A sex-ratio Meiotic Drive System in Drosophila simulans. I: An Autosomal Suppressor

Sex ratio distortion (sex-ratio for short) has been reported in numerous species such as Drosophila, where distortion can readily be detected in experimental crosses, but the molecular mechanisms remain elusive. Here we characterize an autosomal sex-ratio suppressor from D. simulans that we designate as not much yang (nmy, polytene chromosome position 87F3). Nmy suppresses an X-linked sex-ratio distorter, contains a pair of near-perfect inverted repeats of 345 bp, and evidently originated through retrotransposition from the distorter itself. The suppression is likely mediated by sequence homology between the suppressor and distorter. The strength of sex-ratio is greatly enhanced by lower temperature. This temperature sensitivity was used to assign the sex-ratio etiology to the maturation process of the Y-bearing sperm, a hypothesis corroborated by both light microscope observations and ultrastructural studies. It has long been suggested that an X-linked sex-ratio distorter can evolve by exploiting loopholes in the meiotic machinery for its own transmission advantage, which may be offset by other changes in the genome that control the selfish distorter. Data obtained in this study help to understand this evolutionary mechanism in molecular detail and provide insight regarding its evolutionary impact on genomic architecture and speciation.     

A sex-ratio meiotic drive system in Drosophila simulans. II: an X-linked distorter

The evolution of heteromorphic sex chromosomes creates a genetic condition favoring the invasion of sex-ratio meiotic drive elements, resulting in the biased transmission of one sex chromosome over the other, in violation of Mendel's first law. The molecular mechanisms of sex-ratio meiotic drive may therefore help us to understand the evolutionary forces shaping the meiotic behavior of the sex chromosomes. Here we characterize a sex-ratio distorter on the X chromosome (Dox) in Drosophila simulans by genetic and molecular means. Intriguingly, Dox has very limited coding capacity. It evolved from another X-linked gene, which also evolved de nova. Through retrotransposition, Dox also gave rise to an autosomal suppressor, not much yang (Nmy). An RNA interference mechanism seems to be involved in the suppression of the Dox distorter by the Nmy suppressor. Double mutant males of the genotype dox; nmy are normal for both sex-ratio and spermatogenesis. We postulate that recurrent bouts of sex-ratio meiotic drive and its subsequent suppression might underlie several common features observed in the heterogametic sex, including meiotic sex chromosome inactivation and achiasmy.     

A sex-ratio Meiotic Drive System in Drosophila simulans. II: An X-linked Distorter

The evolution of heteromorphic sex chromosomes creates a genetic condition favoring the invasion of sex-ratio meiotic drive elements, resulting in the biased transmission of one sex chromosome over the other, in violation of Mendel's first law. The molecular mechanisms of sex-ratio meiotic drive may therefore help us to understand the evolutionary forces shaping the meiotic behavior of the sex chromosomes. Here we characterize a sex-ratio distorter on the X chromosome (Dox) in Drosophila simulans by genetic and molecular means. Intriguingly, Dox has very limited coding capacity. It evolved from another X-linked gene, which also evolved de nova. Through retrotransposition, Dox also gave rise to an autosomal suppressor, not much yang (Nmy). An RNA interference mechanism seems to be involved in the suppression of the Dox distorter by the Nmy suppressor. Double mutant males of the genotype dox; nmy are normal for both sex-ratio and spermatogenesis. We postulate that recurrent bouts of sex-ratio meiotic drive and its subsequent suppression might underlie several common features observed in the heterogametic sex, including meiotic sex chromosome inactivation and achiasmy.     

