitous success kicked off decades of eradication efforts.
Gene drives for vertebrate pest control: realistic spatial modelling of eradication probabilities and times for island mouse populations
20171A. Birand, P. Cassey, J. V. Ross, J. C. Russell, P. Thomas and T. A. A. Prowse, Molecular Ecology, 2022-01-24 09:06:03.
Abstract Invasive alien species continue to threaten global biodiversity. CRISPR-based gene drives, which can theoretically spread through populations despite imparting a fitness cost, could be used to suppress or eradicate pest populations. We develop an individual-based, spatially explicit, stochastic model to simulate the ability of CRISPR-based homing and X-chromosome shredding drives to eradicate populations of invasive house mice (Mus muculus) from islands. Using the model, we explore the interactive effect of the efficiency of the drive constructs and the spatial ecology of the target population on the outcome of a gene-drive release. We also consider the impact of polyandrous mating and sperm competition, which could compromise the efficacy of some gene-drive strategies. Our results show that both drive strategies could be used to eradicate large populations of mice. Whereas parameters related to drive efficiency and demography strongly influence drive performance, we find that sperm competition following polyandrous mating is unlikely to impact the outcome of an eradication effort substantially. Assumptions regarding the spatial ecology of mice influenced the probability of and time required for eradication, with short-range dispersal capacities and limited mate-search areas producing `chase' dynamics across the island characterised by cycles of local extinction and recolonization by mice. We also show that highly efficient drives are not always optimal, when dispersal and mate-search capabilities are low. Rapid local population suppression around the introduction sites can cause loss of the gene drive before it can spread to the entire island. We conclude that, although the design of efficient gene drives is undoubtedly critical, accurate data on the spatial ecology of target species is critical for predicting the result of a gene-drive release.
Alternatives for mammal pest control in New Zealand in the context of concerns about 1080 toxicant (sodium fluoroacetate)
19067B. Warburton, C. Eason, P. Fisher, N. Hancox, B. Hopkins, G. Nugent, S. Ogilvie, T. A. A. Prowse, J. Ross and P. E. Cowan, New Zealand Journal of Zoology, 43. 2021-10-29 20:19:18.
The ongoing use of 1080 toxin for the control of mammal pests in New Zealand remains highly contentious. Several reviews over the last 25 years identified information gaps and areas of concern, both social and scientific. In this paper these areas of concern are discussed and the extensive scientific and social research that has been undertaken to clarify and address them is reviewed. Although there has been a major national investment in research aimed at finding an alternative to 1080, that has not yet been fully achieved because of low or inconsistent efficacy and/or low cost-effectiveness of alternatives, regulatory difficulties in obtaining approval for aerial delivery of any alternative, and toxic residue concerns. Finding an alternative that has similar efficacy while satisfying the demands for species-selectivity, no residues, and humaneness is a continuing challenge. The most promising prospect appears to be through understanding the genome of the target animals and opportunities for genetic manipulation, either by developing species-specific designer lethal toxicants based on genome mining, or by gene editing to develop non-lethal technologies. Both will require considerable time and funding for research, and considerable effort and engagement to address social and regulatory hurdles.
The Promise of Genetics and Genomics for Improving Invasive Mammal Management on Islands
17936B. T. Burgess, R. L. Irvine, G. R. Howald and M. A. Russello, Frontiers in Ecology and Evolution, 9. 2021-08-03 13:21:15.
Invasive species are major contributors to global biodiversity decline. Invasive mammalian species (IMS), in particular, have profound negative effects in island systems that contain disproportionally high levels of species richness and endemism. The eradication and control of IMS have become important conservation tools for managing species invasions on islands, yet these management operations are often subject to failure due to knowledge gaps surrounding species- and system-specific characteristics, including invasion pathways and contemporary migration patterns. Here, we synthesize the literature on ways in which genetic and genomic tools have effectively informed IMS management on islands, specifically associated with the development and modification of biosecurity protocols, and the design and implementation of eradication and control programs. In spite of their demonstrated utility, we then explore the challenges that are preventing genetics and genomics from being implemented more frequently in IMS management operations from both academic and non-academic perspectives, and suggest possible solutions for breaking down these barriers. Finally, we discuss the potential application of genome editing to the future management of invasive species on islands, including the current state of the field and why islands may be effective targets for this emerging technology.
Genetically Modifying Bats Could Prevent the Next Pandemic, Scientists Say
17744G. Dutton, BioSpace, 2021-07-15 13:26:12.
The next COVID pandemic could be prevented by using a gene drive to preemptively edit the genome of bats to prevent them from becoming hosts for coronaviruses, according to a proposal by scientists from Israel’s Interdisciplinary Center (IDC) Herzelia and the National Institutes of Health (NIH). Meanwhile, a team of researchers from Imperial College London is devising a way to prevent gene drives from spreading and conferring heritable, anti-competitive traits to entire populations. The two projects may be in conflict with one another, or the London project may provide a degree of safety that could manage unintended consequences. The IDC/NIH plan, Preventing COVID-59, was published recently on GitHub by Uaniv Erlich of the (IDC) and Daniel Douek of the Vaccine Research Center, National Institute of Allergies and Infectious Diseases at the NIH in the U.S. Its premise is that the SARS-CoV-2 virus – the third such virus to infect humans in the past 20 years – is part of a growing pattern of betacoronaviruses infecting human populations.
Sustainable Food Production: The Contribution of Genome Editing in Livestock
17590A. Menchaca, Sustainability, 13. 2021-06-21 13:52:55.
