Multiple mating,sperm competition and meiotic drive

Most discussions of ‘sperm competition’ have ignored the potential for competition among the different sperm genotypes present in the ejaculate of a single male. Rivalry within ejaculates may limit cooperation among the members of an ejaculate when they compete with sperm produced by other males. A gene that gains an advantage in competition within an ejaculate (a segregation distorter) may increase in frequency even if it is associated with significant costs to organismal fitness. Therefore, selection will favor genes expressed in males that suppress competition within ejaculates. This may explain why sperm function is largely controlled by the diploid genotype of the male progenitor, rather than by the genotypes of individual haploid sperm. Females who mate with multiple males reduce the relative advantage of a segregation distorter whenever the distorter impairs the competitive effectiveness of the ejaculates in which it occurs. If the distorter is associated with costs to organismal fitness, selection will favor female mating behavior that reduces the distorter's equilibrium frequency. Competition within ejaculates may thus be one reason why females choose to mate with multiple males.     

Coevolutionary dynamics of polyandry and sex‐linked meiotic drive

Segregation distorters located on sex chromosomes are predicted to sweep to fixation and cause extinction via a shortage of one sex, but in nature they are often found at low, stable frequencies. One potential resolution to this longstanding puzzle involves female multiple mating (polyandry). Because many meiotic drivers severely reduce the sperm competitive ability of their male carriers, females are predicted to evolve more frequent polyandry and thereby promote sperm competition when a meiotic driver invades. Consequently, the driving chromosome's relative fitness should decline, halting or reversing its spread. We used formal modeling to show that this initially appealing hypothesis cannot resolve the puzzle alone: other selective pressures (e.g., low fitness of drive homozygotes) are required to establish a stable meiotic drive polymorphism. However, polyandry and meiotic drive can strongly affect one another's frequency, and polyandrous populations may be resistant to the invasion of rare drive mutants.     

A test for meiotic drive in hybrids between Australian and Timor zebra finches

Meiotic drivers have been proposed as a potent evolutionary force underlying genetic and phenotypic variation, genome structure, and also speciation. Due to their strong selective advantage, they are expected to rapidly spread through a population despite potentially detrimental effects on organismal fitness. Once fixed, autosomal drivers are cryptic within populations and only become visible in between‐population crosses lacking the driver or corresponding suppressor. However, the assumed ubiquity of meiotic drivers has rarely been assessed in crosses between populations or species. Here we test for meiotic drive in hybrid embryos and offspring of Timor and Australian zebra finches—subspecies that have evolved in isolation for about two million years—using 38,541 informative transmissions of 56 markers linked to either centromeres or distal chromosome ends. We did not find evidence for meiotic driver loci on specific chromosomes. However, we observed a weak overall transmission bias toward Timor alleles at centromeres in females (transmission probability of Australian alleles of 47%, nominal p = 6 × 10^–5). While this is in line with the centromere drive theory, it goes against the expectation that the subspecies with the larger effective population size (i.e., the Australian zebra finch) should have evolved the more potent meiotic drivers. We thus caution against interpreting our finding as definite evidence for centromeric drive. Yet, weak centromeric meiotic drivers may be more common than generally anticipated and we encourage further studies that are designed to detect also small effect meiotic drivers.     

X-linked meiotic drive can boost population size and persistence

X-linked meiotic drivers cause X-bearing sperm to be produced in excess by male carriers, leading to female-biased sex ratios. Here, we find general conditions for the spread and fixation of X-linked alleles. Our conditions show that the spread of X-linked alleles depends on sex-specific selection and transmission rather than the time spent in each sex. Applying this logic to meiotic drive, we show that polymorphism is heavily dependent on sperm competition induced both by female and male mating behavior and the degree of compensation to gamete loss in the ejaculate size of drive males. We extend these evolutionary models to investigate the demographic consequences of biased sex ratios. Our results suggest driving X-alleles that invade and reach polymorphism (or fix and do not bias segregation excessively) will boost population size and persistence time by increasing population productivity, demonstrating the potential for selfish genetic elements to move sex ratios closer to the population-level optimum. However, when the spread of drive causes strong sex-ratio bias, it can lead to populations with so few males that females remain unmated, cannot produce offspring, and go extinct. This outcome is exacerbated when the male mating rate is low. We suggest that researchers should consider the potential for ecologically beneficial side effects of selfish genetic elements, especially in light of proposals to use meiotic drive for biological control.     