Natural variation of the Y chromosome suppresses sex ratio distortion and modulates testis-specific gene expression in Drosophila simulans

X-linked sex-ratio distorters that disrupt spermatogenesis can cause a deficiency in functional Y-bearing sperm and a female-biased sex ratio. Y-linked modifiers that restore a normal sex ratio might be abundant and favored when a X-linked distorter is present. Here we investigated natural variation of Y-linked suppressors of sex-ratio in the Winters systems and the ability of these chromosomes to modulate gene expression in Drosophila simulans. Seventy-eight Y chromosomes of worldwide origin were assayed for their resistance to the X-linked sex-ratio distorter gene Dox. Y chromosome diversity caused males to sire ∼63% to ∼98% female progeny. Genome-wide gene expression analysis revealed hundreds of genes differentially expressed between isogenic males with sensitive (high sex ratio) and resistant (low sex ratio) Y chromosomes from the same population. Although the expression of about 75% of all testis-specific genes remained unchanged across Y chromosomes, a subset of post-meiotic genes was upregulated by resistant Y chromosomes. Conversely, a set of accessory gland-specific genes and mitochondrial genes were downregulated in males with resistant Y chromosomes. The D. simulans Y chromosome also modulated gene expression in XXY females in which the Y-linked protein-coding genes are not transcribed. The data suggest that the Y chromosome might exert its regulatory functions through epigenetic mechanisms that do not require the expression of protein-coding genes. The gene network that modulates sex ratio distortion by the Y chromosome is poorly understood, other than that it might include interactions with mitochondria and enriched for genes expressed in post-meiotic stages of spermatogenesis.     

Female-driven mechanisms,ejaculate size and quality contribute to the lower fertility of <Emphasis Type="Italic">sex-ratio</Emphasis> distorter males in <Emphasis Type="Italic">Drosophila simulans</Emphasis>

Background  

Sex-ratio meiotic drive refers to the preferential transmission of the X chromosome by XY males. The loss of Y-bearing sperm is caused by an X-linked distorter and results in female-biased progeny. The fertility of sex-ratio (SR) males expressing the distorter is usually strongly reduced compared to wild-type males, especially when they are in competition. The aim of this study was to identify the post-copulatory mechanisms that lower the fertility of SR males in Drosophila simulans. Parameters contributing to male fertility were measured in single and double mating conditions.     

Competition at the Mouse t Complex: Rare Alleles Are Inherently Favored

We investigate the competition between alleles at a segregation distorter locus. The focus is on the invasion prospects of rare mutant distorter alleles in a population in which a wildtype and a resident distorter allele are present. The parameters are chosen to reflect the situation at the t complex of the house mouse, one of the best-studied examples of segregation distortion. By analyzing the invasion chances of rare alleles, we provide an analytical justification of earlier simulation results. We show that a new distorter allele can successfully invade even if it is inferior both at the gamete and at the individual level. In fact, newly arising distorter alleles have an inherent rareness advantage if their negative fitness consequences are restricted to homozygous condition. Likewise, rare mutant wildtype alleles may often invade even if their viability or fertility is reduced. As a consequence, the competition between alleles at a segregation distorter locus should lead to a high degree of polymorphism. We discuss the implications of this conclusion for the t complex of the house mouse and for the evolutionary stability of “honest” Mendelian segregation.     

