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Exceptions to Mendel's law of segregation were important for demonstrating that chromosomes carry genetic material. Scrutiny of additional exceptions to Mendel's law caused by selfish genes has the potential to unravel other unsolved mysteries of genetics.
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Numerous genes required for sexual reproduction remain to be identified even in simple model species like Schizosaccharomyces pombe. To address this, we developed an assay in S. pombe that couples transposon mutagenesis with high-throughput sequencing (TN-seq) to quantitatively measure the fitness contribution of nonessential genes across the genome to sexual reproduction. This approach identified 532 genes that contribute to sex, including more than 200 that were not previously annotated to be involved in the process, of which more than 150 have orthologs in vertebrates. Among our verified hits was an uncharacterized gene, ifs1 (important for sex), that is required for spore viability. In two other hits, plb1 and alg9, we observed a novel mutant phenotype of poor spore health wherein viable spores are produced, but the spores exhibit low fitness and are rapidly outcompeted by wild type. Finally, we fortuitously discovered that a gene previously thought to be essential, sdg1 (social distancing gene), is instead required for growth at low cell densities and can be rescued by conditioned medium. Our assay will be valuable in further studies of sexual reproduction in S. pombe and identifies multiple candidate genes that could contribute to sexual reproduction in other eukaryotes, including humans.
Assuntos
Genes Fúngicos , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Sequenciamento de Nucleotídeos em Larga Escala , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/genética , Esporos Fúngicos/genéticaRESUMO
Meiotic drivers bias gametogenesis to ensure their transmission into more than half the offspring of a heterozygote. In Schizosaccharomyces pombe, wtf meiotic drivers destroy the meiotic products (spores) that do not inherit the driver from a heterozygote, thereby reducing fertility. wtf drivers encode both a Wtfpoison protein and a Wtfantidote protein using alternative transcriptional start sites. Here, we analyze how the expression and localization of the Wtf proteins are regulated to achieve drive. We show that transcriptional timing and selective protein exclusion from developing spores ensure that all spores are exposed to Wtf4poison, but only the spores that inherit wtf4 receive a dose of Wtf4antidote sufficient for survival. In addition, we show that the Mei4 transcription factor, a master regulator of meiosis, controls the expression of the wtf4poison transcript. This transcriptional regulation, which includes the use of a critical meiotic transcription factor, likely complicates the universal suppression of wtf genes without concomitantly disrupting spore viability. We propose that these features contribute to the evolutionary success of the wtf drivers.
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Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Schizosaccharomyces/genética , Esporos Fúngicos/genética , Proteínas de Schizosaccharomyces pombe/genética , Meiose , Fatores de Transcrição/genéticaRESUMO
Meiotic drivers are selfish alleles that can force their transmission into more than 50% of the viable gametes made by heterozygotes. Meiotic drivers are known to cause infertility in a diverse range of eukaryotes and are predicted to affect the evolution of genome structure and meiosis. The wtf gene family of Schizosaccharomyces pombe includes both meiotic drivers and drive suppressors and thus offers a tractable model organism to study drive systems. Currently, only a handful of wtf genes have been functionally characterized and those genes only partially reflect the diversity of the wtf gene family. In this work, we functionally test 22 additional wtf genes for meiotic drive phenotypes. We identify eight new drivers that share between 30-90% amino acid identity with previously characterized drivers. Despite the vast divergence between these genes, they generally drive into >85% of gametes when heterozygous. We also identify three wtf genes that suppress other wtf drivers, including two that also act as autonomous drivers. Additionally, we find that wtf genes do not underlie a weak (64% allele transmission) meiotic driver on chromosome 1. Finally, we find that some Wtf proteins have expression or localization patterns that are distinct from the poison and antidote proteins encoded by drivers and suppressors, suggesting some wtf genes may have non-meiotic drive functions. Overall, this work expands our understanding of the wtf gene family and the burden selfish driver genes impose on S. pombe.
