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Journal of Heredity 2010:101(Supplement 1):S100–S106 doi:10.1093/jhered/esq006 Ó The American Genetic Association. 2010. All rights reserved. For permissions, please email: [email protected]. Male Sex Drive and the Maintenance of Sex: Evidence from Drosophila RAMA S. SINGH AND CARLO G. ARTIERI From the Department of Biology, McMaster University, Hamilton, Ontario, Canada L8S4K1. Carlo G. Artieri is now at the Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892. Address correspondence to Rama S. Singh at the address above, or e-mail: [email protected]. Abstract The resolution of the paradoxes surrounding the evolutionary origins and maintenance of sexual reproduction has been a major focus in biology. The operation of sexual selection—which is very common among multicellular organisms—has been proposed as an important factor in the maintenance of sex, though in order for this hypothesis to hold, the strength of sexual selection must be stronger in males than in females. Sexual selection poses its own series of evolutionary questions, including how genetic variability is maintained in the face of sustained directional selection (known as the ‘‘paradox of the lek’’). In this short review, we present evidence obtained from recent comparative genomics projects arguing that 1) the genomic consequences of sexual selection clearly show that its effect is stronger in males and 2) this sustained selection over evolutionary timescales also has an effect of capturing de novo genes and expression patterns influencing male fitness, thus providing a mechanism via which new genetic variation can be input into to male traits. Furthermore, we argue that this latter process of genomic ‘‘masculinization’’ has an additional effect of making males difficult to purge from populations, as evidence from Drosophila indicates that, for example, many male sexually selected seminal fluid factors are required to ensure maximally efficient reproduction. Newly arising parthenogenic mutations would suffer an immediate reproductive rate disadvantage were these proteins lost. We show that recent studies confirm that genomic masculinization, as a result of ‘‘male sex drive,’’ has important consequences for the evolution of sexually dimorphic species. Key words: maintenance of sex, male biased genes, male sex drive, rapid evolution, sexual selection Few other topics, barring selection and adaptation, has attracted the level of attention that evolutionary biologists have lavished on the evolution of sex. The near ubiquity of sexual reproduction in multicellular organisms suggests that it may be linked with their success; however, the origin and evolution of sexual reproduction remains a mystery. Why should a population tolerate a large proportion of males (typically 50%), individuals who often contribute nothing more than gametes to the act of reproduction? Males’ contribution via gametes is miniscule compared to the resources they consume, and, in theory, a mutation allowing females to reproduce asexually should sweep through the population as an asexual population would benefit from twice the reproductive rate; a concept that Maynard-Smith (1978) termed as the 2-fold cost of sex (or alternatively, the cost of males). The problem of sex— that is, its origin and maintenance—has been at the center of evolutionary biology since the mid-1970s and volumes have been written about it (e.g., Maynard-Smith 1978; Bell 1982). As the origin of sex is embedded in the same pre-Cambrian antiquity as the origin and evolution of multicellularity, it has attracted S100 relatively less attention than its maintenance, though the reigning theory is that sex evolved as a by-product DNA repair mechanisms (Bernstein et al. 1985, but see Margulis and Sagan 1990). The maintenance of sex, being much more tractable to experimentation, has garnered much attention among population geneticists and a host of hypotheses regarding how sexual reproduction is maintained —or how the 2-fold cost of sex is ‘‘paid’’—have been proposed (reviewed in Butlin 2002). These hypotheses generally fall into 2 broad camps: either sex is advantageous because it increases the rate of adaptive evolution by reshuffling genotypes and maintaining additive variation, as epitomized in the classic ‘‘Red Queen’’ hypothesis (Van Valen 1973; Jaenike 1978; Hamilton 1980; Bell 1982), or sex is more efficient at purging deleterious mutations, as exemplified in Kondrashov’s ‘‘deterministic mutation’’ hypothesis (Kondrashov 1988). In addition, it has also been suggested that no single mechanism may explain the prevalence and maintenance of sex but rather that combinations of the various hypotheses may act synergistically (West et al. 1998). Another somewhat different Singh and Artieri Masculinization and the Maintenance of Sex approach for explaining the maintenance of sex is to find situations wherein its cost is reduced: the 2-fold cost is predicated on the assumption that males contribute nothing more than gametes (Maynard-Smith 1978). For instance, there have been numerous attempts made to find examples where males make contributions beside gametes, such as nuptial gifts