This article is focused on the scope and perspectives for the application of this technology, which includes improving production traits, enhancing animal welfare through adaptation and resilience, conferring resistance to infectious diseases, and suppressing pests and invasive species that threaten livestock. The main advantages and concerns that should be overcome by science, policy and people are discussed with the aim that this technology can make a real contribution to our collective future. This review is part of the special issue “Genome Editing in Animal Systems to Support Sustainable Farming and Pest Control”.
New biocontrol research to help prevent mice plagues
17206Anonymous, The National Tribune, 2021-06-04 15:41:51.
Scientists at the University of Adelaide are partnering with the CSIRO and the Centre for Invasive Species Solutions on breakthrough genetic biocontrol research to help control mice populations and prevent future mice plagues. The three-year research program will identify fast acting gene drives, which are designed to spread an inherited characteristic for population control through mice populations at higher-than-normal rates. This would effectively enable scientists to interrupt the breeding cycle and keep mice populations at manageable levels. The NSW Government will provide $1.8 million towards the project to fast-track the delivery of the ‘gene drive technology’ as part of a range of measures not only to mitigate the impacts of the mice currently across NSW, but also to create options to reduce the impact of future population spikes.
Scientists want to alter rodent genes to prevent mice plagues
17092P. Hannon, The Sydney Morning Herald, 2021-05-23 10:52:32.
Mice plagues, such as the one ravaging parts of inland NSW, could become a thing of the past if scientists succeed in modifying the genes of the rodents so that populations crash before they can take off. Paul Thomas, a researcher at the University of Adelaide, is part of an international consortium including the CSIRO and the US Department of Agriculture, studying how to safely alter genes to make female mice infertile. The techniques learned could potentially be applied to other damaging invasive mammals such as cats and foxes.
Widespread haploid-biased gene expression enables sperm-level natural selection
16009K. Bhutani, K. Stansifer, S. Ticau, L. Bojic, A.-C. Villani, J. Slisz, C. M. Cremers, C. Roy, J. Donovan, B. Fiske and R. C. Friedman, Science, eabb1723. 2021-01-14 14:15:08.
Here, we show that a large class of mammalian genes are not completely shared across these bridges. We term these genes “genoinformative markers” (GIMs) and show that a subset can act as selfish genetic elements that spread alleles unevenly through murine, bovine, and human populations. We identify evolutionary pressure to avoid conflict between sperm and somatic function as GIMs are enriched for testis-specific gene expression, paralogs, and isoforms.
Next-generation tools to control biting midge populations and reduce pathogen transmission
15940P. Shults, L. W. Cohnstaedt, Z. N. Adelman and C. Brelsfoard, Parasites and Vectors, 14:31. 2021-01-07 14:52:23.
Biting midges of the genus Culicoides transmit disease-causing agents resulting in a significant economic impact on livestock industries in many parts of the world. Localized control efforts, such as removal of larval habitat or pesticide application, can be logistically difficult, expensive and ineffective if not instituted and maintained properly. With these limitations, a population-level approach to the management of Culicoides midges should be investigated as a means to replace or supplement existing control strategies. Next-generation control methods such as Wolbachia- and genetic-based population suppression and replacement are being investigated in several vector species. Here we assess the feasibility and applicability of these approaches for use against biting midges. We also discuss the technical and logistical hurdles needing to be addressed for each method to be successful, as well as emphasize the importance of addressing community engagement and involving stakeholders in the investigation and development of these approaches.
Invasive Species Control and Resolution of Wildlife Damage Conflicts: A Framework for Chemical and Genetically Based Management Methods
15286L. Clark, J. Eisemann, J. Godwin, K. E. Horak, K. Oh, J. O’Hare, A. Piaggio, K. Pepin and E. Ruell, GMOs: Implications for Biodiversity Conservation and Ecological Processes, 2020-12-02 16:52:40.
Vertebrate wildlife damage management relates to developing and employing methods to mitigate against damage caused by wildlife in the areas of food production, property damage, and animal or human health and safety. Of the many management tools available
Meet Cosmo, the gene-edited Crispr calf
13590S. D. McClain, Capital Press, 2020-07-31 12:56:28.
Cosmo was the grand finale of a series of experiments to create a line of genome-edited cattle tailored for the beef industry. He was designed to produce 75% male offspring.
The future of beef might be a sausage fest
13479N. Johnson, grist, 2020-07-24 21:00:33.
N. Johnson. (2020) grist. A media report on the creation of a cow with a sex ratio altering genetic change expected to lead to 3/4 of the cow's offspring being males. This type of sex ratio distortion results in gene drive and is also being considered to help control populations of invasive mammals.
Meet Cosmo the Frankenbull: Scientists genetically engineer a bull calf so that 75 per cent of its offspring will be male
13476J. Pinkstone, Daily Mail, 2020-07-24 20:58:14.
J. Pinkstone (2020). Daily Mail. A media report on the creation of a cow with a sex ratio altering genetic change expected to lead to 3/4 of the cow's offspring being males. This type of sex ratio distortion results in gene drive and is also being considered to help control populations of invasive mammals.
A Crispr calf is born. It’s definitely a boy
13454M. Molteni, WIRED, 2020-07-24 16:25:14.
M. Molteni (2020). Wired. UC Davis scientists spent years editing a sex-determining gene into bovine embryos. In April, Cosmo arrived—and his DNA reveals how far the field has to go. This type of sex ratio distortion results in gene drive and is also being considered to help control populations of invasive mammals.