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Genes Fúngicos , Meiose/genética , Proteínas de Schizosaccharomyces pombe/genética , Schizosaccharomyces/fisiologia , Esporos Fúngicos/genética , Regulação Fúngica da Expressão Gênica , Proteínas de Schizosaccharomyces pombe/metabolismoRESUMO
Unbiased allele transmission into progeny is a fundamental genetic concept canonized as Mendel's Law of Segregation. Not all alleles, however, abide by the law. Killer meiotic drivers are ultra-selfish DNA sequences that are transmitted into more than half (sometimes all) of the meiotic products generated by a heterozygote. As their name implies, these loci gain a transmission advantage in heterozygotes by destroying otherwise viable meiotic products that do not inherit the driver. We review and classify killer meiotic drive genes across a wide spectrum of eukaryotes. We discuss how analyses of these ultra-selfish genes can lead to greater insight into the mechanisms of gametogenesis and the causes of infertility.
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Alelos , Segregação de Cromossomos/genética , Genética/tendências , Meiose/genética , Eucariotos , HeterozigotoRESUMO
Meiotic drivers are selfish alleles that subvert gametogenesis to increase their transmission into progeny. Drivers impose a fitness cost, putting pressure on the genome to evolve suppressors. Here we investigate the wtf gene family from Schizosaccharomyces pombe, previously shown to contain meiotic drivers in wild isolates. We discovered that wtf13 found in lab stocks is a meiotic driver. wtf13 kills spores that do not inherit it by generating both a diffusible poison and a spore-specific antidote. Additionally, we demonstrate that wtf13 is suppressed by another wtf gene, wtf18-2, that arose spontaneously in the lab and makes only an antidote. Wtf18-2 does not act indiscriminately to prevent spore destruction. Instead, it rescues only the spores that inherit wtf18-2. In this way, wtf18-2 selfishly gains a transmission advantage of its own while dampening the drive of wtf13. This establishes a novel paradigm for meiotic drive suppressors and provides insight into the mechanisms and evolution of drive systems.
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Genes Fúngicos , Meiose/genética , Schizosaccharomyces/genética , Alelos , Sequência de Aminoácidos , Antídotos , Gametogênese/genética , Modelos Genéticos , Mimetismo Molecular/genética , Família Multigênica , Venenos , Sequências Repetitivas de Ácido Nucleico , Schizosaccharomyces/citologia , Proteínas de Schizosaccharomyces pombe/genética , Homologia de Sequência de Aminoácidos , Esporos Fúngicos/genética , Supressão GenéticaRESUMO
Natural selection works best when the two alleles in a diploid organism are transmitted to offspring at equal frequencies. Despite this, selfish loci known as meiotic drivers that bias their own transmission into gametes are found throughout eukaryotes. Drive is thought to be a powerful evolutionary force, but empirical evolutionary analyses of drive systems are limited by low numbers of identified meiotic drive genes. Here, we analyze the evolution of the wtf gene family of Schizosaccharomyces pombe that contains both killer meiotic drive genes and suppressors of drive. We completed assemblies of all wtf genes for two S. pombe isolates, as well as a subset of wtf genes from over 50 isolates. We find that wtf copy number can vary greatly between isolates and that amino acid substitutions, expansions and contractions of DNA sequence repeats, and nonallelic gene conversion between family members all contribute to dynamic wtf gene evolution. This work demonstrates the power of meiotic drive to foster rapid evolution and identifies a recombination mechanism through which transposons can indirectly mobilize meiotic drivers.
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Evolução Molecular , Conversão Gênica , Schizosaccharomyces/genética , Genes Fúngicos , Padrões de Herança , Meiose , Anotação de Sequência Molecular , Família Multigênica , Sequências Repetitivas de Ácido NucleicoRESUMO
Meiotic drivers are selfish DNA loci that can bias their own transmission into gametes. Owing to their transmission advantages, meiotic drivers can spread in populations even if the drivers or linked variants decrease organismal fitness. Meiotic drive was first formally described in the 1950s and is thought to be a powerful force shaping eukaryotic genomes. Classic genetic analyses have detected the action of meiotic drivers in plants, filamentous fungi, insects and vertebrates. Several of these drive systems have limited experimental tractability and relatively little is known about the molecular mechanisms of meiotic drive. Recently, however, meiotic drivers were discovered in a yeast species. The Schizosaccharomyces pombe wtf gene family contains several active meiotic drive genes. This review summarizes what is known about the wtf family and highlights its potential as a highly tractable experimental model for molecular and evolutionary characterization of meiotic drive.
