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PERSPECTIVE doi:10.1111/j.1558-5646.2011.01316.x SOME INCONVENIENT TRUTHS ABOUT SEX CHROMOSOME DOSAGE COMPENSATION AND THE POTENTIAL ROLE OF SEXUAL CONFLICT Judith E. Mank,1,2 David J. Hosken,3 and Nina Wedell3 1 Department of Zoology, Edward Grey Institute, University of Oxford, Oxford OX1 3PS, United Kingdom 2 3 E-mail: [email protected] Biosciences, University of Exeter, Cornwall Campus, Penryn, Cornwall TR10 9EZ, United Kingdom Received November 16, 2010 Accepted March 29, 2011 Sex chromosome dosage compensation was once thought to be required to balance gene expression levels between sex-linked and autosomal genes in the heterogametic sex. Recent evidence from a range of animals has indicated that although sex chromosome dosage compensation exists in some clades, it is far from a necessary companion to sex chromosome evolution, and is in fact rather rare in animals. This raises questions about why complex dosage compensation mechanisms arise in some clades when they are not strictly needed, and suggests that the role of sex-specific selection in sex chromosome gene regulation should be reassessed. We show there exists a tremendous diversity in the mechanisms that regulate gene dosage and argue that sexual conflict may be an overlooked agent responsible for some of the variation seen in sex chromosome gene dose regulation. KEY WORDS: Evolutionary genomics, sexual conflict, sex. In diploid sexual species with morphologically distinct sex chromosomes, the heterogametic sex has only half as many copies of all X- or Z-linked genes outside the pseudoautosomal region compared to the homogametic sex, and only half as many copies of Xor Z-linked genes compared to the autosomes. Reduced gene dose can result in reduced gene transcription, as fewer copies of a locus present fewer targets to which the transcriptional machinery can bind, and the result will be large differences in gene expression for sex-linked and autosomal genes in the heterogametic sex. This has the potential to create tensions in gene networks that span sexlinked and autosomal loci (Birchler and Veitia 2010), theoretically with deleterious phenotypic implications to the heterogametic sex (Ohno 1967; Charlesworth 1978; Marin et al. 2002). “Sex chromosome dosage compensation” is the name given to the regulatory mechanisms that balance gene expression between the autosomes and sex chromosomes in the heterogametic 1 C 2011 The Author(s). Evolution sex, and although compensation is achieved in a variety of ways, chromosome-wide dosage compensating mechanisms have been documented in the major animal model systems, including therian mammals, Drosophila, and C. elegans. Because of the presence of dosage compensation in these animal models, and the fact that gene expression levels are often under selection (Hebbert 1984; Khaitovich et al. 2006), it has largely become dogma that dosage compensation is essential and universal to avoid the detrimental effects of unequal levels of gene expression caused by sex chromosome divergence (Griffin et al. 2008; Pierce 2008; Naurin et al. 2010). The universality of sex chromosome dosage compensation has informed other aspects of evolutionary genetics, most notably sex chromosome evolution. Additionally, sex chromosome dosage compensation can be used to understand the fitness costs of hypo- and hyper-expression, an important step in determining PERSPECTIVE the relationship between the genome and the organism it encodes. Studying differences in gene expression between males and females is also increasingly useful for evolutionary examinations of intralocus sexual antagonism (Innocenti and Morrow 2010; Wyman et al 2009; Mank and Ellegren 2009c), and therefore understanding selection on sex-specific gene expression patterns is key to correctly using these data to test evolutionary theory. As we discuss below, sex chromosome dosage compensation also illustrates how selection in one sex for altered transcription rates can negatively affect the transcription rates of the other sex, and therefore can be studied in the context of intralocus sexual antagonism. Although traditional models of intralocus sexual conflict result in different gene expression levels between the sexes, sexually antagonistic selection for sex chromosome dosage compensation is unusual in that the end result is balanced gene expression levels between males and females. Hence, there is clearly a link between the evolutionary dynamics of sex chromosomes and their gene expression patterns with sexual conflict, but the implication of sexual conflict for dosage compensation remains largely unexplored. The spread of microarrays and next-generation sequencing of RNA has made tenable studies of sex chromosome dosage compensation well outside the traditional model organisms, and the results have challenged the dogma of universal sex chromosome dosage compensation. Although some nonmodel organisms, such as Anopheles (Hahn and Lanzaro 2005), show evidence of a nearly complete mechanism of sex chromosome dosage compensation, many other animals do not, including birds (Itoh et al. 2007; Ellegren et al. 2007), stickleback fish (Leder et al. 2010), monotremes (Deakin et al 2008), and lepidoptera (Arunkumar et al. 2009; Zha et al. 2009), although see Walters and Hardcastle (in press). In addition to this new data, reevaluation of model systems that were thought to exhibit universal sex chromosome dosage compensation has demonstrated that a significant proportion of the sex chromosomes are not dosage compensated. For example, in humans about 15% of X-linked genes escape random-X inactivation (Carrel and Willard 2005), as do many noncoding