Recurrent Selection on the Winters sex-ratio Genes in Drosophila simulans

Selfish genes, such as meiotic drive elements, propagate themselves through a population without increasing the fitness of host organisms. X-linked (or Y-linked) meiotic drive elements reduce the transmission of the Y (X) chromosome and skew progeny and population sex ratios, leading to intense conflict among genomic compartments. Drosophila simulans is unusual in having a least three distinct systems of X chromosome meiotic drive. Here, we characterize naturally occurring genetic variation at the Winters sex-ratio driver (Distorter on the X or Dox), its progenitor gene (Mother of Dox or MDox), and its suppressor gene (Not Much Yang or Nmy), which have been previously mapped and characterized. We survey three North American populations as well as 13 globally distributed strains and present molecular polymorphism data at the three loci. We find that all three genes show signatures of selection in North America, judging from levels of polymorphism and skews in the site-frequency spectrum. These signatures likely result from the biased transmission of the driver and selection on the suppressor for the maintenance of equal sex ratios. Coalescent modeling indicates that the timing of selection is more recent than the age of the alleles, suggesting that the driver and suppressor are coevolving under an evolutionary “arms race.” None of the Winters sex-ratio genes are fixed in D. simulans, and at all loci we find ancestral alleles, which lack the gene insertions and exhibit high levels of nucleotide polymorphism compared to the derived alleles. In addition, we find several “null” alleles that have mutations on the derived Dox background, which result in loss of drive function. We discuss the possible causes of the maintenance of presence–absence polymorphism in the Winters sex-ratio genes.MEIOTIC drive can leave signatures in the genome similar to positive natural selection without increasing the fitness of an organism (Lyttle 1993). Drive elements are preferentially transmitted during meiosis by disrupting the development or function of sperm carrying the homologous chromosome (Zimmering et al. 1970, meiotic drive sensu lato), or by true chromosome segregation defects during meiosis (Sandler and Novitski 1957, meiotic drive sensu stricto; Tao et al. 2007a). While drive elements may arise on any chromosome, sex-linked drivers have higher population invasion probabilities than autosomal drivers and are more easily detected due to their impact on progeny sex ratios (Hurst and Pomiankowski 1991). To survive, a driver must maintain tight linkage with an insensitive target locus lest it drive against itself, a condition ensured by the lack of recombination between sex chromosomes (Charlesworth and Hartl 1978). Because of the impact drive elements have on sex ratios, sex-linked drivers are often referred to as “sex-ratio distorters” and the phenotype of skewed progeny sex ratios is termed “sex-ratio.” The mere transmission advantage of a driver, unless balanced by some detrimental fitness effect or masked by a suppressor, can cause it to sweep through a population in a manner similar to a positively selected mutation (Edwards 1961; Vaz and Carvalho 2004).Obviously, a complete sweep of a sex-linked driver dooms a male-less (or female-less) population to extinction (Hamilton 1967), and natural selection strongly favors genetic factors that suppress drive and restore Mendelian segregation. Fisher (1930) presented a qualitative argument for the maintenance of an equal sex ratio, which predicts selection on any heritable variant that increases the production of the rarer sex. Fisher''s principle has been formalized mathematically and demonstrated empirically (e.g., Bodmer and Edwards 1960; Carvalho et al. 1998). Suppressors have been identified in a wide variety of meiotic drive systems and are predicted to be strongly favored by natural selection for the maintenance of equal sex ratios (reviewed by Jaenike 2001). Furthermore, the evolution of linked enhancer genes may enable drivers to evade suppression, setting off another bout of Fisherian selection for equal sex ratios (Hartl 1975).Meiotic drive is widespread, with systems identified in mammals, insects, and plants (Jaenike 2001). Drosophila is the most extensively studied insect taxon, and sex-chromosome meiotic drive systems have been identified in more than a dozen species (Jaenike 2001). Cryptic (i.e., suppressed) distorters may be identified when the association between driver and suppressor is lost, such as in hybrids between species or populations that do not share meiotic drive systems (Mercot et al. 1995). The coevolutionary arms race between drivers and suppressors likely contributes to Haldane''s rule (the preferential sterility or inviability of heterogametic hybrids) and is a leading explanation for the importance of X-linked loci in causing hybrid male sterility (Frank 1991; Hurst and Pomiankowski 1991; Tao et al. 2007b; Presgraves 2008). Indeed, two recently characterized hybrid male sterility factors are also sex-ratio distorters—direct evidence of a link between meiotic drive and speciation (Tao et al. 2001; Orr and Irving 2005; Phadnis and Orr 2009).The three X-linked drive systems of Drosophila simulans are genetically distinct and have been termed Paris, Durham, and Winters (Tao et al. 2007a). Here, we focus on the Winters sex-ratio (SR), whose driver and suppressor have been mapped to the gene level and whose molecular and cellular features have been elucidated (Tao et al. 2007a,b). Distortion requires two genes, Distorter on the X (Dox) and Mother of Dox (MDox); Dox is a duplicate copy of MDox (Tao et al. 2007a; Y. Tao, personal communication). The dominant suppressor, Not Much Yang (Nmy), is a retrotransposed copy of Dox on chromosome 3R (Tao et al. 2007b). Nmy likely suppresses Dox through an RNA interference mechanism by forming a double stranded RNA with homology to the distorter RNAs (Tao et al. 2007b). The genes of the Winters sex-ratio are not found in D. melanogaster, which diverged from D. simulans ∼2.3 million years ago (Li et al. 1999). Initial surveys of the genes in the simulans clade indicate that a functional Nmy gene is present in D. mauritiana (Tao et al. 2007b). Thus, the Winters genes are >250,000 years old, the speciation time of D. simulans, D. mauritiana, and D. sechellia (McDermott and Kliman 2008).Signatures of positive selection have been previously detected at genomic regions linked to Drosophila sex-ratio distorters. However, this study represents the first evidence of selection acting directly on a sex-ratio distorter gene and its suppressor gene. In D. recens, driving X chromosomes show reduced nucleotide and haplotype variability relative to standard (nondriving) X chromosomes, and linkage disequilibrium extends over 130 cM of the driving chromosome (Dyer et al. 2007). The Paris driver has been localized to a pair of duplicated loci 150 kb apart; recent work shows reduced haplotype diversity and linkage disequilibrium between variants associated with drive (Derome et al. 2008). In this study, we characterize patterns of genetic variation in natural populations of North American D. simulans and find signatures of recent and strong positive selection at all three genes of the Winters sex-ratio.     