Meet the first genetically modified bull. Why did scientists change it
13473J. Kessler, Free News, 2020-07-23 20:52:51.
J. Kessler (2020). Free News. UC Davis scientists have successfully introduced a bovine embryo, or the bovine SRY gene, which is responsible for the development of the male. This is the first demonstration of targeted gene insertion for large DNA sequences through embryo-mediated genome editing in cattle. This type of sex ratio distortion results in gene drive and is also being considered to help control populations of invasive mammals.
Scientists use CRISPR technology to insert sex-determining gene
13452A. Quinton, Phys Org, 2020-07-23 16:21:10.
A. Quinton (2020). Phys Org. Scientists at the University of California, Davis, have successfully produced a bull calf, named Cosmo, who was genome-edited as an embryo so that he'll produce more male offspring. The research was presented in a poster on July 23 at the American Society of Animal Science meeting. This type of sex ratio distortion results in gene drive and is also being considered to help control populations of invasive mammals.
First they cloned Dolly the sheep. Now they’re targeting grey squirrels
6218Leake, J., The Times, 2020-01-05 21:25:05.
For 150 years they have wreaked havoc on Britain’s woods and wildlife, but the destructive reign of the grey squirrel could soon be over — ended by DNA editing to ensure that all future females are born infertile. Researchers at the Roslin Institute, the genetics laboratory renowned for its 1996 creation of Dolly the Sheep, the world’s first mammal cloned from an adult cell, want to create gene-edited squirrels for eventual release into the wild.
Dolly the sheep scientists hope DNA editing can wipe out grey squirrels
6215McLaughlin, M., The Scotsman, 2020-01-05 21:20:21.
They have been poisoned, shot at, and stumbled into traps laid by those who regard them as a ruinous blight on the country’s woodland and wildlife. But now, the grey squirrel is facing arguably its biggest threat yet, with plans to harness the cutting edge of genetic science to bring their destructive reign to an end.
Genetically engineering wild mice to combat Lyme disease: An ecological perspective
5631Snow, A. A., BioScience, 69:746-756. 2019-12-17 16:51:55.
Genetic engineering of wild populations has been proposed for reducing human diseases by altering pathogens’ hosts. For example, CRISPR- based genome editing may be used to create white-footed mice (Peromyscus leucopus) that are resistant to the Lyme disease spirochete vectored by blacklegged ticks (Ixodes scapularis). Toward this goal, academic researchers are developing Lyme-resistant and tick-resistant white-footed mice, which are a primary pathogen reservoir for Lyme disease in the United States. If field trials on small, experimental islands are successful, the project would scale up to the larger islands of Nantucket and Martha’s Vineyard, Massachusetts, and possibly to the mainland, most likely with a local gene drive to speed the traits’ proliferation, pending approvals from relevant constituents. Despite considerable publicity, this project has yet to be evaluated by independent professional ecologists. In the present article, I discuss key ecological and evolutionary questions that should be considered before such genetically engineered mice are released into natural habitats
How gene drives could transform pest control
5530TEDx Youth, 2019-08-13 19:49:22.
In New Zealand, 25 million native birds are killed each year by introduced predators. New Zealand has an ambitious goal to be predator free by the year 2050; however, current pest control methods will not achieve this goal. In this thought-provoking and compelling talk, researcher Anna Clark makes the case to add gene drives to the pest control tool box in order to protect New Zealand’s unique native species.
Meiotic drive shapes rates of karyotype evolution in mammals
5921Blackmon, H., J. Justison, I. Mayrose and E. E. Goldberg, Evolution, 73:511-523. 2019-03-01 16:47:19.
Chromosome number is perhaps the most basic characteristic of a genome, yet generalizations that can explain the evolution of this trait across large clades have remained elusive. Using karyotype data from over 1000 mammals, we developed and applied a phylogenetic model of chromosome evolution that links chromosome number changes with karyotype morphology. Using our model, we infer that rates of chromosome number evolution are significantly lower in species with karyotypes that consist of either all bibrachial or all monobrachial chromosomes than in species with a mix of both types of morphologies. We suggest that species with homogeneous karyotypes may represent cases where meiotic drive acts to stabilize the karyotype, favoring the chromosome morphologies already present in the genome. In contrast, rapid bouts of chromosome number evolution in taxa with mixed karyotypes may indicate that a switch in the polarity of female meiotic drive favors changes in chromosome number. We do not find any evidence that karyotype morphology affects rates of speciation or extinction. Furthermore, we document that switches in meiotic drive polarity are likely common and have occurred in most major clades of mammals, and that rapid remodeling of karyotypes may be more common than once thought.
Super-Mendelian inheritance mediated by CRISPR-Cas9 in the female mouse germline
3914Grunwald, HAG, V. M.; Poplawski, G.; Xu, X. R. S.; Bier, E.; Cooper, K. L., Nature, 566:105-109. 2019-01-12 00:00:00.