in insects and parental care in birds and in mammals (Andersson 1994). Although these instances illustrate cases wherein males make significant contributions to reproduction, they involve taxon specific ecological situations, and thus are unsuitable as a general mechanism explaining the maintenance of sexual reproduction (see Meirmans and Neiman 2006). Finally, a yet another approach goes further in terms of disassociating the origins of sexual reproduction from its maintenance. Ignoring the question of the origins of sexual reproduction, this line of reasoning makes use of the argument that once sex evolves it is difficult to eliminate (see Engelstädter 2007 for review). Under such hypotheses, it is argued that once the specific cellular, physiological, and genetic systems underlying sexual reproduction have evolved to require the input of both parents, it is difficult for a mutation causing asexual reproduction to arise and reach an appreciable frequency in the population in the first place. For example, it has been shown in a variety of species that male gametic factors are required in order to initiate embryonic development (e.g., Stricker 1999; Manandhar et al. 2005) and have presumably evolved in order to prevent cell cycle arrest due to unfertilized eggs having only a haploid chromosome complement. Thus in order for asexuality to evolve, these physiological ‘‘checkpoints’’ would first have to be obviated. Although this does not make reversion to asexuality in a sexual lineage impossible, it increases the number of evolutionary ‘‘steps’’ required to complete the process, the intermediates of which are frequently expected to show reduced fitness (Engelstädter 2007). There has been very little attention given to the possibility that the process of reproduction itself, rather than its consequences in terms of generation and modulation of variation, may have a role to play in the maintenance of sex. Sexual selection is a common feature of higher organisms, particularly insects, birds, and mammals, and although it cannot explain the origins of sexual reproduction, recent hypotheses have suggested that it may be involved in its maintenance. For instance, Agrawal (2001) and Siller (2001) proposed that if the deleterious phenotypic effects of mutation are stronger in males than in females, the higher reproductive variance of males as compared with females will allow them to act as a sieve through which deleterious mutations are purged, leading to an increase in overall population fitness. More recently, Whitlock and Agrawal (2009) have reexamined this hypothesis and argued that the condition dependence that is often observed in the case of male traits (i.e., the association of the strength of their expression with overall male genetic condition) increases the likelihood that deleterious mutations will have a stronger negative effect on male—rather than female— reproductive fitness; deleterious mutations will likely decrease male condition and thus reduce their success rate in intrasexual competition. However, this reformulated argument requires that sexual selection has a stronger effect on males than females; a situation that the authors claim that there ‘‘are almost no data available to address.’’ In this short review, we build on the data that were previously used in order to propose the theory of male sex drive (MSD) (Singh and Kulathinal 2005) or the elevated effect of sexual selection on males due to male–male competition and their interest in overcoming female resistance. Furthermore, we argue that the inherent interest of males in producing the maximum number of possible offspring may lead to a situation wherein a greater number of offspring, and hence reproductive rate, is achieved in sexual as compared with asexual systems. Recent evidence collected from the fields of speciation and comparative genomics have revealed a pronounced pattern of genomic ‘‘masculinization’’ or the observation that a greater proportion of the genome is involved in male-specific function as compared with female-specific function or expressed at higher levels in males. This results from the capture of new male-biased expression patterns, mutations in existing genes, as well as de novo genes—via processes such as duplication and retrotransposition—that assist in the ability of males to secure copulation. This pattern of masculanization provides ample support for the notion that selection is stronger in males than in females and also suggests a mechanism by which the amount of heritable genetic variation associated with male traits is increased, reducing the difficulties associated with the ‘‘lek paradox,’’ or the expected depletion of heritable additive genetic variation in the face of strong directional selection (Borgia 1979). Although our discussion will focus mainly on Drosophila, several recent analyses have extended the observations made in fruit flies to a number of different organisms, and we will note these when appropriate. Rapid Male Evolution Early 2-dimensional gel electrophoresis studies noted that proteins expressed in the male reproductive tract showed greater intra- and interspecific divergence in Drosophila species in