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Rearranjo Gênico/genética , Genes Fúngicos , Meiose/genética , Viabilidade Microbiana/genética , Venenos/metabolismo , Schizosaccharomyces/genética , Especiação Genética , Modelos Genéticos , Sequências Repetitivas de Ácido Nucleico , Schizosaccharomyces/citologia , Schizosaccharomyces/metabolismo , Esporos Fúngicos/genética , Esporos Fúngicos/metabolismoRESUMO
Meiotic drivers are selfish genetic loci that can be transmitted to more than half of the viable gametes produced by a heterozygote. This biased transmission gives meiotic drivers an evolutionary advantage that can allow them to spread over generations until all members of a population carry the driver. This evolutionary power can also be exploited to modify natural populations using synthetic drivers known as 'gene drives.' Recently, it has become clear that natural drivers can spread within genomes to birth multicopy gene families. To understand intragenomic spread of drivers, we model the evolution of two or more distinct meiotic drivers in a population. We employ the wtf killer meiotic drivers from Schizosaccharomyces pombe, which are multicopy in all sequenced isolates, as models. We find that a duplicate wtf driver identical to the parent gene can spread in a population unless, or until, the original driver is fixed. When the duplicate driver diverges to be distinct from the parent gene, we find that both drivers spread to fixation under most conditions, but both drivers can be lost under some conditions. Finally, we show that stronger drivers make weaker drivers go extinct in most, but not all, polymorphic populations with absolutely linked drivers. These results reveal the strong potential for natural meiotic drive loci to duplicate and diverge within genomes. Our findings also highlight duplication potential as a factor to consider in the design of synthetic gene drives.
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Fungi can cause devastating invasive infections, typically in immunocompromised patients. Treatment is complicated both by the evolutionary similarity between humans and fungi and by the frequent emergence of drug resistance. Studies in fungal pathogens have long been slowed by a lack of high-throughput tools and community resources that are common in model organisms. Here we demonstrate a high-throughput transposon mutagenesis and sequencing (TN-seq) system in Cryptococcus neoformans that enables genome-wide determination of gene essentiality. We employed a random forest machine learning approach to classify the Cryptococcus neoformans genome as essential or nonessential, predicting 1,465 essential genes, including 302 that lack human orthologs. These genes are ideal targets for new antifungal drug development. TN-seq also enables genome-wide measurement of the fitness contribution of genes to phenotypes of interest. As proof of principle, we demonstrate the genome-wide contribution of genes to growth in fluconazole, a clinically used antifungal. We show a novel role for the well-studied RIM101 pathway in fluconazole susceptibility. We also show that 5' insertions of transposons can drive sensitization of essential genes, enabling screenlike assays of both essential and nonessential components of the genome. Using this approach, we demonstrate a role for mitochondrial function in fluconazole sensitivity, such that tuning down many essential mitochondrial genes via 5' insertions can drive resistance to fluconazole. Our assay system will be valuable in future studies of C. neoformans, particularly in examining the consequences of genotypic diversity.
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Meiotic drivers are selfish elements that bias their own transmission into more than half of the viable progeny produced by a driver+/driver- heterozygote. Meiotic drivers are thought to exist for relatively short evolutionary timespans because a driver gene or gene family is often found in a single species or in a group of very closely related species. Additionally, drivers are generally considered doomed to extinction when they spread to fixation or when suppressors arise. In this study, we examine the evolutionary history of the wtf meiotic drivers first discovered in the fission yeast Schizosaccharomyces pombe. We identify homologous genes in three other fission yeast species, S. octosporus, S. osmophilus, and S. cryophilus, which are estimated to have diverged over 100 million years ago from the S. pombe lineage. Synteny evidence supports that wtf genes were present in the common ancestor of these four species. Moreover, the ancestral genes were likely drivers as wtf genes in S. octosporus cause meiotic drive. Our findings indicate that meiotic drive systems can be maintained for long evolutionary timespans.