Genetic Dissection of Segregation Distortion II. Mechanism of Suppression of Distortion by Certain Inversions

In(2L+2R)Cy and In(2LR)Pm² are inversion-bearing chromosomes, the former carrying a paracentric inversion in each arm and the latter carrying a long pericentric. Both chromosomes produce normal segregation ratios when present in heterozygous males with certain segregation distorter chromosomes. The apparent suppression of distortion by these chromosomes was long attributed to a failure of synapsis, but this hypothesis has fallen out of favor recently because a large number of chromosome aberrations, particularly translocations and inversions, suppress distortion even though their breakpoints fall into no recognizable pattern. Although failure of synapsis does not appear to be the mechanism of suppression of distortion, what is responsible for the suppression remains unknown. In this paper it is shown that In(2L+2R)Cy and In(2LR)Pm² suppress segregation distortion because they carry Rsp, a component of the segregation distorter system that renders a chromosome insensitive to distortion. Both chromosomes induce "suicide" of chromosomes carrying Sd Rsp⁺.     

Identification of the t Complex–encoded Cytoplasmic Dynein Light Chain Tctex1 in Inner Arm I1 Supports the Involvement of Flagellar Dyneins in Meiotic Drive

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 I1. 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.     

The evolution of autosomal suppressors of sex-ratio drive in Drosophila simulans

Sex-ratio drive, which results in males siring female-biased progeny, has been reported in several Drosophila species, including D. simulans. It is caused by X-linked drivers that prevent the production of Y-bearing sperm. In natural populations of D. simulans, the drivers are usually cryptic, because their spread has elicited the evolution of drive suppressors. We investigated autosomal suppression in flies from Madagascar, Réunion and Kenya. Autosomal suppressors were found in all three places, indicating that they are a regular component of drive suppression over this geographic area, where strong Y-linked suppressors also occur. These suppressors were suspected of being polymorphic in Madagascar and Réunion and proved to be polymorphic in Kenya. We developed a model simulating the evolution of neutral autosomal suppressors in order to explore the effects of the number of suppressor genes, their relative strength and the co-occurrence of Y-linked suppressors. The most interesting prediction of the model is that when suppression is multigenic, suppressor loci can remain polymorphic despite the absence of balancing selection if an equal sex-ratio is restored in the population before the suppressor alleles become fixed at all loci. The model also emphasises the importance of the sterility of distorters sons in suppressor dynamics.     