A gene drive biases the transmission of one of the two copies of a gene such that it is inherited more frequently than by random segregation. Highly efficient gene drive systems have recently been developed in insects, which leverage the sequence-targeted DNA cleavage activity of CRISPR-Cas9 and endogenous homology-directed repair mechanisms to convert heterozygous genotypes to homozygosity(1-4). If implemented in laboratory rodents, similar systems would enable the rapid assembly of currently impractical genotypes that involve multiple homozygous genes (for example, to model multigenic human diseases). To our knowledge, however, such a system has not yet been demonstrated in mammals. Here we use an active genetic element that encodes a guide RNA, which is embedded in the mouse tyrosinase (Tyr) gene, to evaluate whether targeted gene conversion can occur when CRISPR-Cas9 is active in the early embryo or in the developing germline. Although Cas9 efficiently induces double-stranded DNA breaks in the early embryo and male germline, these breaks are not corrected by homology-directed repair. By contrast, Cas9 expression limited to the female germline induces double-stranded breaks that are corrected by homology-directed repair, which copies the active genetic element from the donor to the receiver chromosome and increases its rate of inheritance in the next generation. These results demonstrate the feasibility of CRISPR-Cas9-mediated systems that bias inheritance of desired alleles in mice and that have the potential to transform the use of rodent models in basic and biomedical research.
A genetic system for biasing the sex ratio in mice
3952Yosef, IEB, Liat; Globus, Rea; Shlomovitz, Inbar; Munitz, Ariel; Gerlic, Motti; Qimron, Udi, EMBO reports, 20:e48269. 2019-01-10 00:00:00.
Biasing the sex ratio of populations of different organisms, including plants, insects, crustacean, and fish, has been demonstrated by genetic and non-genetic approaches. However, biasing the sex ratio of mammalian populations has not been demonstrated genetically. Here, we provide a first proof of concept for such a genetic system in mammals by crossing two genetically engineered mouse lines. The maternal line encodes a functional Cas9 protein on an autosomal chromosome, whereas the paternal line encodes guide RNAs on the Y chromosome targeting vital mouse genes. After fertilization, the presence of both the Y-encoded guide RNAs from the paternal sperm and the Cas9 protein from the maternal egg targets the vital genes in males. We show that these genes are specifically targeted in males and that this breeding consequently self-destructs solely males. Our results pave the way for a genetic system that allows biased sex production of livestock.
Genetic manipulation of sex ratio in mammals: the Reaper comes for Mickey
3947Smanski, MJZ, David, EMBO reports, 20:e48577. 2019-01-05 00:00:00.
In most animals, sexual reproduction results in a 1:1 ratio of females to males. For several sectors of agriculture, for example, milk or egg production, only a single sex is needed. Biasing the sex ratio so that only offspring of the desired sex are produced has the potential to increase breeding efficiency. In this issue of EMBO Reports, Yosef et al [1] demonstrate a genetic approach to bias the sex ratio in mice by specifically disrupting essential genes in male embryos. Their approach is an important first step toward generating sex-ratio biasing applications for agriculture
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.
Gene drive technology considered in the fight to save native animals from feral cats
4585Smail, S, ABC News Online, 2018-05-30 00:00:00.
Feral cats kill thousands of native animals every minute — now a controversial plan to use gene drive technology as a weapon against them is being considered by the Federal Government
A Framework for the risk assessment and management of gene drive technology in contained use
4023van der Vlugt, CJBB, David D.; Lehmann, Kathleen; Leunda, Amaya; Willemarck, Nicolas, Applied Biosafety, 23:25-31. 2018-01-21 00:00:00.
The utilisation of the CRISPR/Cas9 technology has sparked a renewed interest in gene drive mechanisms. These mechanisms of biased inheritance may yield promising applications in the fields of vector control and nature conservation. However, the same properties that will enable these applications may also pose a risk if organisms that are equipped with gene drive cassettes are unintentionally released into the environment. Although several groups of scientists and regulators have started to address these safety concerns, there are currently no dedicated guidelines published on the required risk assessment and minimal control measures applicable to gene drive organisms in contained use. To fill this gap, this paper describes a fundamental approach to assessing the risks of these organisms while handled in a contained laboratory environment. Based on the likelihood that an adverse effect will arise from the handling of a gene drive organism and the severity of this effect, three risk classes for contained use activities are presented. Finally, specific minimum requirements regarding physical measures and working practices are proposed according to the presented risk classes and tailored to activities with rodents, insects, and fungi, which are most likely to be used for gene drive applications in the near future.
Switchable genome editing via genetic code expansion
4018Suzuki, TA, Maki; Patel, Sanjay G.; Luk, Louis Y. P.; Tsai, Yu-Hsuan; Perry, Anthony C. F., Scientific Reports, 8:10051. 2018-01-16 00:00:00.
Multiple applications of genome editing by CRISPR-Cas9 necessitate stringent regulation and Cas9 variants have accordingly been generated whose activity responds to small ligands, temperature or light. However, these approaches are often impracticable, for example in clinical therapeutic genome editing in situ or gene drives in which environmentally-compatible control is paramount. With this in mind, we have developed heritable Cas9-mediated mammalian genome editing that is acutely controlled by the cheap lysine derivative, Lys(Boc) (BOC). Genetic code expansion permitted non-physiological BOC incorporation such that Cas9 (Cas9BOC) was expressed in a full-length, active form in cultured somatic cells only after BOC exposure. Stringently BOC-dependent, heritable editing of transgenic and native genomic loci occurred when Cas9BOC was expressed at the onset of mouse embryonic development from cRNA or Cas9BOC transgenic females. The tightly controlled Cas9 editing system reported here promises to have broad applications and is a first step towards purposed, spatiotemporal gene drive regulation over large geographical ranges.
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 …
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.
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.
Sry gene drive for rodent control: Reply to Gemmell and Tompkins
4051Kanavy, DS, M., Trends in Ecology & Evolution, 32:315-316. 2017-01-09 00:00:00.