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Schizosaccharomyces , Meiose/genética , Schizosaccharomyces/genéticaRESUMO
Meiotic drivers are genetic elements that break Mendel's law of segregation to be transmitted into more than half of the offspring produced by a heterozygote. The success of a driver relies on outcrossing (mating between individuals from distinct lineages) because drivers gain their advantage in heterozygotes. It is, therefore, curious that Schizosaccharomyces pombe, a species reported to rarely outcross, harbors many meiotic drivers. To address this paradox, we measured mating phenotypes in S. pombe natural isolates. We found that the propensity for cells from distinct clonal lineages to mate varies between natural isolates and can be affected both by cell density and by the available sexual partners. Additionally, we found that the observed levels of preferential mating between cells from the same clonal lineage can slow, but not prevent, the spread of a wtf meiotic driver in the absence of additional fitness costs linked to the driver. These analyses reveal parameters critical to understanding the evolution of S. pombe and help explain the success of meiotic drivers in this species.
The fission yeast, Schizosaccharomyces pombe, is a haploid organism, meaning it has a single copy of each of its genes. S. pombe cells generally carry one copy of each chromosome and can reproduce clonally by duplicating these chromosomes and then dividing into two cells. However, when the yeast are starving, they can reproduce sexually. This involves two cells mating by fusing together to create a 'diploid zygote', which contains two copies of each gene. The zygote then undergoes 'meiosis', a special type of cell division in which the zygote first duplicates its genome and then divides twice. This results in four haploid spores which are analogous to sperm and eggs in humans that each contain one copy of the genome. The spores will grow and divide normally when conditions improve. The genes carried by each of the haploid spores depend on the cells that formed the zygote. If the two 'parent' yeast had the same version or 'allele' of a gene, all four spores will have it in their genome. However, if the two parents have different alleles, only 50% of the offspring will carry each version. Although this is usually the case, there are certain alleles, called meiotic drivers, that are transmitted to all offspring even in situations where it is only carried by one parent. Meiotic drivers can be found in many organisms, including mammals, but their behavior is easiest to study in yeast. Meiotic drivers known as killers achieve this by disposing of any 'sister' spores that do not inherit the same allele of this gene. This 'killing' can only happen when only one of the 'parents' carries the driver. This scenario is thought to rarely occur in species that inbreed, as inbreeding leads to both gene copies being the same. However, this does not appear to be the case for S. pombe, which contain a whole family of killer meiotic drivers, the wtf genes, despite also being reported to mainly inbreed. To investigate this contradiction, López Hernández et al. isolated several genetically distinct populations of S.pombe. These isolates were grown together to determine how often the each one would outcross (mate with an individual from a different population) or inbreed. The results found that levels of inbreeding varied between isolates. Next, López Hernández et al. used mathematical modelling and experimental evolution analyses to study how wtf drivers spread amongst these populations. This revealed that wtf genes spread faster in populations with more outcrossing. In some instances, the wtf driver was linked to a gene that could harm the population. In these cases, López Hernández et al. found than inbreeding could purge these drivers and stop them from spreading the dangerous alleles through the population. López Hernández et al. establish a simple experimental system to model driver evolution and experimentally demonstrate how key parameters, such as outcrossing rates, affect the spread of these genes. Understanding how meiotic drivers spread is important, as these systems could potentially be used to modify populations important to humans, such as crops or disease vectors.
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Meiose/genética , Fenótipo , Proteínas de Schizosaccharomyces pombe/genética , Schizosaccharomyces/genética , Heterozigoto , Schizosaccharomyces/fisiologia , Proteínas de Schizosaccharomyces pombe/metabolismo , Esporos Fúngicos/genéticaRESUMO
In this Quick Guide, Srinivasa and Zanders provide an overview of meiotic drivers and the diverse mechanisms these genetic elements use to bias their transmission to the next generation.