Transmission ratio distortion in mouse t-haplotypes is due to multiple distorter genes acting on a responder locus

Transmission ratios of male mice heterozygous for various combinations of partial t-haplotypes provide evidence in support of a model for the genetic basis of ratio distortion, involving two or more distorter genes acting on a responder locus. The t form of the responder locus, Tcr, in the medial part of the haplotype, must be present and heterozygous for distortion to occur. When the responder alone is present, as in t^low haplotypes, the chromosome carrying it is transmitted in a low ratio (<50%). The t forms of the distorter loci act additively, in cis or trans, to raise the transmission of whichever chromosome carries Tcr. Identified distorter loci are Tcd-1, in the proximal part of the haplotype, Tcd-2, distal to Tcr, and probably Tcd-3, lying between Tcr and Tcd-2. In the absence of Tcr the distorters are transmitted normally. The system is compared with the SD system of Drosophila.     

Competition at the mouse t complex: rare alleles are inherently favored

We investigate the competition between alleles at a segregation distorter locus. The focus is on the invasion prospects of rare mutant distorter alleles in a population in which a wildtype and a resident distorter allele are present. The parameters are chosen to reflect the situation at the t complex of the house mouse, one of the best-studied examples of segregation distortion. By analyzing the invasion chances of rare alleles, we provide an analytical justification of earlier simulation results. We show that a new distorter allele can successfully invade even if it is inferior both at the gamete and at the individual level. In fact, newly arising distorter alleles have an inherent rareness advantage if their negative fitness consequences are restricted to homozygous condition. Likewise, rare mutant wildtype alleles may often invade even if their viability or fertility is reduced. As a consequence, the competition between alleles at a segregation distorter locus should lead to a high degree of polymorphism. We discuss the implications of this conclusion for the t complex of the house mouse and for the evolutionary stability of "honest" Mendelian segregation.     

ATRX,a guardian of chromatin

ATRX (alpha-thalassemia mental retardation X-linked) is one of the most frequently mutated tumor suppressor genes in human cancers, especially in glioma, and recent findings indicate roles for ATRX in key molecular pathways, such as the regulation of chromatin state, gene expression, and DNA damage repair, placing ATRX as a central player in the maintenance of genome stability and function. This has led to new perspectives about the functional role of ATRX and its relationship with cancer. Here, we provide an overview of ATRX interactions and molecular functions and discuss the consequences of its impairment, including alternative lengthening of telomeres and therapeutic vulnerabilities that may be exploited in cancer cells.     

Silence of the killers: discovery of male-killing suppression in a rearing strain of the small brown planthopper,Laodelphax striatellus

According to evolutionary theory, sex ratio distortions caused by reproductive parasites such as Wolbachia and Spiroplasma are predicted to be rapidly normalized by the emergence of host nuclear suppressors. However, such processes in the evolutionary arms race are difficult to observe because sex ratio biases will be promptly hidden and become superficially unrecognizable. The evolution of genetic suppressors has been reported in just two insect species so far. In the small brown planthopper, Laodelphax striatellus, female-biases caused by Spiroplasma, which is a ‘late’ male-killer, have been found in some populations. During the continuous rearing of L. striatellus, we noted that a rearing strain had a 1 : 1 sex ratio even though it harboured Spiroplasma. Through introgression crossing experiments with a strain lacking suppressors, we revealed that the L. striatellus strain had the zygotic male-killing suppressor acting as a dominant trait. The male-killing phenotype was hidden by the suppressor even though Spiroplasma retained its male-killing ability. This is the first study to demonstrate the existence of a late male-killing suppressor and its mode of inheritance. Our results, together with those of previous studies, suggest that the inheritance modes of male-killing suppressors are similar regardless of insect order or early or late male killing.     