We would like to thank Gemmell and Tompkins for their interest and comments onthe articlebyPiaggioet al. [1].Theissues raised by Gemmell and Tompkins [2] are very pertinent, and they correctly identified that the format of the article did not lend itself to a comprehensive discussion of the ideas of using gene drives in mice. The method being considered in the Piaggio et al. article is to utilize a naturally occurring t-allele transgene (Tg) to sex-bias amouse population, causing it to crash. Inserting the sex-determining region on the Y chromosome (Sry) into the Tg allows biased inheritance where the majority of the offspring born are phenotypically male.
Genetic engineering to eradicate invasive mice on islands: modeling the efficiency and ecological impacts
4079Backus, GAG, K., Ecosphere, 7:e01589. 2016-01-17 00:00:00.
Invasive rodents are usually eradicated from islands through the application of chemical toxicants that can harm surrounding ecosystems. A recently proposed alternative involves engineering a house mouse (Mus musculus) to carry a genetic construct that would cause a majority of its offspring to be male, many of which would be sterile. Releasing these genetically engineered mice to interbreed with an invasive population would reduce the number of fertile female mice until no more remain. We constructed a mathematical model to analyze the population dynamics of eradication with this genetically engineered mouse and determined its eradication efficiency through model analysis and simulations. Because genetically engineered mice would likely have a fitness disadvantage compared to wild mice, we found that they would need to be repeatedly released into the population to ensure complete eradication. However, if genetically engineered mice have a substantial survival advantage, we determined that the genetic construct could theoretically spread and eradicate a population after a single pulsed release onto the target island or after an engineered mouse escapes to a non-target location. Also, while the species specificity of genetic engineering avoids some of the non-target impacts of traditional eradication methods, ecological impacts could manifest indirectly. We compared several metrics to estimate potential transient impacts on the ecosystem and found that there is a trade-off between the speed of an eradication and the intensity of increased disruptive ecological interactions. Together, our results can inform safe and efficient ecological practices for eradication with developing genetic engineering technology.
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.
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.
The next generation of rodent eradications: Innovative technologies and tools to improve species specificity and increase their feasibility on islands
4109Campbell, KJB, J.; Eason, C. T.; Glen, A. S.; Godwin, J.; Gould, F.; Holmes, N. D.; Howald, G. R.; Madden, F. M.; Ponder, J. B.; Threadgill, D. W.; Wegmann, A. S.; Baxter, G. S., Biological Conservation, 185:47-58. 2015-01-07 00:00:00.
Rodents remain one of the most widespread and damaging invasive alien species on islands globally. The current toolbox for insular rodent eradications is reliant on the application of sufficient anticoagulant toxicant into every potential rodent territory across an island. Despite significant advances in the use of these toxicants over recent decades, numerous situations remain where eradication is challenging or not yet feasible. These include islands with significant human populations, unreceptive stakeholder communities, co-occurrence of livestock and domestic animals, or vulnerability of native species. Developments in diverse branches of science, particularly the medical, pharmaceutical, invertebrate pest control, social science, technology and defense fields offer potential insights into the next generation of tools to eradicate rodents from islands. Horizon scanning is a structured process whereby current problems are assessed against potential future solutions. We undertook such an exercise to identify the most promising technologies, techniques and approaches that might be applied to rodent eradications from islands. We highlight a Rattus-specific toxicant, RNA interference as species-specific toxicants, rodenticide research, crab deterrent in baits, prophylactic treatment for protection of non-target species, transgenic rodents, virus vectored immunocontraception, drones, self-resetting traps and toxicant applicators, detection probability models and improved stakeholder community engagement methods. We present a brief description of each method, and discuss its application to rodent eradication on islands, knowledge gaps, challenges, whether it is incremental or transformative in nature and provide a potential time-line for availability. We outline how a combination of new tools may render previously intractable rodent eradication problems feasible. (C) 2014 Elsevier Ltd. All rights reserved.
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.
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.
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.
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.
Guidance on the environmental risk assessment of genetically modified animals
16055European Food Safety Authority, European Food Safety Authority, 2013-05-23 20:45:04.
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.
Mechanism of meiotic drive in mammals
4170Chmatal, 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.
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.
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.
Evolution of the Schlafen genes, a gene family associated with embryonic lethality, meiotic drive, immune processes and orthopoxvirus virulence
4221Bustos, ON, S.; Ayers, G.; Casola, C.; Perez-Lamigueiro, M. A.; Chippindale, P. T.; Pritham, E. J.; de la Casa-Esperon, E., Gene, 447:11-Jan. 2009-01-19 00:00:00.
Genes of the Schlafen family, first discovered in mouse, are expressed in hematopoietic cells and are involved in immune processes. Previous results showed that they are candidate genes for two major phenomena: meiotic drive and embryonic lethality (DDK syndrome). However, these genes remain poorly understood, mostly due to the limitations imposed by their similarity, close location and the potential functional redundancy of the gene family members. Here we use genomic and phylogenetic studies to investigate the evolution and role of this family of genes. Our results show that the Schlafen family is widely distributed in mammals, where we recognize four major clades that experienced lineage-specific expansions or contractions in various orders, including primates and rodents. In addition, we identified members of the Schlafen family in Chondrichthyes and Amphibia, indicating an ancient origin of these genes. We find evidence that positive selection has acted on many Schlafen genes. Moreover, our analyses indicate that a member of the Schlafen family was horizontally transferred from murine rodents to orthopoxviruses, where it is hypothesized to play a role in allowing the virus to survive host immune defense mechanisms. The functional relevance of the viral Schlafen sequences is further underscored by our finding that they are evolving under purifying selection. This is of particular importance, since orthopoxviruses infect mammals and include variola, the causative agent of smallpox, and monkeypox, an emerging virus of great concern for human health. (C) 2009 Elsevier B.V. All rights reserved.