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Meiose/fisiologia , Sequências Repetitivas de Ácido Nucleico , Seleção Genética , Animais , Feminino , MasculinoRESUMO
Killer meiotic drivers are genetic parasites that destroy 'sibling' gametes lacking the driver allele. The fitness costs of drive can lead to selection of unlinked suppressors. This suppression could involve evolutionary tradeoffs that compromise gametogenesis and contribute to infertility. Schizosaccharomyces pombe, an organism containing numerous gamete (spore)-killing wtf drivers, offers a tractable system to test this hypothesis. Here, we demonstrate that in scenarios analogous to outcrossing, wtf drivers generate a fitness landscape in which atypical spores, such as aneuploids and diploids, are advantageous. In this context, wtf drivers can decrease the fitness costs of mutations that disrupt meiotic fidelity and, in some circumstances, can even make such mutations beneficial. Moreover, we find that S. pombe isolates vary greatly in their ability to make haploid spores, with some isolates generating up to 46% aneuploid or diploid spores. This work empirically demonstrates the potential for meiotic drivers to shape the evolution of gametogenesis.
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Genes Fúngicos , Meiose/genética , Proteínas de Schizosaccharomyces pombe/genética , Esporos Fúngicos/genética , Regulação Fúngica da Expressão Gênica , Schizosaccharomyces , Proteínas de Schizosaccharomyces pombe/metabolismoRESUMO
Meiotic drivers are parasitic loci that force their own transmission into greater than half of the offspring of a heterozygote. Many drivers have been identified, but their molecular mechanisms are largely unknown. The wtf4 gene is a meiotic driver in Schizosaccharomyces pombe that uses a poison-antidote mechanism to selectively kill meiotic products (spores) that do not inherit wtf4. Here, we show that the Wtf4 proteins can function outside of gametogenesis and in a distantly related species, Saccharomyces cerevisiae. The Wtf4poison protein forms dispersed, toxic aggregates. The Wtf4antidote can co-assemble with the Wtf4poison and promote its trafficking to vacuoles. We show that neutralization of the Wtf4poison requires both co-assembly with the Wtf4antidote and aggregate trafficking, as mutations that disrupt either of these processes result in cell death in the presence of the Wtf4 proteins. This work reveals that wtf parasites can exploit protein aggregate management pathways to selectively destroy spores.
Meiotic drivers are genes that break the normal rules of inheritance. Usually, a gene has a 50% chance of passing on to the next generation. Meiotic drivers force their way into the next generation by poisoning the gametes (the sex cells that combine to form a zygote) that do not carry them. Harnessing the power of genetic drivers could allow scientists to spread beneficial genes across populations. One group of meiotic drivers found in fission yeast is called the 'with transposon fission yeast', or 'wtf' gene family. The wtf drivers act during the production of spores, which are the fission yeast equivalent of sperm, and they encode both a poison that can destroy the spores and its antidote. The poison spreads through the sac holding the spores, and can affect all of them, while the antidote only protects the spores that make it. This means that the spores carrying the wtf genes survive, while the rest of the spores are killed. To understand whether it is possible to use the wtf meiotic drivers to spread other genes, perhaps outside of fission yeast, scientists must first establish exactly how the proteins coded for by genes behave. To do this, Nuckolls et al. examined a member of the wtf family called wtf4. Attaching a fluorescent label to the poison and antidote proteins produced by wtf4 made it possible to see what they do. This revealed that the poison clumps, forming toxic aggregates that damage yeast spores. The antidote works by mopping up these aggregates and moving them to the cell's main storage compartment, called the vacuole. Mutations that disrupted the ability of the antidote to interact with the poison or its ability to move the poison into storage stopped the antidote from working. Nuckolls et al. also showed that if genetic engineering was used to introduce wtf4 into a distantly related species of budding yeast the effects of this meiotic driver were the same. This suggests that the wtf genes may be good candidates for future genetic engineering experiments. Engineered systems known as 'gene drives' could spread beneficial genetic traits through populations. This could include disease-resistance genes in crops, or disease-preventing genes in mosquitoes. The wtf genes are small and work independently of other genes, making them promising candidates for this type of system. These experiments also suggest that the wtf genes could be useful for understanding why clumps of proteins are toxic to cells. Future work could explore why clumps of wtf poison kill spores, while clumps of poison plus antidote do not. This could aid research into human ailments caused by protein clumps, such as Huntington's or Alzheimer's disease.