RNAs (Renius et al. 2010). More importantly, recent evidence suggests that random-X inactivation, originally thought to be a mechanism of dosage compensation (Nguyen and Disteche 2006), does not achieve dosage compensation in eutherian mammals, rather it extends the problem of reduced gene dose to females (Gupta et al 2006; Xiong et al. 2010). In fact differences in gene dosage can be important in sex determination (Smith et al. 2009a) and lack of dosage compensation can potentially facilitate sex-specific evolution and defuse intralocus sexual conflict (Bonduriansky and Chenoweth 2009). In this review, we address some assumptions that are unsupported to dispel several myths about dosage compensation, ask why dosage compensation exists in some taxa and 2 EVOLUTION 2011 not others, and then discuss potential reasons for variation in the proportion of genes that are compensated. In particular, we discuss the potential role of sexual conflict in the evolution of dosage compensation mechanisms. Before we begin, it is worth defining precisely what is meant by sex chromosome dosage compensation. Sex chromosome dosage compensation is a mechanism, acting in the heterogametic sex, to increase transcription of the single X or Z chromosome to that level expected from a diploid complement. Empirical tests of dosage compensation often assess the gene expression differences for X- or Z-linked genes between the sexes, with dosage compensation concluded when male/female levels are near one. Although one consequence of sex chromosome dosage compensation mechanisms in some species is that transcription rates for X- and Z-linked genes are equalized between males and females, this is not actually the selective cause of dosage compensation, but rather simply a consequence of it, and balanced transcription rates in males and females for X- or Z-linked genes is, by itself, not sufficient to demonstrate the presence of dosage compensation. Because sex chromosome dosage compensation results from the need to balance transcription between X- or Z-linked genes and autosomal loci in the heterogametic sex (Mank 2009), the most important test for sex chromosome dosage compensation is whether the X:A or Z:A transcriptional ratio = 1 (Fig. 1) in the heterogametic sex. This X:A and Z:A balance is important for gene networks and pathways that encompass both sex-linked and autosomal loci, as the functional interactions between sex-linked and autosomal genes are different between uncompensated heterogametic individuals and the homogametic sex. Although this distinction is subtle, it has important implications for organisms that actually do have sex chromosome dosage compensation (discussed below). Dosage compensation can be achieved most simply via a specific mechanism to hyper-express the single sex chromosome in the heterogametic sex (Fig. 1), such as the mechanism seen in Drosophila. However, selection for hyper-transcription in the heterogametic sex can result in overexpression in the homogametic sex, which then results in selection in this sex to downregulate transcription rates from the sex chromosomes (Charlesworth 1978). Myth No. 1: Dosage Compensation For Gene Expression Will Accompany Sex Chromosome Evolution As the X and Y chromosomes gradually diverge from one another, the gene content of the Y chromosome degrades, leaving males with just one functional copy of many X-linked genes. The single copy results in a more limited transcriptional target PERSPECTIVE Figure 1. (A) In male heterogametic organisms, heteromorphic sex chromosomes produce a X:A ratio < 1 in males, who only have one copy of X-linked genes for every autosomal loci. This can be fixed via the evolution of dosage compensative mechanisms that increase transcription from the single male X chromosome. (B) In female heterogametic organisms, the single copy of the Z chromosome in females produces a Z:A ratio < 1 in this sex. This can be corrected via the hyper-transcription of Z-linked genes in females. for gene expression machinery, and a reduction in the overall X:A ratio in males. For female-heterogametic lineages, a similar process of W chromosome degeneration produces a lower Z:A ratio in females. Sex chromosomes in many animals are large, and harbor a significant portion of the coding content of the genome. In Drosophila melanogaster, the X is home to more than 15% of the total coding loci, and the Caenorhabditis elegans X holds nearly 14% of the genomic tally of coding genes. Vertebrates have somewhat smaller sex chromosomes, but their contribution is still significant, with the human X and chicken Z both harboring around 5% of all coding genes (www.ensembl.org). Although the process is gradual, the degeneration of the Y or W coding content would be expected to be deleterious to the heterogametic sex due to the reduced expression of many genes on the X or Z chromosome. Genes with critical dosage sensitivity would need to be compensated in the heterogametic sex, and this compensation mechanism would theoretically eventually spread to the entire sex chromosome. In line with this model, early findings from model animals revealed complex chromosome-wide regulatory machinery counteracting the problems associated with sex chromosome divergence. This topic has been the subject of several recent reviews (e.g., see Straub and Becker 2007), so we will not go into great detail about the regulatory mechanics of sex chromosome dosage compensation. Briefly, Drosophila males achieve X:A parity by hyper-transcribing their single X chromosome (Lucchesi 1973). The mechanism does not affect expression in females, although chromatin-structure on the X has been altered for this process and that can