Non-Mendelian transmission in dentatorubral-pallidoluysian atrophy and Machado-Joseph disease: the mutant allele is preferentially transmitted in male meiosis.

Autosomal dominant dentatorubral-pallidoluysian atrophy (DRPLA) and Machado-Joseph disease (MJD) are neurodegenerative disorders caused by CAG trinucleotide repeat expansions. An inverse correlation of age at onset with the length of the expanded CAG trinucleotide repeats has been demonstrated, and the intergenerational instability of the length of the CAG trinucleotide repeats, which is more prominent in paternal than in maternal transmissions, has been shown to underlie the basic mechanisms of anticipation in DRPLA and MJD. Our previous observations on DRPLA and MJD pedigrees, as well as a review of the literature, have suggested that the numbers of affected offspring exceed those of unaffected offspring, which is difficult to explain by the Mendelian principle of random segregation of alleles. In the present study, we analyzed the segregation patterns in 211 transmissions in 24 DRPLA pedigrees and 80 transmissions in 7 MJD pedigrees, with the diagnoses confirmed by molecular testing. Significant distortions in favor of transmission of the mutant alleles were found in male meiosis, where the mutant alleles were transmitted to 62% of all offspring in DRPLA (chi2 = 7.69; P<.01) and 73% in MJD (chi2 = 6.82; P<.01). The results were consistent with meiotic drive in DRPLA and MJD. Since more prominent meiotic instability of the length of the CAG trinucleotide repeats is observed in male meiosis than in female meiosis and meiotic drive is observed only in male meiosis, these results raise the possibility that a common molecular mechanism underlies the meiotic drive and the meiotic instability in male meiosis.     

Kinesin-1 prevents capture of the oocyte meiotic spindle by the sperm aster

Centrioles are lost during oogenesis and inherited from the sperm at fertilization. In the zygote, the centrioles recruit pericentriolar proteins from the egg to form a mature centrosome that nucleates a sperm aster. The sperm aster then captures the female pronucleus to join the maternal and paternal genomes. Because fertilization occurs before completion of female meiosis, some mechanism must prevent capture of the meiotic spindle by the sperm aster. Here we show that in wild-type Caenorhabditis elegans zygotes, maternal pericentriolar proteins are not recruited to the sperm centrioles until after completion of meiosis. Depletion of kinesin-1 heavy chain or its binding partner resulted in premature centrosome maturation during meiosis and growth of a sperm aster that could capture the oocyte meiotic spindle. Kinesin prevents recruitment of pericentriolar proteins by coating the sperm DNA and centrioles and thus prevents triploidy by a nonmotor mechanism.     

Meiotic drive at the Om locus in wild-derived inbred mouse strains

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.  © 2005 The Linnean Society of London, Biological Journal of the Linnean Society , 2005, 84 , 487–492.     

Male-offspring-specific, haplotype-dependent, nonrandom cosegregation of alleles at loci on two mouse chromosomes

F(1) backcrosses involving the DDK and C57BL/6 inbred mouse strains show transmission ratio distortion at loci on two different chromosomes, 11 and X. Transmission ratio distortion on chromosome X is restricted to female offspring while that on chromosome 11 is present in offspring of both sexes. In this article we investigate whether the inheritance of alleles at loci on one chromosome is independent of inheritance of alleles on the other. A strong nonrandom association between the inheritance of alleles at loci on both chromosomes is found among male offspring, while independent assortment occurs among female offspring. We also provide evidence that the mechanism by which this phenomenon occurs involves preferential cosegregation of nonparental chromatids of both chromosomes at the second meiotic division, after the ova has been fertilized by a C57BL/6 sperm bearing a Y chromosome. These observations confirm the influence of the sperm in the segregation of chromatids during female meiosis, and indicate that a locus or loci on the Y chromosome are involved in this instance of meiotic drive.     