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
Broadening the application of evolutionarily based genetic pest management
4237Gould, F, Evolution, 62:500-510. 2008-01-15 00:00:00.
Insect- and tick-vectored diseases such as malaria, dengue fever, and Lyme disease cause human suffering, and current approaches for prevention are not adequate. Invasive plants and animals such as Scotch broom, zebra mussels, and gypsy moths continue to cause environmental damage and economic losses in agriculture and forestry Rodents transmit diseases and cause major pre- and postharvest losses, especially in less affluent countries. Each of these problems might benefit from the developing field of Genetic Pest Management that is conceptually based on principles of evolutionary biology This article briefly describes the history of this field, new molecular tools in this field, and potential applications of those tools. There will be a need for evolutionary biologists to interact with researchers and practitioners in a variety of other fields to determine the most appropriate targets for genetic pest management, the most appropriate methods for specific targets, and the potential of natural selection to diminish the effectiveness of genetic pest management. In addition to producing environmentally sustainable pest management solutions, research efforts in this area could lead to new insights about the evolution of selfish genetic elements in natural systems and will provide students with the opportunity to develop a more sophisticated understanding of the role of evolutionary biology in solving societal problems.
Meiotic drive at the Om locus in wild-derived inbred mouse strains
4277Kim, KT, S.; Howard, I. B.; Bell, T. A.; Doherty, H. E.; Ideraabdullah, F.; Detwiler, D. A.; De Villena, F. P. M., Biological Journal of the Linnean Society, 84:487-492. 2005-01-15 00:00:00.
Meiotic drive is an evolutionary force in which natural selection is uncoupled from organismal fitness. Recently, it has been proposed that meiotic drive and genetic drift represent major forces in the evolution of the mammalian karyotype. Meiotic drive involves two types of genetic elements, Responders and Distorters, the latter being required to induce transmission ratio distortion at the former. We have previously described the Om meiotic drive system in mouse chromosome 11. To investigate the natural history of this drive system we have characterized the alleles present at the distorter in wild-derived inbred strains. Our analysis of transmission of maternal alleles in both classical and wild-derived inbred strains indicated that driving alleles are found at high frequency in natural populations and that the existence of driving alleles predates the split between the Mus spicilegus and M. musculus lineages. (c) 2005 The Linnean Society of London.
Sex chromosome meiotic drive in hybrid males of the common shrew (Sorex araneus)
4273Fedyk, SB, U.; Chetnicki, W., Folia Biologica-Krakow, 53:133-141. 2005-01-11 00:00:00.
Patterns of sex chromosome segregation in six homozygous males of the common Shrew (Sorex araneus LINNAEUS, 1758) belonging to two chromosomal races, as well as in 16 interracial hybrids were studied. I ascd on their karyotypes the hybrids can be subdivided into two groups: (a) complex heterozygotes, which form meiotic quadrivalents in chain and chain + ring configurations, and (b) complex heterozygotes, which Form meiotic pentavalents in chain configurations. Random 1 : 1) segregation of sex chromosomes was found ill homozygous as well as those he erozygous males which form meiotic complexes Of four chromosomes. However, in some, hybrids with meiotic pentavalents we observed a strong preferential segregation in favou of X chromosomes.
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.
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.
An unusual sex-determination system in South American field mice (genus Akodon): The role of mutation, selection, and meiotic drive in maintaining XY females
4330Hoekstra, HEH, J. M., Evolution, 55:190-197. 2001-01-08 00:00:00.
The mechanism of sex determination in mammals appears highly conserved: the presence of a Y chromosome triggers the male developmental pathway, whereas the absence of a Y chromosome results in a default female phenotype. However, if the Y chromosome fails to initiate the male pathway (referred to as Y*), XY* females can result, as is the case in several species of South American field mice (genus Akodon). The breeding genetics in this system inherently select against the Y* chromosome such that the frequency of XY* females should decrease rapidly to very low frequencies. However, in natural populations of Akodon, XY* females persist at substantial frequencies; for example, 10% of females are XY* in A. azarae and 30% in A. boliviensis. We develop a mathematical model that considers the potential roles of three evolutionary forces in maintaining XY* females: Y-to-Y* chromosome transitions (mu ration), chromosome segregation distortion (meiotic drive), and differential fecundity (selection). We then test the predictions of our model using data from breeding colonies of A. azarae. We conclude that any single force is inadequate to maintain XY* females. However, a combination of segregation bias of the male and female Y chromosomes during spermatogenesis/oogenesis and increased fecundity in XY* females could account for the observed frequencies of XY* females.
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.
Nonrandom segregation of the mouse univalent X chromosome: Evidence of spindle-mediated meiotic drive
4344LeMaire-Adkins, RH, P. A., Genetics, 156:775-783. 2000-01-02 00:00:00.