affect females (Zhang and Oliver 2009). The mechanics of sex chromosome dosage compensation is more complex in C. elegans, where the X chromosome is hyper-transcribed in both sexes during development (Xiong et al. 2010), resulting in balanced X:A ratio in males and X:A > 1 in hermaphrodites. Over-transcription in hermaphrodites is then countered by a secondary sex-specific compensatory mechanism (Ercan et al. 2007; McDonel et al. 2006), returning hermaphrodite expression of X-linked genes to the ancestral, diploid level. Strangely, hyper-transcription abates in adult C. elegans, resulting in X:A < 1 in both males and hermaphrodites (Xiong et al. 2010). The mechanism of compensation is not understood in the mosquito, Anopheles gambiae, however the X is neither hypertranscribed in males nor hypo-transcribed in females, indicating some compensatory regulation takes place (Hahn and Lanzaro 2005). Eutherian mammals also show sex chromosome gene regulation. However not all elements of X chromosome regulation in eutherians may be related to dosage compensation, and therefore we will address the mechanism and consequences later. The regulatory machineries that affect the Drosophila and C. elegans X chromosomes act across the entire chromosome at once, and are remarkably, almost awe-inspiringly, complex. EVOLUTION 2011 3 PERSPECTIVE The discovery of these regulatory mechanisms affecting entire sex chromosomes confirmed Ohno’s predictions (1967) and led to the development of a long-standing dogma in molecular and evolutionary genetics stating that complicated compensation methods to correct for gene dose across the entire sex chromosome accompanies sex chromosome differentiation (Straub and Becker 2007). It was accepted that sex chromosome dosage compensation is required for successful development (Payer and Lee, 2008), as the imbalance in gene dosage between the sex chromosomes and the autosomes would be potentially fatal in the heterogametic sex (Deng and Disteche 2007). The genes affected by sex chromosome divergence were all linked, and this was a hypothesis put forward to explain why dosage compensation mechanisms regulated the entire sex chromosome together, rather than more common mechanisms in the rest of the genome of localized regulatory control, where nearby enhancers direct the expression of individual genes (Larsson and Meller 2006). Because sex chromosome dosage compensation was concluded to be a required companion of sex chromosome divergence, it was assumed that it would be present in all organisms with highly dimorphic sex chromosomes. This is why there was such a surprise when global gene expression studies in the zebra finch and chicken (Itoh et al. 2007; Ellegren et al. 2007; Itoh Table 1. et al. 2010) showed that there was no global mechanism to balance avian Z chromosome gene dose. This was quickly followed by genome-wide data for the silkworm (Zha et al., 2009; Arunkumar et al. 2009) indicating that the lepidopteran Z is also not dosage compensated. Studies in the platypus (Deakin et al. 2008; 2009) indicate incomplete X chromosome dosage compensation in the monotremes, and data from stickleback fish show that the X is expressed more in females than males (Leder et al. 2010), consistent with a lack of sex chromosome dosage compensation. Following this, a recent reappraisal of model organisms (Xiong et al. 2010) indicates that dosage compensation is present in Drosophila, is developmentally transient in C. elegans, and is not present in therian mammals (discussed in more detail below). Combining the new data from model and nonmodel organisms suggests that chromosome-wide dosage compensation is actually rather rare in animals, and is present in the truest sense only in Drosophila and possibly Anopheles (Table 1). These examples clearly indicate that dosage compensation of the entire X or Z chromosome is not required for sex chromosome evolution. In retrospect, there were hints that complete sex chromosome dosage compensation might not be a requirement for life. At the phenotypic level, the difference in expression in females and males for Z-linked genes that affect plumage The current status of dosage compensation in animals. Clade or species Type of sex chromosomes Dosage compensation Results Most recent citation Drosophila XY Yes Xiong et al. (2010) Therian mammals XY No C. elegans XO Partial, during development Anopheles XY Birds ZW Probably, but must be confirmed with next-generation data Partial, gene-by-gene Xmale = Xfemale Xmale = Autosomes Xmale = Xfemale Xmale < Autosomes Xfemale < Autosomes During development: Xmale = Xfemale Xmale = Autosomes Adults: Xmale = Xfemale Xmale < Autosome Xfemale < Autosomes Xmale = Xfemale Xmale = Autosomes Itoh et al. (2007) Lepidoptera ZW Partial, gene by gene Sticklebacks Platypus XY XY Absent or partial Partial, gene-by gene Zmale > Zfemale Zfemale < autosomes Zmale > Zfemale Zfemale < autosomes Xmale < Xfemale Xmale < Xfemale Tribolium XY In males, not females 4 EVOLUTION 2011 Xmale < Xfemale Xmale = autosomes Xfemale > autosomes Xiong et al. (2010) Xiong et al. (2010) Hahn and Lanzarro (2005) Zha et al. (2009) Leder et al. (2010) Deakin et al. (2008, 2009) Prince et al. (2010) PERSPECTIVE has been known for more than a century by poultry fanciers (Spillman 1908; Punnett 1923), although at the genetic level, a lack of dosage compensation for some genes was reported as far back as the 1950s, with similar reports trickling into the literature since then (e.g., Stehr 1959; Cock 1964; Johnson and Turner 1979; Hebbert 1984). Furthermore, many animal clades show incredible turnover of the sex chromosomes. This process, whereby ancestral sex chromosomes are replaced by new proto-sex