Sexually Antagonistic Zygotic Drive: A New Form of Genetic Conflict between the Sex Chromosomes

Sisters and brothers are completely unrelated with respect to the sex chromosomes they inherit from their heterogametic parent. This has the potential to result in a previously unappreciated form of genetic conflict between the sex chromosomes, called sexually antagonistic zygotic drive (SA-ZD). SA-ZD can arise whenever brothers and sisters compete over limited resources or there is brother–sister mating coupled with inbreeding depression. Although theory predicts that SA-ZD should be common and influence important evolutionary processes, there is little empirical evidence for its existence. Here we discuss the current understanding of SA-ZD, why it would be expected to elude empirical detection when present, and how it relates to other forms of genetic conflict.When a diploid individual reproduces sexually, the two alleles at heterozygous loci are necessarily in competition because reproduction by one allele must be at the expense of the other. Such competition is an inescapable component of the organismal level of evolution that was originally advanced by Darwin and later integrated with the field of genetics during the modern synthesis of the early 20th century (Huxley 1942). If the competition is mediated by Mendelian segregation followed by (1) differences in the Darwinian fitness (i.e., survival and fecundity) that each allele produces in offspring, (2) random sampling (genetic drift), and/or (3) differences in the alleles’ mutation or migration rates, then no genetic conflict exists and only canonical evolution at the organismal level occurs. But alleles can also compete outside the context of organismal evolution via diverse mechanisms of selection at the level of the gene that are collectively called genomic conflict (or selfish, ultraselfish, and parasitic DNA). These mechanisms can be divided into three general classes (Burt and Trivers 2006): (1) gonotaxis (in which the selfish elements bias Mendelian segregation by moving away from dead-end polar bodies and into the functional egg during oogenesis, i.e., meiotic or centromeric drive), (2) interference (in which the selfish element kills or debilitates noncarrier gametes or offspring, i.e., segregation distortion and zygotic drive), and (3) overreplication (in which the selfish element increases its copy number in the genome, e.g., biased gene conversion, transposable elements, and homing endonucleases). De novo mutations can also gain a transmission advantage by increasing the rate of stem cell division in the germ line (germline drive) (e.g., Yoon et al. 2013). All of these genomic conflict mechanisms have been described in detail in Burt and Trivers (2006).Genomic conflict frequently leads to reduced fitness at the organismal level. Meiotic drive can harm the organism as a whole because the attributes that provide a segregation advantage in oogenesis (e.g., the structure of the centromere and neighboring heterochromatin) can be maladaptive during spermatogenesis and contribute to male sterility (see, for review, Elde et al. 2011). Segregation distorters and zygotic drivers can substantially reduce a carrier male’s fitness because they kill up to half of his sperm (leading to reduced fertility) and offspring, respectively. Sex-linked, meiotic drivers in WZ females (like birds) and segregation distorters and zygotic drivers in XY males (like insects and mammals) cause biased sex ratios that reduce fitness with respect to Fisherian sex ratio selection and can also reduce population growth and potentially drive species to extinction. Biased gene conversion and germline drive (Yoon et al. 2013) reduce organismal fitness when harmful mutations accumulate to elevated levels (i.e., beyond the conventional values predicted by mutation-selection balance) because they have a molecular drive advantage over an allele that is more beneficial at the organismal level. Transposable elements insert at new places in the genome where they can disrupt gene function and thereby reduce their carrier’s fitness.Zygotic drive is an unusual form of genetic conflict because it directly reduces Darwinian fitness by killing or debilitating offspring. It is favored by gene-level selection when there is competition among siblings for limiting resources. By killing or weakening noncarrier competitor siblings, the gene(s) coding for zygotic drive gain a selective advantage because their survival is increased at the expense of siblings carrying alleles that are not identical by descent—despite any fitness loss to the parents, siblings, or other parts of the genome.Zygotic drive of the autosomes has been observed in a wide diversity of model organisms (e.g., worms, beetles, and mice) (reviewed in Burt and Trivers 2006) in which it can be efficiently detected because of the availability of numerous genetic markers. In general, an autosomal zygotic driver must have both a driver allele at one locus and a protective allele at a responder locus. In worms (Caenorhabditis elegans), a molecular mechanism leading to zygotic drive was recently discovered. Here a zygotic driver is coded by a pair of tightly linked genes, in which an allele at one gene (peel-1) produces a toxin, the driver locus, which is packaged in the sperm and transmitted to the zygote, whereas an allele at another gene (zeel-1) produces an antidote (the protective allele, which is expressed very early in development) that rescues only those embryos that inherit zeel-1 (and usually also the tightly linked driver, peel-1) (Seidel et al. 2011). Zygotic drive on the autosomes is expected to be difficult to evolve—and therefore to be relatively rare in genomes—because it requires an improbable phenotype (i.e., a functionally coupled driver gene product and a responder gene sequence or product) and genotype (i.e., very close linkage between the loci coding for the driver and responder).     