comparison with female or nonreproductive proteins (Coulthart and Singh 1988; Civetta and Singh 1995). These observations were confirmed at the nucleotide coding sequence level using reproductive and nonreproductive genes in a number of species groups including Drosophila (Civetta and Singh 1998), abalone (Swanson and Vacquier 1995), Caenorhabditis (Reinke et al. 2004; Artieri et al. 2008), and mammals (Torgerson et al. 2002) (reviewed in Swanson and Vacquier 2002). Furthermore, the recent increase in the application of large-scale sequencing has extended these observations to both the genomic and transcriptomic levels. Haerty et al. (2007) used the recently released full sequences of 12 Drosophila species (Drosophila 12 Genomes Consortium 2007) in order to examine patterns of sex and reproduction related (SRR) gene evolution, both male and female, relative to nonsex genes. Genes with known male-specific function or known to be expressed in male S101 Journal of Heredity 2010:101(Supplement 1) tissues (see below) were shown to evolve significantly more rapidly than female-specific or nonsex genes. In addition, genes expressed in the female reproductive tract (but not the ovary) were significantly more conserved than nonsex genes. Furthermore, the study noted that genes involved in male reproductive function were significantly less likely than female or nonsex genes to share identifiable orthologs among the 12 species examined, indicating either that these genes are so diverged that orthology cannot be unambiguously assigned or that there is an overrepresentation of lineage-specific, de novo genes among those with male function (Haerty et al. 2007; see below). In addition to their rapid evolution at the coding sequence level, several studies have shown that male genes evolve more rapidly at the level of gene expression as well (reviewed in Ellegren and Parsch 2007). The first studies to examine the dynamics of sex-biased gene expression, that is, genes that are expressed at elevated levels in one sex relative to the other, in Drosophila noted that male-biased genes (MBGs) show more expression polymorphism within species (Meiklejohn et al. 2003), and divergence between Drosophila melanogaster and D. simulans (;2.5 million years diverged [MYD]) than female-biased genes (FBGs) or unbiased genes (Ranz et al. 2003). These results were questioned, however, due to the possibility that they were an artifact of having used a D. melanogaster microarray to measure expression levels in D. simulans, without the use of appropriately stringent specificity thresholds (see Gilad et al. 2005). Nevertheless, the accelerated rate of divergence of MBGs was subsequently confirmed in a larger scale study of 7 Drosophila species using species-specific microarrays (Zhang et al. 2007). Not only did this study note that MBGs were more diverged at both the transcriptome and coding sequence levels but also that in most species, a significantly greater fraction of the genome is male-biased as compared with female-biased (see below). This pattern of rapid evolution of MBG expression is not restricted to flies, and similar patterns have been observed in humans (Khaitovich et al. 2005) and mice (Voolstra et al. 2007). The Masculinized Genome The remarkable patterns of evolution seen in male-biased and male-specific genes are not confined to the level of accelerated divergence between species; in addition, evidence continues to accumulate attesting to the notion that the genomes of sexual species are being reorganized in such a way that male genes are located in favorable positions and also that an overall greater proportion of genes are involved in male function (Singh and Kulathinal 2005). For instance, a number of recent studies have found a paucity of MBGs on the X chromosome in Drosophila (Parisi et al. 2003; Ranz et al. 2004; Sturgill et al. 2007), mammals (Emerson et al. 2004), and Caenorhabditis (Reinke et al. 2000; Artieri et al. 2008). These observations were originally found to be puzzling as theory had predicted that in XY systems, newly arising, recessive male-beneficial mutations would be favored on the X, especially if these mutations produced an S102 antagonistic effect in females. Such mutations are directly exposed to selection in hemizygous males and will not experience strong counterselection in females until they reach a significant frequency in the population (Charlesworth et al. 1987). If, however, male-beneficial mutations tend to be at least partially dominant (d . 