chromosomes carrying nascent sex-determining mechanisms, results in heteromorphic nonhomologous sex chromosomes in closely related lineages. The best known examples are in fish, including the sticklebacks (Peichel et al., 2004; Ross et al., 2009; Shapiro et al., 2009), salmon (Woram et al., 2003; 2004), and ricefish (Matsuda et al., 2002; 2003; Takehana et al., 2007; 2008; Tanaka et al., 2007), although there are also examples in reptiles (Ezaz et al., 2005, 2009), and insects (Bachtrog 2004; Carvalho and Clark 2005). Many more examples are probably only waiting to be identified. Global mechanisms to balance gene dose are extraordinarily complex, and the requirement of a similar and independent mechanism for all sex chromosome systems presents a substantial evolutionary barrier to sex chromosome evolution. Yet we know that nonhomologous sex chromosomes occur in countless lineages, and it is difficult to see how sex chromosomes could arise, decay, and be replaced rapidly if chromosome-wide dosage compensation was obligatory. Although we do not know how often the origin of new sex chromosomes is accompanied by dosage compensation, we already know that it is not an absolute relationship, adding further weight to the conclusion that total dosage compensation is not compulsory. Myth No. 2: Regulating the Gene Expression of An Entire Sex Chromosome is Simpler Than Regulating Specific Genes One of the reasons for myth that global dosage compensation was necessary for sex chromosome evolution was the assumption that halving gene copy number resulted in halved gene expression. Additionally, genes do not do their work in isolation, but rather together in networks (Falconer 1981; Carroll 2000; Oliver 2007), and the reduced gene expression of X- or Z-linked genes was expected to perturb all the other interacting genes throughout the genome. The relative expression of interacting genes is important for phenotypes and fitness (e.g., Smith et al., 2009b), therefore because the reduction in transcription from X-linked genes might disrupt gene networks in the heterogametic sex, large deletions or rapid loss of Y chromosome homologs were thought to cause total network collapse in the absence of compensation mechanisms. All of this was incorporated into the model that chromosomewide regulatory machinery was needed for sex chromosome compensation. These chromosome-level regulatory mechanisms are complex, which implied that selection for sex chromosome dosage compensation must be very strong during sex chromosome evolution—how else could such complicated apparati evolve? There are several lines of evidence contradicting these assumptions. To understand the transcriptional and phenotypic consequences of halving gene dose in the heterogametic sex, we can look to studies of autosomal monosomy, which is functionally equivalent (Birchler et al. 2005). Although studies indicate that monosomy is often deleterious in large blocks (Dallapiccola et al. 1978), there are reasons to think that the uncompensated X chromosome itself is not largely deleterious for most genes. This is because those complex gene networks actually buffer gene dose, as studies of monosomy indicate that regulatory buffering reduces the expression-level effect for many genes undergoing a 1 -fold reduction in gene dose (Vietia et al. 2008; McAnally and 2 Yampolsky 2010; Stenberg et al. 2009). For those genes that do show expression reductions associated with gene dose reduction, many will fall under the Kascer–Burns model of dominance for enzymatic and metabolic genes (Kascer and Burns 1981). This model suggests that 12 -fold reduction in protein titers will not greatly affect functionality, and therefore the phenotypic effects would be negligible. However, it should be noted that we do not know at this point what percentage of genes are described by the Kascer–Burns model. Studies of gene expression patterns from sex chromosomes systems lacking complete dosage compensation show many similar patterns to autosomal monosomy. Consistent with reports that gene expression is not necessarily an additive trait (Auger et al. 2005), studies of dosage compensation in birds indicate that 12 -fold reduction in gene dose in the heterogametic sex does not result in halved gene expression. Rather, when averaged across all genes on the Z, the single dose in females results in a 0.7- to 0.8-fold decrease in gene expression (Itoh et al. 2007), but within these numbers is a complex pattern of different regulatory machineries. Some genes on the avian Z chromosome are equally transcribed in the sexes (Itoh et al. 2007; Mank and Ellegren 2009a), and this is primarily due to increased transcription in females (Mank et al. 2008). Hyper-transcription of Z-linked loci in females varies by tissue and ontogenetically (Mank and Ellegren 2009a; Itoh et al. 2010), and it appears that the genes on the Z chromosome are locally dosage compensated when and where balanced transcription is needed in the heterogametic sex. This local pattern of hyper-transcription represents a much simpler method to balance gene dose for those genes that have critical expression titers (Mank 2009). Sex-specific gene regulation affects large proportions of autosomal genes in animals (Ranz et al. 2003; Reinke et al. 2004; Cutter and Ward EVOLUTION 2011 5 PERSPECTIVE 2005; Reinius et al. 2008; Mank et al. 2010), and because this mechanism was in place before the evolution of any specific set of sex chromosomes and is clearly effective at regulating dosagesensitive genes on the sex chromosomes of some animals, it raises the question as to why complex chromosome-wide mechanisms evolved in some organisms at all. Put another way, female birds