Sex ratio distorter reduces sperm competitive ability in an insect

Selfish genetic elements (SGEs) are ubiquitous in animals and often associated with low male fertility due to reduced sperm number in male carriers. In the fruit fly Drosophila pseudoobscura , the meiotic driving X chromosome "sex ratio" kills Y-bearing sperm in carrier males (SR males), resulting in female only broods. We competed SR males against the ejaculates of noncarrying standard males (ST males), and quantified the number of sperm transferred by SR and ST males to females. We show that SR males are very poor sperm competitors, which is partly related to transfer of fewer sperm during mating. However, sperm numbers alone cannot explain the observed paternity reduction, indicating SR males' sperm may be of reduced quality, possibly due to damage during the killing of the noncarrying Y-sperm. The reduction in sperm competitive ability due to SR is large enough to potentially stabilize the spread of sex ratio drive through populations. The poor sperm competitive ability of SR males coupled with their low fitness as mates could favor increased remating by females to reduce paternity by SR males. Given the generally poor performance of SGE-carrying males in sperm competition, this may generate strong selective pressure favoring polyandry in many species.     

Maternal transmission ratio distortion at the mouse Om locus results from meiotic drive at the second meiotic division

We have observed maternal transmission ratio distortion (TRD) in favor of DDK alleles at the Ovum mutant (Om) locus on mouse chromosome 11 among the offspring of (C57BL/6 x DDK) F(1) females and C57BL/6 males. Although significant lethality occurs in this backcross ( approximately 50%), differences in the level of TRD found in recombinant vs. nonrecombinant chromosomes among offspring argue that TRD is due to nonrandom segregation of chromatids at the second meiotic division, i.e., true meiotic drive. We tested this hypothesis directly, by determining the centromere and Om genotypes of individual chromatids in zygote stage embryos. We found similar levels of TRD in favor of DDK alleles at Om in the female pronucleus and TRD in favor of C57BL/6 alleles at Om in the second polar body. In those embryos for which complete dyads have been reconstructed, TRD was present only in those inheriting heteromorphic dyads. These results demonstrate that meiotic drive occurs at MII and that preferential death of one genotypic class of embryo does not play a large role in the TRD.     

Chromosomally-Induced Meiotic Drive in Drosophila Males: Checkpoint or Fallout?

In male Drosophila melanogaster, anomalies in sex chromosome pairing at meiosis often lead to complete or partial sperm dysfunction. This observation has led to the suggestion that defects in either the efficiency or configuration of chromosome pairing at metaphase trigger a checkpoint mechanism that leads to the elimination of meiotic products. Here, we discuss this model in consideration of recent observations on the conservation of metaphase checkpoint components in male meiosis, and on the phenotype of new alleles of the male-specific meiotic mutant teflon. Based on these observations, we propose an alternative hypothesis for the cause of sperm dysfunction in cases of chromosomal sterility and drive. We suggest that disruption of the prophase compartmentalization of sex chromatin, rather than abnormal pairing at metaphase, may be the causative defect. Such disruption may occur as a result of perturbations in sex chromosome pairing, or by translocations involving autosomal and sex chromatin. We discuss how this hypothesis may account for previously described examples chromosomal causes of meiotic drive and sterility in Drosophila. This revised version was published online in July 2006 with corrections to the Cover Date.     

Meiotic drive influences the outcome of sexually antagonistic selection at a linked locus

Most meiotic drivers, such as the t‐haplotype in Mus and the segregation distorter (SD) in Drosophila, act in a sex‐specific manner, gaining a transmission advantage through one sex although suffering only the fitness costs associated with the driver in the other. Their inheritance is thus more likely through one of the two sexes, a property they share with sexually antagonistic alleles. Previous theory has shown that pairs of linked loci segregating for sexually antagonistic alleles are more likely to remain polymorphic and that linkage disequilibrium accrues between them. I probe this similarity between drive and sexual antagonism and examine the evolution of chromosomes experiencing these selection pressures simultaneously. Reminiscent of previous theory, I find that: the opportunity for polymorphism increases for a sexually antagonistic locus that is physically linked to a driving locus; the opportunity for polymorphism at a driving locus also increases when linked to a sexually antagonistic locus; and stable linkage disequilibrium accompanies any polymorphic equilibrium. Additionally, I find that drive at a linked locus favours the fixation of sexually antagonistic alleles that benefit the sex in which drive occurs. Further, I show that under certain conditions reduced recombination between these two loci is selectively favoured. These theoretical results provide clear, testable predictions about the nature of sexually antagonistic variation on driving chromosomes and have implications for the evolution of genomic architecture.     