Segretation distortion in a deme-structured population: opposing demands of gene,individual and group selection

The evolution of segregation distortion is governed by the interplay of selection at different levels. Despite their systematic advantage at the gamete level, none of the well-known segregation distorters spreads to fixation since they induce severe negative fitness effects at the individual level. In a deme-structured population, selection at the population level also plays a role. By means of a population genetical model, we analyse the various factors that determine the success of a segregation distorter in a metapopulation. Our focus is on the question of how the success of a distorter allele is affected by its segregation ratio and its fitness effects at the individual level. The analysis reveals that distorter alleles with high segregation ratios are the best invaders and reach the highest frequencies within single demes. However, the productivity of a deme harbouring a distorter with a high segregation ratio may be significantly reduced. As a consequence, an efficient distorter will be underrepresented in the migrant pool and, moreover, it may increase the probability of deme extinction. In other words, efficient distorters with high segregation ratios may well succumb to their own success. Therefore, distorters with intermediate segregation ratios may reach the highest frequency in the metapopulation as a result of the opposing forces of gamete, individual and group selection. We discuss the implications of this conclusion for the t complex of the house mouse.     

THE SEX-RATIO TRAIT IN DROSOPHILA SIMULANS: GEOGRAPHICAL DISTRIBUTION OF DISTORTION AND RESISTANCE

The sex-ratio trait we describe here in Drosophila simulans results from X-linked meiotic drive. Males bearing a driving X chromosome can produce a large excess of females (about 90%) in their progeny. This is, however, rarely the case in the wild, where resistance factors, including autosomal suppressors and insensitive Y chromosomes, prevent the expression of the driver. In this study, we searched for drive and resistance factors in strains of Drosophila simulans collected all over the world. Driving X chromosomes were found in all populations whenever a good sample size was available. Their frequency may reach up to 60%. However, the presence of driving X chromosomes never results in an excess of females, due to the systematic co-occurrence of resistance factors. The highest frequencies of driving X chromosomes were observed in islands, while populations from East and Central Africa (the supposed center of origin of the species) showed the highest level of resistance. The geographical pattern of drive and resistance factors, as well as the results of crosses between strains from different geographical areas, suggest that the sex-ratio system described here has a unique and ancient origin in the species.     

A Genetic Basis for a Postmeiotic X Versus Y Chromosome Intragenomic Conflict in the Mouse

Intragenomic conflicts arise when a genetic element favours its own transmission to the detriment of others. Conflicts over sex chromosome transmission are expected to have influenced genome structure, gene regulation, and speciation. In the mouse, the existence of an intragenomic conflict between X- and Y-linked multicopy genes has long been suggested but never demonstrated. The Y-encoded multicopy gene Sly has been shown to have a predominant role in the epigenetic repression of post meiotic sex chromatin (PMSC) and, as such, represses X and Y genes, among which are its X-linked homologs Slx and Slxl1. Here, we produced mice that are deficient for both Sly and Slx/Slxl1 and observed that Slx/Slxl1 has an opposite role to that of Sly, in that it stimulates XY gene expression in spermatids. Slx/Slxl1 deficiency rescues the sperm differentiation defects and near sterility caused by Sly deficiency and vice versa. Slx/Slxl1 deficiency also causes a sex ratio distortion towards the production of male offspring that is corrected by Sly deficiency. All in all, our data show that Slx/Slxl1 and Sly have antagonistic effects during sperm differentiation and are involved in a postmeiotic intragenomic conflict that causes segregation distortion and male sterility. This is undoubtedly what drove the massive gene amplification on the mouse X and Y chromosomes. It may also be at the basis of cases of F1 male hybrid sterility where the balance between Slx/Slxl1 and Sly copy number, and therefore expression, is disrupted. To the best of our knowledge, our work is the first demonstration of a competition occurring between X and Y related genes in mammals. It also provides a biological basis for the concept that intragenomic conflict is an important evolutionary force which impacts on gene expression, genome structure, and speciation.     