simply increase transcription for those genes that require dosage compensation, and do not seem to suffer any cost due to the unbalanced expression of other genes. Although the fitness consequences of incomplete dosage compensation need to be confirmed empirically, it nevertheless suggests that we may have been asking the wrong questions. Instead of asking why birds, therian mammals, monotremes, sticklebacks, and lepidopterans lack complete sex chromosome dosage compensation, we should be asking why this complex and seemingly unnecessary adaptation exists in flies, developing nematodes, and mosquitoes. Additionally, the gradual process of Y and W chromosome degeneration cannot have an immediate and strongly deleterious effect on the heterogametic sex. If it did individuals bearing strongly deleterious deletions or disintegrations on the Y and W chromosomes would be removed from the gene pool, arresting the process of sex chromosome divergence and presenting a significant barrier to the origin of any heteromorphic pair of sex chromosomes. The fact that the Y and W do slowly degenerate suggests that the process is at most mildly deleterious to the heterogametic sex. Therefore, selection for dosage compensation cannot be terribly strong, as the uncompensated phenotypes are not at a large disadvantage. This leads to the question of how complex chromosome-wide mechanisms of dosage compensation arise if they are not the focus of strong selection. Myth No. 3: Most Sex-Specific Regulation of The Sex Chromosomes is a Product Of Selection for Dosage Compensation Dosage compensation has become an umbrella term, and is applied to aspects of sex chromosome gene regulation that may not have anything to do with the need to balance the transcription in the heterogametic sex. Additionally, a great deal of confusion exists about what exactly dosage compensation achieves. Simply put, sex chromosome dosage compensation is the result of the need to balance transcription between the sex chromosomes and the autosomes in the heterogametic sex (Ohno 1967). This results in a Z:A or X:A ratio of 1 in the heterogametic sex. The confusion exists because compensation of the X or Z chromosome in the heterogametic sex also has the side-effect of balancing X or Z chromosome transcription between males and females. However, 6 EVOLUTION 2011 balanced transcription between males and females alone does not constitute dosage compensation, and, in some cases, can run counter to it. Applying this precise definition, some sex chromosome regulatory mechanisms that were classified as dosage compensating possibly are not. The best example of this is the pattern of X chromosome inactivation in therian mammals. In marsupial and placental mammals, one X chromosome is inactivated in females (X chromosome inactivation, or XCI). In marsupials, the paternal X is always inactivated (Sharman 1971). In placentals, the process is somewhat more baroque, with the initial paternal XCI reversed at the blastocyst stage and replaced with random XCI (reviewed in Payer and Lee 2008), resulting in females that are chimeric for the functional X chromosome. This process extends the problems of hemizygosity and X:A imbalance, confined to males in all other XY animals, to females (Oliver 2007). Results and interpretation conflict among studies, with some reports that the single X chromosome is upregulated in both sexes to achieve X:A parity (Nguyen and Disteche 2006; Lin et al. 2007), and other reports that X chromosome inactivation in females results in an X:A ratio < 1 in both sexes (Gupta et al. 2006; Xiong et al. 2010). Interestingly, the locus-specific hyper-transcription patterns bear some resemblance to the gene-by-gene hyper-transcription seen on the female Z chromosome (Deng et al. 2009). XCI in Eutheria therefore may not balance X:A ratios in males so much as drag females away from a balanced X:A. Despite this, eutherian XCI is typically described as fulfilling the needs of sex chromosome dosage compensation because it balances transcription for most genes on the X between males and females. Similarly, sexual dimorphism in gene expression on the sex chromosomes can be confused with dosage compensation if precise definitions are not used. For example, there is a region of the chicken Z chromosome that is hyper-methylated in males (Male Hypermethylated Region, or MHM), and therefore expressed more in females despite the fact that female birds have only one copy of the Z (Melamed and Arnold 2007). Although there is a sex-specific mechanism to regulate gene expression in MHM of the chicken Z chromosome, this is not strictly speaking a dosage compensation mechanism because the Z:A ratio of the MHM is < 1 in females and << 1 in males (Mank and Ellegren 2009b). This ratio reflects the fact that the MHM is not hyper-transcribed in females, but is instead hypo-transcribed in males. Therefore it does not balance gene dose between the Z and autosomes in females, but rather represents some other form of sex-specific gene regulation. Because it is clear that sex chromosome dosage compensation is not required for life, we cannot assume that all sex-specific gene regulation of sex chromosomes achieves dosage compensation. This is increasingly important with the recent trend of using sex-biased gene expression to test sexual conflict theory PERSPECTIVE (Mank and Ellegren 2009c; Wyman et al. 2009; Innocenti Morrow 2010), a topic we address in more detail later. Myth No. 4. The Need for Dosage Compensation Will Prevent Sex Chromosome Turnover The final myth that we address is that sex chromosome turnover, where ancestral sex chromosomes are replaced by new nonhomologous ones, will be retarded by