Females of the grasshopper Chorthippus parallelus (Zett.) do not remate for fresh sperm

The evolution of female multiple mating is still a largely debated field. Among the benefits that have been proposed to explain this risky behaviour is the replenishment of sperm reserves. Apart from an increase in total sperm number, it can be an expression of post-copulatory mate choice or can be directed towards the uptake of fresh sperm. Using fresh sperm for fertilization instead of sperm aged by storage in the female genital tract may avoid a lowered fertilization capacity, an increase in deleterious effects or a skewed offspring sex ratio. We investigated the influence of sperm age on female fitness in the grasshopper Chorthippus parallelus, a species where females mate multiply. After copulation, females store sperm over the course of weeks until fertilization. An average ejaculate of 250 000 spermatozoa exponentially declined with time within the female''s spermatheca. The number of days since copulation better explained the variation in actual sperm number than the number of pods or eggs laid. We investigated differences in female fitness parameters in two treatments. In the first, females were mated only once, while in the second, females always had freshly ejaculated sperm available. Although in our experiment, multiply mated females had heavier offspring than singly mated females, egg number per pod, hatching and fertilization success, their composite effects and offspring sex ratio did not vary with respect to season or sperm age. We therefore reject the hypothesis that the reason for remating in females of this species is the uptake of fresh sperm.     

Meiotic segregation analysis of RB1 alleles in retinoblastoma pedigrees by use of single-sperm typing

In hereditary retinoblastoma, different epidemiological studies have indicated a preferential paternal transmission of mutant retinoblastoma alleles to offspring, suggesting the occurrence of a meiotic drive. To investigate this mechanism, we analyzed sperm samples from six individuals from five unrelated families affected with hereditary retinoblastoma. Single-sperm typing techniques were performed for each sample by study of two informative short tandem repeats located either in or close to the retinoblastoma gene (RB1). The segregation probability of mutant RB1 alleles in sperm samples was assessed by use of the SPERMSEG program, which includes experimental parameters, recombination fractions between the markers, and segregation parameters. A total of 2,952 single sperm from the six donors were analyzed. We detected a significant segregation distortion in the data as a whole (P=.0099) and a significant heterogeneity in the segregation rate across donors (.0092). Further analysis shows that this result can be explained by segregation distortion in favor of the normal allele in one donor only and that it does not provide evidence of a significant segregation distortion in the other donors. The segregation distortion favoring the mutant RB1 allele does not seem to occur during spermatogenesis, and, thus, meiotic drive may result either from various mechanisms, including a fertilization advantage or a better mobility in sperm bearing a mutant RB1 gene, or from the existence of a defectively imprinted gene located on the human X chromosome.     

Mechanisms that prevent catastrophic interactions between paternal chromosomes and the oocyte meiotic spindle

Meiosis produces haploid gametes by accurately reducing chromosome ploidy through one round of DNA replication and two subsequent rounds of chromosome segregation and cell division. The cell divisions of female meiosis are highly asymmetric and give rise to a large egg and two very small polar bodies that do not contribute to development. These asymmetric divisions are driven by meiotic spindles that are small relative to the size of the egg and have one pole juxtaposed against the cell cortex to promote polar body extrusion. An additional unique feature of female meiosis is that fertilization occurs before extrusion of the second polar body in nearly all animal species. Thus sperm-derived chromosomes are present in the egg during female meiosis. Here, we explore the idea that the asymmetry of female meiosis spatially separates the sperm from the meiotic spindle to prevent detrimental interactions between the spindle and the paternal chromosomes.     