A fundamental principle of Mendelian inheritance is random segregation of alleles to progeny; however, examples of distorted transmission either of specific alleles or of whole chromosomes have been described in a variety of species. In humans and mice, a distortion in chromosome transmission is often associated with a chromosome abnormality. One such example is the fertile XO female mouse. A transmission distortion effect that results in an excess of XX over XO daughters among the progeny of XO females has been recognized for nearly four decades. Utilizing contemporary methodology that combines immuno-fluorescence, FISH, and three-dimensional confocal microscopy, we have readdressed the meiotic segregation behavior of the single X chromosome in oocytes from XO females produced on two different inbred backgrounds. Our studies demonstrate that segregation of the univalent X chromosome at the first meiotic division is nonrandom, with preferential retention of the X chromosome in the oocyte in similar to 60% of cells. We propose that this deviation from Mendelian expectations is facilitated by a spindle-mediated mechanism. This mechanism, which appears to be a general feature of the female meiotic process, has implications the frequency of nondisjunction in our species.
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.
Transmission ratio distortion at the INS-IGF2 VNTR
4352Eaves, IAB, S. T.; Forster, P.; Ferber, K. M.; Ehrmann, D.; Wilson, A. J.; Bhattacharyya, S.; Ziegler, A. G.; Brinkmann, B.; Todd, J. A., Nature Genetics, 22:324-325. 1999-01-10 00:00:00.
Transmission ratio distortion (TRD) is defined as a statistically significant departure from mendelian transmission. So far, evidence of this in humans has been limited or controversial1,2,3,4, and the few established examples involve chromosome rearrangements in lower organisms5.; ; The variable number of tandem repeat (VNTR) polymorphism 596 bp 5´ of the insulin gene (INS) regulates expression of both INS and the gene encoding insulin-like growth factor 2 (IGF2). The VNTR can be subdivided into two main allele sizes, class I and class III, in Europeans. Class III alleles are associated with reduced expression of INS and IGF2 in the pancreas and placenta6. As lower expression of VNTR class III-associated INS/IGF2 alleles early in fetal development may reduce the chances of survival in utero, the locus is considered a candidate for exhibiting TRD.
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.
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.
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.
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.
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?
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.
Analysis of meiotic segregation, using single-sperm typing: Meiotic drive at the myotonic dystrophy locus
4396Leeflang, EPM, M. S.; Arnheim, N., American Journal of Human Genetics, 59:896-904. 1996-01-14 00:00:00.
Meiotic drive at the myotonic dystrophy (DM) locus has recently been suggested as being responsible for maintaining the frequency, in the human population, of DM chromosomes capable of expansion to the disease state. In order to test this hypothesis, we have studied samples of single sperm from three individuals heterozygous at the DM locus, each with one allele larger and one allele smaller than 19 CTG repeats. To guard against the possible problem of differential PCR amplification rates based on the lengths of the alleles, the sperm were also typed at another closely linked marker whose allele size was unrelated to the allele size at the DM locus. Using statistical models specifically designed to study single-sperm segregation data, we find no evidence of meiotic segregation distortion. The upper limit of the two-sided 95% confidence interval for the estimate of the common segregation probability for the three donors is at or below .515 for all models considered, and no statistically significant difference from .5 is detected in any of the models. This suggests that any greater amount of segregation distortion at the myotonic dystrophy locus must result from events following sperm ejaculation. The mathematical models developed make it possible to study segregation distortion with high resolution by using sperm-typing data from any locus.
The mouse t-complex-encoded protein Tctex-1 is a light chain of brain cytoplasmic dynein
4395King, SMD, J. F.; Benashski, S. E.; Lye, R. J.; PatelKing, R. S.; Pfister, K. K., Journal of Biological Chemistry, 271:32281-32287. 1996-01-13 00:00:00.
Mammalian brain cytoplasmic dynein contains three light chains of M(r) = 8,000, 14,000, add 22,000 (King, S. M., Barbarese, E., Dillman, J. F., III, Patel-King, R. S., Carson, J. H., and Pfister, K. Kr (1996) J. Biol. Chem. 271, 19358-19366). Peptide sequence data (16/16 residues correct) implicate the M(r) = 14,000 polypeptide as Tctex-1, a protein encoded within the mouse t-complex. Tctex-1 cosediments with microtubules and is eluted with ATP or salt but not with GTP as expected for a dynein subunit, The ATP-eluted protein precisely cosediments with known cytoplasmic dynein proteins in sucrose density gradients, Tctex-1 also is immunoprecipitated from brain and other tissue homogenates by a monoclonal antibody raised against the 74-kDa cytoplasmic dynein intermediate chain, Quantitative densitometry indicates that Tctex-1 is a stoichiometric component of the dynein complex, As Tctex-1 is a candidate for involvement in the transmission ratio distortion (meiotic drive) of mouse t-haplotypes, these results suggest that cytoplasmic dynein dysfunction may play an important role in non-mendelian chromosome segregation.
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.
Tctex2 – a sperm tail surface protein mapping to the t-complex
4405Huw, LYG, A. S.; Willison, K.; Artzt, K., Developmental Biology, 170:183-194. 1995-01-03 00:00:00.
Transmission ratio distortion (TRD) in mouse t-haplotypes remains the most significant example of meiotic drive in vertebrates. While the underlying mechanism that fuels it is still mysterious, TRD is clearly a complex multigene phenomenon. The characterization of Tctex2 (t-complex testis expressed 2) shows it to be one of several candidates for involvement in TRD, Tctex2 maps to the t-complex and encodes a membrane-associated protein found exclusively on the sperm tail. The t-haplotype form of Tctex2 is aberrant in both the level of its expression and its primary amino acid sequence, but is nonetheless translated and transported to its normal location. The multiple amino acid changes in the t-form make it extremely unlikely that it can function normally and, since it is found on sperm tails, suggest that it may actively interfere with the development of normal gamete function in males. The possible role of Tctex2 in t-complex transmission ratio distortion and sterility is discussed. (C) 1995 Academic Press, Inc.