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Morte Celular/genética , Genes Fúngicos , Saccharomyces cerevisiae/genética , Schizosaccharomyces/genética , Agregados Proteicos/genéticaRESUMO
Genetic conflicts arise when the evolutionary interests of two genetic elements are not aligned. Conflicts between genomes (e.g. pathogen versus host) or within the same genome (e.g. internal parasitic DNA sequences versus the rest of the host genome) can both foster 'molecular arms races', in which genes on both sides of the conflict rapidly evolve due to bouts of adaptation and counter-adaptation. Importantly, a source of genetic novelty is needed to fuel these arms races. In this review, we highlight gene conversion as a major force in generating the novel alleles on which selection can act. Using examples from both intergenomic and intragenomic conflicts, we feature the mechanisms by which gene conversion facilitates the rapid evolution of genes in conflict.
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Variações do Número de Cópias de DNA/genética , Evolução Molecular , Conversão Gênica , Interações Hospedeiro-Parasita/genética , Imunidade Inata/genética , Meiose/genética , Adaptação Fisiológica/genética , Alelos , Animais , Loci Gênicos , Modelos Genéticos , Seleção GenéticaRESUMO
Spok genes are meiotic drivers that increase their own chances of transmission by killing gametes that do not inherit them.
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Meiose/genética , Podospora/genética , Esporos Fúngicos/genética , Segregação de Cromossomos/genética , Cruzamentos Genéticos , Células Germinativas/crescimento & desenvolvimento , Podospora/patogenicidade , Schizosaccharomyces/genética , Schizosaccharomyces/patogenicidadeRESUMO
In sexual reproduction, opportunities are limited and the stakes are high. This inevitably leads to conflict. One pervasive conflict occurs within genomes between alternative alleles at heterozygous loci. Each gamete and thus each offspring will inherit only one of the two alleles from a heterozygous parent. Most alleles 'play fair' and have a 50% chance of being included in any given gamete. However, alleles can gain an enormous advantage if they act selfishly to force their own transmission into more than half, sometimes even all, of the functional gametes. These selfish alleles are known as 'meiotic drivers', and their cheating often incurs a high cost on the fertility of eukaryotes ranging from plants to mammals. Here, we review how several types of meiotic drivers directly and indirectly contribute to infertility, and argue that a complete picture of the genetics of infertility will require focusing on both the standard alleles - those that play fair - as well as selfish alleles involved in genetic conflict.
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Eucariotos/fisiologia , Fertilidade/genética , Meiose/fisiologia , Eucariotos/genéticaRESUMO
Meiotic drivers are selfish genes that bias their transmission into gametes, defying Mendelian inheritance. Despite the significant impact of these genomic parasites on evolution and infertility, few meiotic drive loci have been identified or mechanistically characterized. Here, we demonstrate a complex landscape of meiotic drive genes on chromosome 3 of the fission yeasts Schizosaccharomyces kambucha and S. pombe. We identify S. kambucha wtf4 as one of these genes that acts to kill gametes (known as spores in yeast) that do not inherit the gene from heterozygotes. wtf4 utilizes dual, overlapping transcripts to encode both a gamete-killing poison and an antidote to the poison. To enact drive, all gametes are poisoned, whereas only those that inherit wtf4 are rescued by the antidote. Our work suggests that the wtf multigene family proliferated due to meiotic drive and highlights the power of selfish genes to shape genomes, even while imposing tremendous costs to fertility.