Fertilization initiates the transition from anaphase I to metaphase II during female meiosis in C. elegans

Oocytes from most animals arrest twice during the meiotic cell cycle. The universally conserved prophase I arrest is released by a maturation hormone that allows progression to a second arrest point, typically metaphase I or II. This second arrest allows for short-term storage of fertilization-competent eggs and is released by signaling that occurs during fertilization. Nematodes are unique in that the maturation hormone is secreted by sperm rather than by the mother's somatic tissues. We have investigated the nature of the second arrest in matured but unfertilized Caenorhabditis elegans embryos using time-lapse imaging of GFP-tubulin or GFP-histone. Unfertilized embryos completed anaphase I but did not form polar bodies or assemble meiosis II spindles. Nevertheless, unfertilized embryos assembled female pronuclei at the same time as fertilized embryos. Analysis of embryos fertilized by sperm lacking the SPE-11 protein indicated that fertilization promotes meiotic cytokinesis through the SPE-11 protein but assembly of the meiosis II spindle is initiated through an SPE-11-independent pathway.     

Selective Loss of Sperm Bearing a Compound Chromosome in the Drosophila Female

The Drosophila compound entire second chromosome, C(2)EN, displays paternal transmission well below Mendelian expectations (NOVITSKI et al. 1981). Because C(2)EN stocks also show higher-than-expected rates of zygotic lethality, it was proposed that this reduced paternal inheritance might be wholly or partially due to postfertilization events. Efforts to investigate this phenomenon have been hampered because the progeny of crosses between C(2)EN-bearing individuals and those with normal karyotypes die during embryogenesis. We have circumvented this obstacle by employing fluorescence in situ hybridization to directly karyotype early embryos from crosses involving C(2)EN-bearing individuals. This analysis reveals that the distortion in paternal transmission is established before fertilization. Moreover, measurement of the sperm ratios within both the male and female reproductive organs demonstrates that C(2)EN-bearing sperm are selectively lost after sperm transfer to the female and before storage of sperm in the seminal receptacles and spermathecae. Our results are consistent with a model of meiotic drive in which aberrations occuring early in meiosis lead ultimately to sperm dysfunction.     

Genetic Studies of Mei-1 Gene Activity during the Transition from Meiosis to Mitosis in Caenorhabditis Elegans

Genetic evidence suggests that the mei-1 locus of Caenorhabditis elegans encodes a maternal product required for female meiosis. However, a dominant gain-of-function allele, mei-1(ct46), can support normal meiosis but causes defects in subsequent mitotic spindles. Previously identified intragenic suppressors of ct46 lack functional mei-1 activity; null alleles suppress only in cis but other alleles arise frequently and suppress both in cis and in trans. Using a different screen for suppressors of the dominant ct46 defect, the present study describes another type of intragenic mutation that also arises at high frequency. These latter alleles appear to have reduced meiotic activity and retain a weakened dominant effect. Characterization of these alleles in trans-heterozygous combinations with previously identified mei-1 alleles has enabled us to define more clearly the role of the mei-1 gene product during normal embryogenesis. We propose that a certain level of mei-1 activity is required for meiosis but must be eliminated prior to mitosis. The dominant mutation causes mei-1 activity to function at mitosis; intragenic trans-suppressors act in an antimorphic manner to inactivate multimeric mei-1 complexes. We propose that inactivation of meiosis-specific functions may be an essential precondition of mitosis; failure to eliminate such functions may allow ectopic meiotic activity during mitosis and cause embryonic lethality.     

Sex-ratio meiotic drive in Drosophila simulans is related to equational nondisjunction of the Y chromosome

The sex-ratio trait, an example of naturally occurring X-linked meiotic drive, has been reported in a dozen Drosophila species. Males carrying a sex-ratio X chromosome produce an excess of female offspring caused by a deficiency of Y-bearing sperm. In Drosophila simulans, such males produce approximately 70-90% female offspring, and 15-30% of the male offspring are sterile. Here, we investigate the cytological basis of the drive in this species. We show that the sex-ratio trait is associated with nondisjunction of Y chromatids in meiosis II. Fluorescence in situ hybridization (FISH) using sex-chromosome-specific probes provides direct evidence that the drive is caused by the failure of the resulting spermatids to develop into functional sperm. XYY progeny were not observed, indicating that few or no YY spermatids escape failure. The recovery of XO males among the progeny of sex-ratio males shows that some nullo-XY spermatids become functional sperm and likely explains the male sterility. A review of the cytological data in other species shows that aberrant behavior of the Y chromosome may be a common basis of sex-ratio meiotic drive in Drosophila and the signal that triggers differential spermiogenesis failure.