the need for dosage compensation. This makes intuitive sense under the old paradigm: if sex chromosome dosage compensation is an absolute requirement, then turnover of sex chromosomes would be impeded by the need for complex (and rare) chromosome-wide regulatory machinery. As we have mentioned above, in many clades, sex chromosome turnover is rapid, and therefore the need for complex dosage compensating mechanisms is clearly no hindrance to sex chromosome evolution. Perhaps however the presence of sex-chromosome regulatory machinery in some instances can explain why some clades exhibit strong conservation of sex chromosomes and others undergo rapid turnover. It has been argued that dosage compensation mechanisms can retard the invasion of new sex chromosomes as the heterogametic sex with a newly arisen Y (or W) chromosome would now have two upregulated ancestral X or Z chromosomes (van Doorn and Kirkpatrick 2007, Fig. 2). Closer examination suggests that although this may explain some of the data, there are some examples that contradict the Figure 2. How the invasion of a new male-determining factor may be retarded by chromosome-wide dosage compensation. In the ancestral state, the single male X is upregulated, and as a result, the single male X is expressed at twice that of each female X (upper panel). However, as a new male-determining factor (the star in the lower panel) arises on the neo-Y, males can now carry two (ancestral) X chromosomes that are upregulated. Any cost associated with this double upregulation will select against the new male-determining factor and, hence, will select against sexchromosome turnover. prediction. For example, although the X is largely conserved in Drosophila (Drosophila 12 Genomes Consortium 2007) and therian mammals (Veyrunes et al. 2008), both of which regulate their entire respective X chromosomes, the extreme conservation of the avian Z (Shetty et al. 1999) is clearly not explained by a sex chromosome regulatory mechanism. More data are needed to determine general trends of this prediction. Toward A New Synthesis Studies of sex chromosome dosage compensation can illuminate the fundamental connection between genes and phenotypes. More important for an evolutionary biologist, correctly classifying dosage compensation versus more generalized sex-specific gene regulation is needed to understand the relationship between sex-specific selection, sex-biased gene expression, and sexually dimorphic phenotypes. This is especially imperative for the sex chromosomes, as the X and Z chromosomes are predicted to play a disproportionately large role in the evolution of sexually dimorphic phenotypes (Rice 1984; 1996), through mechanisms that include the evolution of sex-biased gene expression. Is it possible that in ZW taxa, where the sex-determination system is predicted to favor the evolution of exaggerated male ornaments through female choice (e.g., birds and butterflies: Reeve and Pfennig 2003; Kirkpatrick and Hall 2004; Albert and Otto 2005), incomplete dosage compensation has enabled differential gene expression in males and females of other Z-linked loci important in sexual dimorphism to occur? To date, there are no data available linking gene expression levels of such sexually selected traits in butterflies and birds to examine this possibility. Much sex-biased gene expression is thought to result from sexually antagonistic selection for fitness optima (Connallon and Knowles 2005; Bondurianky and Chenoweth 2009), and sexual conflict is expected to play out in an unusual way on the sex chromosomes (Rice 1984). For example in XY systems, dominant female benefit alleles are expected to accumulate on the X as the X has a longer residence time in females. Male benefit recessive alleles will also accumulate on the X as these genes will always be expressed in the hemizygous male, but will only be expressed in homozygous females (Rice 1984). Furthermore, selection could favor the movement of male-specific alleles that originally accumulate on the Y to the X because the Y is degenerate (Rice 1996; Gibson et al. 2002). In Drosophila, there is also evidence of extensive gene traffic on the Y chromosome to and from the autosomes, with more Y chromosome gene gains from the autosomes than gene losses (Carvalho et al. 2009). Thus there are good reasons to predict an association between sexually selected phenotypes and the sex chromosomes (assuming no X chromosome inactivation in females). There is also phenotypic and gene expression data consistent with this. For example, the X-chromosome has been EVOLUTION 2011 7 PERSPECTIVE shown to harbor almost all the genome-wide ontogenetic sexually antagonistic variation in D. melanogaster (Gibson et al. 2002), and gene expression patterns are consistent with dominant female, but not male, benefit alleles accumulating on the Drosophila X (Connallon and Knowles 2005; Bachtrog et al. 2010, but see Gallach et al. 2011 and Zhang et al. 2010 for a more nuanced view). Furthermore, the sex determination system can have profound effects on the fixation of sexually antagonistic alleles when females choose their mates (Albert and Otto 2005). In ZW systems, dominant male benefit alleles are predicted to fix on the Z even if they cause some harm to females, whereas in XY systems it should be dominant female benefit alleles that are preferentially selected for on the X even if they cause some harm to males. Again, these predictions are predicated on the assumption of no Z/X inactivation. As sex chromosome dosage compensation becomes more complete, the predictions associating the sex chromosomes to sexual dimorphism break down as the gene expression from the X and Z chromosome are