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.