0.5), they will be favored on autosomes: each X chromosome spends two-third of its time in females and thus selection for male-specific traits will experience reduced efficiency. The overwhelming pattern observed in the genomic data is thus suggestive of positive selection acting to maintain at least partially dominant malebeneficial mutations (see below). The idea that a larger proportion of the genome is involved in male-specific function had been suspected long prior to the advent of genomics as several decades worth of data from mutation screens and introgression studies had shown a consistent bias toward a larger number of genes whose mutation produced male sterile as compared with female-sterile phenotypes (e.g., Lindsley and Lifschytz 1972; Hollocher and Wu 1996; True et al. 1996; Masly and Presgraves 2007). These observations were also supported via the work of expression studies, which, as noted above revealed that the majority of Drosophila species show a significant bias toward a larger number of genes with male-biased expression (Zhang et al. 2007). This may be largely due to the effect of the testes deploying a larger number of unique genes when compared with the ovary (Parisi et al. 2003). In addition and as noted above, the availability of whole genome sequences has revealed that genes involved in male-biased and male-specific functions experience an increased rate of turnover (Haerty et al. 2007; Zhang et al. 2007). Although there is abundant evidence of lineage-specific acquisition of genes affecting male function from a variety of different systems (e.g., Durand et al. 2006; Haerty et al. 2007; Krzywinska E and Krzywinski J 2009), we will focus on one well-studied group of genes in Drosophila: the accessory gland proteins (acps), which illustrate many of the concepts raised in this review. Acps are the product of the male accessory glands, paired structures located adjacent to the testes in the insect abdomen. These glands contain secretory tissue that is responsible for producing a number of products that are added to the male’s ejaculate via their attachment to the ejaculatory duct (for a recent review of the accessory glands and their products see Ram and Wolfner 2007). It has long been known from transplantation studies that the products of the accessory glands have direct physiological effects on females (Garcia-Bellido 1964; Merle 1968). Using modern genomic technology, more than 100 distinct acps have been identified in Drosophila whose effects in females include decreasing their attractiveness to males, decreasing their receptivity to mating, elevating their egg-laying rate, and increasing their rate of sperm storage (Wolfner 1997). The overall commonality among acp function is that the vast majority of those characterized have the net effect of enhancing male reproductive success (Wolfner 1997). Consonant with the idea that acps are the product of sexual selection and competition acting to increase male Singh and Artieri Masculinization and the Maintenance of Sex reproductive success and overcome female resistances, acps are among the most rapidly evolving MBGs—thus making them among the most rapidly evolving genes in the fly genome (Haerty et al. 2007; Ram and Wolfner 2007). Perhaps even more intriguing than their rapid rate of evolution, acps appear to be subject to frequent lineagespecific gene acquisition. For instance, in their analysis of genomic patterns of divergence in SRR and nonsex proteins, Haerty et al. (2007) noted that .97% of female reproductive tract genes had identifiable 1:1 best reciprocal hit orthologs in comparisons as distant as that between D. melanogaster and D. grimshawii (;60 MYD; Tamura et al. 2004). In contrast, ,50% of male seminal fluid proteins had identifiable orthologs in the same comparison. Therefore, as is the case for other genes involved in male function, acps experience not only accelerated evolution but also increased rates of lineage-specific acquisition via processes such as tandem duplication, retrotransposition, and de novo generation. De novo generation of acps is likely rather rare, and it is likely that generation of male-specific paralogs via various mechanisms of gene duplication play a disproportionate role in this process. Finally, acps are not found only in insects but rather appear to be the result of a phenomenon applicable to all sexual taxa; evidence for their rapid evolution also exists in primates, for example (Clark and Swanson 2005). What Drives Rapid Evolution and Masculinization? Although the patterns of rapid evolution observed in male genes are interesting in their own right, the more significant question remains, ‘‘what drives the more rapid evolution of MBGs as compared FBGs?’’ The 3 most popular hypotheses are 1) relaxed selective constraint, 2) adaptation via sexual conflict, or 3) adaptation via sexual selection. Relaxed selective constraint in male proteins may occur via 2 nonmutually exclusive mechanisms. First, male systems may simply be less sensitive to perturbation, and thus tolerate a larger number of partially deleterious nonsynonymous substitutions, leading to the elevated dN/dS ratios observed in these genes. However, this would appear to contradict the observation that male reproductive functions are more sensitive to perturbation in mutagenesis or introgression experiments (Wu and Davis 1993; Singh and Kulathinal 2005). Second, male-limited expression of MBGs reduces the efficacy of selection (see above), and thus divergence could accumulate ‘‘neutrally’’ in females (Wade 1998; Cruickshank and Wade 2008; Morrow et al. 2008). Although it is quite likely that this process is taking place, a similar process should be occurring on autosomal FBGs, and yet we do not observe the widespread rapid evolution of female genes. Consequently, it would appear that relaxed selective constraint cannot account