Local dynamics of a fast‐evolving sex‐ratio system in Drosophila simulans

By distorting Mendelian transmission to their own advantage, X‐linked meiotic drive elements can rapidly spread in natural populations, generating a sex‐ratio bias. One expected consequence is the triggering of a co‐evolutionary arms race between the sex chromosome that carries the distorter and suppressors counteracting its effect. Such an arms race has been theoretically and experimentally established and can have many evolutionary consequences. However, its dynamics in contemporary populations is still poorly documented. Here, we investigate the fate of the young X‐linked Paris driver in Drosophila simulans from sub‐Saharan Africa to the Middle East. We provide the first example of the early dynamics of distorters and suppressors: we find consistent evidence that the driving chromosomes have been rising in the Middle East during the last decade. In addition, identical haplotypes are at high frequencies around the two co‐evolving drive loci in remote populations, implying that the driving X chromosomes share a recent common ancestor and suggesting that East Africa could be the cradle of the Paris driver. The segmental duplication associated with drive presents an unusual structure in West Africa, which could reflect a secondary state of the driver. Together with our previous demonstration of driver decline in the Indian Ocean where suppression is complete, these data provide a unique picture of the complex dynamics of a co‐evolutionary arms race currently taking place in natural populations of D. simulans.     

A Model-Based Approach for Identifying Signatures of Ancient Balancing Selection in Genetic Data

While much effort has focused on detecting positive and negative directional selection in the human genome, relatively little work has been devoted to balancing selection. This lack of attention is likely due to the paucity of sophisticated methods for identifying sites under balancing selection. Here we develop two composite likelihood ratio tests for detecting balancing selection. Using simulations, we show that these methods outperform competing methods under a variety of assumptions and demographic models. We apply the new methods to whole-genome human data, and find a number of previously-identified loci with strong evidence of balancing selection, including several HLA genes. Additionally, we find evidence for many novel candidates, the strongest of which is FANK1, an imprinted gene that suppresses apoptosis, is expressed during meiosis in males, and displays marginal signs of segregation distortion. We hypothesize that balancing selection acts on this locus to stabilize the segregation distortion and negative fitness effects of the distorter allele. Thus, our methods are able to reproduce many previously-hypothesized signals of balancing selection, as well as discover novel interesting candidates.     

EVOLUTION AT THE MOUSE t COMPLEX: WHY IS THE t HAPLOTYPE PRESERVED AS AN INTEGRAL UNIT?

Abstract Segregation distorters are selfish genetic elements that bias Mendelian segregation in their favor. All well-known segregation distortion systems consist of one or more "distorter" loci that act upon a "responder" locus. At the t complex of the house mouse, segregation distortion is brought about by the harmful effect of t alleles at a number of distorter loci on the wild-type variant of the responder locus. The responder and distorter alleles are closely linked by a number of inversions, thus forming a coherent t haplotype. It has been conjectured that the close integration of the various components into a "complete" t haplotype has been crucial for the evolutionary success of these selfish genetic elements. By means of a population genetical metapopulation model, we show that this intuition may be unfounded. In fact, under most circumstances an "insensitive" t haplotype retaining only the responder did invade and reach a high frequency, despite the fact that this haplotype has a strong segregation disadvantage. For certain population structures, the complete t haplotype was even competitively excluded by partial t haplotypes with lower segregation ratios. Moreover, t haplotypes carrying one or more recessive lethals only prevailed over their nonlethal counterparts if the product of local population size and migration rate ( Nm ) was not much smaller or larger than one. These phenomena occurred for rather realistic fitness, segregation, and recombination values. It is therefore quite puzzling that partial t haplotypes are absent from natural house mousepopulations, and that t haplotypes carrying recessive lethals prevail over nonlethal t haplotypes.