increasingly constrained by chromosome-wide regulatory mechanisms rather than locus-specific sex-specific selection. However, thought of from a different perspective, the evolution of dosage compensation, and all sex-specific gene regulation, is the result of sexual conflict over optimal trait values for males and females. Does Conflict Explain Sex-Specific Gene Regulation? Sex-specific regulation of the sex chromosomes, either for dosage compensation or other reasons, can be thought of in terms of sex-specific selection (Engelstadter and Haig 2008; Rice 1987b). When sex-specific selection to increase transcription and counterreduced chromosome dose in the heterogametic sex does not affect expression in the homogametic sex, dosage compensation is not antagonistic. The hyper-transcription of the X in Drosophila males is an example of a sex chromosome dosage compensating mechanism that is not sexually antagonistic, as it does not affect female expression (Vicoso and Charlesworth 2009). The same is true of the locus-by-locus hyper-transcription of the Z in female birds (Mank and Ellegren 2009a). However, selection in the heterogametic sex can have sexually antagonistic consequences when the evolutionary response in gene regulation affects the homogametic sex (Rice 1987b). This is likely the case in C. elegans, where the initial evolution of X chromosome hyper-transcription affected both sexes, resulting in X:A = 1 in males, but X:A > 1 in hermaphrodites. Although any negative consequences of X:A > 1 in hermaphrodites were outweighed by the effects of an uncompensated X in males, they were apparently sufficiently harmful to result in a 8 EVOLUTION 2011 compensatory hermaphrodite-specific regulatory apparatus that counters the hyper-transcription, returning X:A to 1 in hermaphrodites (Ercan et al. 2007; McDonel et al. 2006). Tribolium beetles have progressed through the first stage of the C. elegans dosage compensation pathway, with hyper-transcription affecting the X chromosome in both sexes, resulting in balanced X:A ratios in males and elevated X:A in females (Prince et al. 2010). However, the female-specific countering mechanism is not present, either because the effects of X:A > 1 in females are not sufficiently harmful, or because the hyper-transcription mechanism is nascent and a compensatory mechanism in females has not yet arisen. Where the deleterious effects of incomplete dosage in the heterogametic sex result in the upregulation of the gene in both sexes, this will benefit the hemizygous sex (which experiences compensation), but be detrimental to the homogametic sex (which experiences over-compensation). However, assuming the effects are mild in both sexes, because the allele is on a sex chromosome, it will spread in the population even if the harm suffered by the homogametic sex outweighs the gain to the heterogametic one (Rice 1996; Connallon and Clark 2010), as reduced gene dose would act in the same manner as a recessive sexually antagonistic allele. This will proceed until the average transcription from Zand X- linked loci is greater than that from autosomal genes in both sexes. At this point, the heterogametic sex is dosage compensated, but the homogametic sex experiences hyper-transcription of the majority of genes on the sex chromosomes (Charlesworth 1978). Over time, sex-specific regulatory mutations in the homogametic sex would develop to counter this hyper-transcription, and X:A or Z:A balance will be restored in both sexes. This scenario is subtly different than the traditional concept of intralocus sexual antagonism, which extended to gene regulation, results in greater differences between female and male expression (Lande 1980; Rice 1984). In the case of dosage compensation, sexually antagonistic selection ultimately results in similar gene expression levels in both sexes for sex-linked genes, however the rate of transcription is different, as females and males have different copy numbers. Even though it may have little to do with dosage compensation, it is possible mammalian XCI can be reinterpreted in light of sexual conflict as well. If the marsupial model of paternal XCI is the ancestral form, which seems likely as placental mammals recapitulate paternal XCI early in development before progressing to random XCI and the paternal X remains inactivated in extraembryonic tissues (reviewed in Payer and Lee 2008), then XCI is simply a form of genomic imprinting (Iwasa and Pomiankowski 2001). Imprinting can represent the resolution of sexual conflict (Day and Bonduriansky 2004), and as the conflict between the mother and father over fetal growth rates for internally gestating animals would be particularly fierce, it is possible that XCI PERSPECTIVE is simply genomic imprinting on a vast scale, with the epigenetic regulation affecting the entire chromosome rather than the more traditional model of single-gene imprinting (Haig 2006; Engelstadter and Haig 2008). What Do We Expect If Sex-Specific Sex Chromosome Regulation Is A Product Of Sexual Conflict? Dosage compensation has been assumed to be a prerequisite for sex chromosome evolution, and in some organisms, selection for equalizing X:A ratios in males has clearly resulted in the evolution of dosage compensating mechanisms. However, the data in birds, sticklebacks and Tribolium beetles unequivocally show that sex chromosomes need not always be dosage compensated in both sexes, and that when dosage is critical for any single sex-linked gene, chromosome-wide regulatory mechanisms are not always the result (see Table 1). This means that we must reinterpret sexspecific gene regulation of sex chromosomes, and incorporate models of sexual conflict into the