for the genome-level patterns that we observe. In contrast, there appears to be extensive evidence that the increased rate of divergence occurring in many of the genes involved in male reproductive function show evidence of having been driven by positive selection (Civetta and Singh 1999; Singh and Kulathinal 2000; Swanson and Vacquier 2002; Pröschel et al. 2006). For instance, ;36% of identified acps show evidence of having been subjected to recent positive selection (Swanson et al. 2001; Mueller et al. 2005; Haerty et al. 2007). A plausible mechanism driving the accelerated evolution of acps is sexual conflict or the coevolutionary arms race between the sexes in the attempt to force each other to reproduce at opposing reproductive optima (see Arnqvist and Rowe 2005 for extensive review). Under this scenario, males evolve strategies, such as acps, that force females to reproduce above their own optimal rate, whereas females evolve counteradaptations in order to favor their own reduced optimum. Although evidence for sexual conflict is persuasive and continues to accumulate (e.g., Arnqvist and Rowe 2005; Hall et al. 2008), the simple observation that we do not see a similar pattern of accelerated evolution in female genes would appear to rule out the possibility that sexual conflict is the dominant driver of male evolutionary change (Civetta and Singh 2005; Kulathinal and Singh 2008). This, of course, assumes that both sides of the conflict involve mutations occurring in similar underlying genetic architectures. If, however, adaptations occurring in females that confer resistance to males generally require fewer mutational steps, then conflict could explain the excess of rapid male evolution. Barring such a situation, the most plausible driver of rapid divergence of genes associated with male function is a combination of intersexual conflict and traditional Darwinian notions of sexual selection, with special emphasis placed on male–male competition, especially in the form of sperm competition. MSD Theory and the Input of Variation MSD can be defined as the differential/elevated effects of all actions performed by the male, as compared with the female, during mating—from the start of the search for mates to the beginning of the next mating cycle (Singh and Kulathinal 2005). This will include, but is not limited to, male–male competition, searching for mates, vigorous display and courting, mating and copulation duration, sperm quantity and quality, mate guarding, and readiness for remating. The MSD theory is based on the assumption that sexual selection is stronger in males as compared with females (except, of course, where in cases the sexual role is reversed), which can be seen among males in all aspects of mating as noted above. Darwin noted the heightened expression of sexual selected traits in the male and remarked ‘‘males with their superior strength, pugnacity, armaments, unwieldy passion and love songs, are almost always the more active and most often, the initiators of sexual interactions’’ (Darwin 1871). Being preoccupied with providing explanations for individual traits, Darwin was not able to see overall, long-term consequences of stronger sexual selection in males. Effectively, MSD is the result of elevated sexual selection in the male over the female and can therefore be expressed as ‘‘male-biased sexual selection’’—of course, it also includes the effect of sexual and natural selection. MSD provides an explanation for the unique genomic features observed in males and acts S103 Journal of Heredity 2010:101(Supplement 1) as a contrast to such features being the result of female choice. Traditionally, the presence of sustained directional selection as is observed in males of species subject to strong sexual selection would be expected to deplete additive genetic variation, leading to fixation of particular male traits (Crow 2008). However, if such were the case, it would no longer be in the interest of females to be choosy. The lack of male variability would preclude selected traits from being a reliable indicator of mate quality: a situation that has been called the paradox of the lek (Borgia 1979; Andersson 1994). And yet, females continue to choose; thus an integral subject of recent interest in the field of sexual selection has been to explain how such variability is maintained. One particularly promising avenue of investigation has been to suggest that male traits provide an especially large mutational target such that sufficient variability can be maintained at mutation–selection balance (see Tomkins et al. 2004 for review). Within this framework, much attention has been paid to the ‘‘genic capture hypothesis’’ (Rowe and Houle 1996), which suggests that male traits are often condition-dependent. This means that the strength of their overall expression is determined by overall genetic condition, and thus is subject to the input of a large proportion of the genome. Therefore variation at a great many genomic loci inputs into the overall variability of the male trait and trait variability is maintained even in the face of strong directional selection. Evidence for the genic capture hypothesis is abundant and it almost