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
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
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.
Bewildering Bs – An impression of the 1st B-chromosome conference
4408Beukeboom, LW, Heredity, 73:328-336. 1994-01-06 00:00:00.
Ever since their first discovery B chromosomes have attracted attention. Why are they so appealing? The standard chromosomes of an organism are A chromosomes; B chromosomes are extra to this normal complement. In the B chromosome 'bible' (Jones & Rees, 1982) Bs are defined as dispensable supernumerary chromosomes that are not homologous and do not pair with A chromosomes. They have been further characterized as (1) morphologically different from As (usually smaller), (2) being inherited in a nonMendelian fashion, (3) not (or only rarely) having nucleolus organisers, (4) often displaying nondisjunction at anaphase of mitosis resulting in frequencies varying between organs in the same individual, (5) reducing fertility and growth when present in high numbers, and (6) carrying no genes with major effects. These features of Bs were recently discussed at an international conference and the main ideas presented by the participants are reported here. From 21 to 25 September 19
Meiotic drive on aberrant Chromosome-1 in the mouse is determined by a linked distorter
4418Agulnik, SIS, I. D.; Orlova, G. V.; Ruvinsky, A. O., Genetical Research, 61:91-96. 1993-01-16 00:00:00.
An aberrant chromosome 1 carrying an inverted fragment with two amplified DNA regions was isolated from wild populations of Mus musculus. Meiotic drive favouring the aberrant chromosome was demonstrated for heterozygous females. Its cause was preferential passage of aberrant chromosome 1 to the oocyte. Genetic analysis allowed us to identify a two-component system conditioning deviation from equal segregation of the homologues. The system consists of a postulated distorter and responder. The distorter is located on chromosome 1 distally to the responder, between the ln and Pep-3 genes, and it acts on the responder when in trans position. Polymorphism of the distorters was manifested as variation in their effect on meiotic drive level in the laboratory strain and mice from wild populations.
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.
Meiotic drive for the aberrant Chromosome-1 in mice is determined by a linked distorter
4429Agulnik, SIS, I. D.; Orlova, G. V.; Ruvinsky, A. O., Genetika, 28:47-57. 1992-01-07 00:00:00.
AN aberrant chromosome 1 carrying an inverted fragment with two amplified DNA regions was isolated from natural populations of Mus musculus. A meiotic drive favouring the aberrant chromosome was previously demonstrated for heterozygous females. The cause for this was the preferential passage of the chromosome 1 to the oocyte. Genetic analysis made it possible to identify a two-component system conditioning the deviation from equal segregation of the homologues. The system consists of the postulated distorter and a responder. The distorter is located on the chromosome 1 distally to the responder, between the ln and Pep 3 genes, the former acting on the responder when in the trans position. Polymorphism of the distorters was manifested as variation in their effect on the meiotic drive level in the laboratory strain and mice from natural populations.
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.
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.
Molecular and chromosomal studies on the origin of t-haplotypes in mice
4444Hammer, MF, American Naturalist, 137:359-365. 1991-01-02 00:00:00.
Mouse t haplotypes are variant forms of the proximal third of chromosome 17 that enhance their representation in the gene pool by means of a male-specific transmission-ratio distortion. As with other systems of meiotic drive, they are maintained as independent genetic entities by inversions that suppress recombination with their wild-type homologues. This article reviews some of the evidence for the origin of this complex system based on DNA and chromosomal comparisons. Such comparisons suggest a stepwise evolution of t haplotypes, whereby the proximal and distal inversion occurred on separate chromosomal lineages and at different times. The initial event leading to the spread of t haplotypes may have been an inversion occurring on the wild-type chromosome (nondriving) 2-4 million yr ago. An additional implication of the data is that meiotic drive gives t haplotypes the ability to traverse species boundaries and spread rapidly around the world.
Meiotic drive in female mice heterozygous for the HSR inserts on Chromosome-1
4460Agulnik, SIA, A. I.; Ruvinsky, A. O., Genetical Research, 55:97-100. 1990-01-18 00:00:00.
Chromosome 1 with one or two long insertions has been previously found in natural mouse populations. The inheritance of chromosome 1 with two insertions from the Yakutsk population is analysed in this paper. It was demonstrated that heterozygous females transmit this chromosome to 80–85% of offspring. The observations made at M II, in conjunction with the recombination data, allowed us to conclude that preferential passage of the chromosome 1 with insertions to the oocyte and egg, rather than to the first and second polar bodies at meiosis, is the causative factor of the distorted segregation. A meiotic drive of such potency has not been previously reported for female mammals. The possible mechanism of the drive is discussed.
Meiotic drive of the aberrant Chromosome-1 in the house mouse
4459Agulnik, SIA, A. I.; Ruvinsky, A. O., Genetika, 26:664-669. 1990-01-17 00:00:00.
Animals with aberrant chromosome 1 carrying one or two large insertions were earlier described in natural populations of Mus musculus. In the present work, inheritance of the aberrant chromosome 1 from the Yakutsk population was investigated. It was shown that 80-85% of the progeny from heterozygous females received chromosome 1 with insertions. From chromosomal analysis of blastocytes and oocytes at the MII stage, it was concluded that the preferential distribution of the aberrant chromosome into oocytes during the first and especially, the second meiotic divisions is relevant to the segregation distortion observed. The mechanism of this powerful meiotic drive is discussed.
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.
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).
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