reanalysis. Doing so results in several predictions: (1) Random X-inactivation in eutherian females, and paternal X-inactivation in marsupials, is possibly not a mechanism to achieve dosage compensation. Some reports indicate that transcription of X-linked genes is less than that from autosomes in both sexes, and therefore X-inactivation actually takes females further away from X:A balance and does nothing to restore it in males (Gupta et al. 2006), although not all studies support this (Nguyen and Disteche 2006; Lin et al. 2007). Other theoretical explanations for X-inactivation have been presented (Iwasa and Pomiankowski 2001; Haig 2006; Engelstadter and Haig 2008), stemming from the parental conflict over foetal growth rates in taxa with internal gestation, suggesting that XCI, although potentially not related to dosage compensation, may be the product of sexual conflict. (2) Dosage compensation of sex chromosomes is less likely in organisms that can tolerate aneuploidy and polyploidy, as there will be few phenotypic consequences in either sex of incomplete gene dose. This predicts that dosage compensation will be rare in fish and plants, both of which tolerate variation in ploidy, but does not explain the lack of compensation in birds that suffer embryonic lethality from variations in chromosome copy number (Forstmeier and Ellegren 2010). (3) Uncompensated phenotypes cannot be strongly deleterious or sex chromosomes would simply not diverge, therefore selection for dosage compensation is relatively weak and sexlimited. This may suggest that the evolution of dosage compensation is a relatively slow process, although expression data from the Drosophila neo-X chromosome indicate that existing dosage compensating machineries can quickly engulf new additions to the X chromosome (Bachtrog 2005; Steinemann and Steinemann 2007). (4) Selection for dosage compensation results in equalized expression levels for females and males for genes residing on the sex chromosomes. This means that traditional theories predicting the sex chromosomes to foster the evolution of sexual dimorphism (Lande 1980; Rice 1984) via gene expression differences between the sexes may not be directly applicable to systems with complete sex chromosome dosage compensation. (5) Unequal gene expression can resolve sexual conflict involving sexually antagonistic alleles (but see Harano et al. 2010). Hence the lack of dosage compensation of many genes or even whole sex chromosomes in many animals may represent one resolution to sexual conflict. In these cases, we expect the genes involved to bear the hallmark of sexually antagonistic alleles (i.e., male-benefit female-detriment alleles or vice versa). This may suggest an overall association between sexually antagonistic variation and the incidence of dosage compensation. (6) The most informative taxa to test ideas about the adaptive nature of dosage compensation are clearly those that have recently acquired new sex chromosomes (e.g., some fish and insects), which appear to be frequent targets of sexually antagonistic selection. It has recently been proposed that sexually antagonistic selection can directly favor the establishment of new sex chromosomes by acting on loci that become linked to the new sexdetermination genes (van Doorn and Kirkpatrick 2010). Alternatively, sexually antagonistic alleles accumulated only once the establishment of the new sex chromosomes had occurred (Rice 1987a). However, it s not clear to what extent local versus complete chromosome gene dosage may either aid or perturb evolution of sexual dimorphism in gene expression in response to sex-specific selection stemming from sexual conflict. This review is intended to dispel current dogma about dosage compensation and to additionally clarify some misconceptions about precisely what dosage compensation is. By showing that dosage compensation is not as imperative as current tenets suggest, we can now move beyond this blinkered position and turn our attention to new research questions, including why complicated chromosome-wide dosage compensation mechanisms evolved in some taxa whereas in other taxa gene dosage is regulated on a more local scale, and what precise role sexually antagonistic selection has in the evolution of dosage compensation. Furthermore, one or two potentially thorny issues remain to be resolved. Arguably the most pressing of these is a transcription/translation issue, because although lack of dosage compensation has been documented at the translation level for a handful of genes, typically allozymes (e.g., Johnson and Turner 1979), for the most part the patterns described above are transcriptional. Although it is fully expected that genome-wide translational patterns will EVOLUTION 2011 9 PERSPECTIVE resemble those seen in transcription, this remains to be established, and as such it remains possible that the review to follow this one will be able to reinstate the orthodoxy of dosage compensation. We look forward to reading about it. ACKNOWLEDGMENTS We thank A. Agrawal, M. Kirkpatrick, D. Punzalan, J. Walters, and A. Wright for discussion and helpful comments on previous drafts of this manuscript. The authors gratefully acknowledge support by NERC (DJH, NW), BBSRC (JEM), and the ERC under the European Community’s 7th Framework Programme (grant agreement no 260233 to JEM) LITERATURE CITED Albert, A. Y. K., and S. P. Otto. 2005. Sexual selection can resolve sex-linked sexual antagonism. Science 310:119–121. Arunkumar, K. P., K. Mita, and J. Nagaraju. 2009. The silkworm Z chromosome is enriched in testis-specific genes. Genetics 182:493–501. Auger, D. L., A. D. Gray, T. S. Ream, A. 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