certainly plays a significant (if not predominant) role in resolving the lek paradox (Tomkins et al. 2004; Arnqvist and Rowe 2005). Nevertheless, we wish to suggest that the MSD hypothesis, via sustained directional selection, provides another avenue via which male traits may be expected to provide an especially large mutational target (Singh and Kulathinal 2005). As noted in the numerous examples presented above, the genomes of sexually selected taxa are becoming progressively masculinized, including a larger proportion (acompared to females) of genes involved in male reproductive traits, a larger proportion of genes expressed at higher levels in males, and also a larger number of male lineage-specific de novo genes. Each of these examples indicates that the genome is dynamic and that male traits may present a larger mutational target because, over evolutionary timescales, selection will favor the retention of any novel genes (duplications, retrotranspositions, exonization, etc.) or expression patterns that are beneficial to males, consequently increasing the overall proportion of the genome affecting male traits under selection. Our example of the acps in Drosophila illustrates the notion that strong directional selection leads to an increase in lineage-specific acquisition of functional paralogs and de novo genes. Even in the case of sexually selected nondisplay traits, such as those involved in sexual conflict scenarios, which should not be expected to be subject to condition dependence, variability may be maintained via mechanism outlined in MSD. S104 Implications for the Maintenance of Sex Finally, we wish to suggest that the net effect of increased sexual selection in males may foster a situation wherein males are difficult to eliminate, thus favoring the maintenance of sex in the face of invasion from asexuals. MSD posits that genomic masculinization occurs due to strong selection pressure favoring the ability of males to secure copulation by all means—via mating-related male–male competition or male–female interaction—and induce females to reproduce at their maximum capacity, which even goes so far as to involve acps that induce increased ovulation, for example (Wolfner 1997). A typical assumption of sexual conflict theory has been that the female’s mating rate is optimal, whereas the male’s is excessive. Thus, such conflict may favor a situation wherein female’s mating acceptance threshold is increased and can only be overcome by zealous males. Although a classic paper in the field of sexual conflict theory showed that experimental removal of such competition via enforced monogamy led to higher reproductive output (Holland and Rice 1999), such removal of competition is impossible in nature. Thus, in the short term, removal of male input into mating may lead to an overall reduced reproductive output. Also, as noted above, it has been determined that in many species, male gamete- and seminal fluid-specific factors are required in order to ensure proper fertilization (beyond the obvious contribution of one-half the total 2n genomic complement) (see Engelstädter 2007 for review). Under MSD, such factors will be favored if they increase the success rate of male fertilization or increase the total number of progeny produced. These factors, either in the gametes themselves or in the form of acps, may initially be nonessential but, over evolutionary time, become required to complete fertilization. A plausible example of an intermediate step in such a process is the ovulin acp in Drosophila that induces ovulation in females and for which evidence suggests it mimics the female’s own egglaying hormones (Monsma and Wolfner 1998; Ram and Wolfner 2007). By reducing the need for the presence of the their own ovulation proteins, females could eventually become dependent on the male’s acps in order to lay eggs at an elevated rate. Thus, loss of the male’s input in the case of a fictional, newly arising parthenogenesis mutation would incur an immediate penalty in terms of a reduced reproductive rate. Conclusion Our purpose in this short review has been 2-fold. First, we have argued that the overall effect of this increased selection pressure acting on males, which Singh and Kulathinal (2005) have termed MSD, may have implications for both the maintenance of genetic variation as well as for the maintenance of sexual reproduction itself. Various lines of evidence suggest that male-specific gene acquisition is prevalent in sexually selected taxa and that this will increase the mutational target of male-specific traits allowing the continued input of heritable variation. Furthermore, the net Singh and Artieri Masculinization and the Maintenance of Sex effect of these male-driven sexual behaviors—physical, physiological, and behavioral—is that MSD provides direct benefits to reproducing pairs. This manifests itself in terms of favoring elevated reproductive rates, perhaps ultimately leading to a greater number of offspring being produced in sexual versus asexual multicellular species, both making males difficult to purge and perhaps assisting to compensate for the 2-fold cost of sex. 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