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Disproportionate Roles for the X Chromosome and Proteins in Adaptive Evolution

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Disproportionate Roles for the X Chromosome and Proteins in Adaptive Evolution COMMENTARY HIGHLIGHTED ARTICLE Disproportionate Roles for the X Chromosome and Proteins in Adaptive Evolution Bret A. Payseur Laboratory of Genetics, University of Wisconsin, Madison, Wisconsin 53706 daptation requires genetic variation. A complete under- the X chromosome (Avery 1984), elevating the rate of evolu- Astanding of this key evolutionary process includes identifica- tion relative to autosomal loci. In an influential theoretical tion of the mutations that confer adaptive change. High-resolution article, Charlesworth et al. (1987) quantified this connection genetic dissection of particular adaptive phenotypes can pinpoint between dominance and “faster X” evolution and identified these mutations, but this is a challenging task and the resulting the biological conditions under which it applies. With several conclusions are restricted to the traits under consideration. assumptions, the relative rates of molecular evolution at An alternative approach is to examine characteristics of X-linked and autosomal loci can even be used to estimate adaptive mutations through the powerful lens of population the average dominance of new advantageous mutations, an genetics. By measuring intraspecific polymorphism and in- important quantity in evolutionary biology. terspecific divergence across genomes, evolutionary properties The study of faster X evolution is also motivated by a desire of those mutations targeted by natural selection can be to explain the outsized role of the X chromosome in speciation. discovered. Under this framework as well, generalities are In a wide variety of species pairs, the sterility and/or inviability widely sought and difficult to identify. A useful way to make of hybrids created by interspecific crosses maps differentially to progress is to compare patterns of adaptive evolution among the X chromosome (Coyne and Orr 2004). This bias seems to different categories of loci. Two contrasts are based on the ge- reflect a higher density of hybrid incompatibilities involving the nomic location of mutations: X linked vs. autosomal and pro- X chromosome (Masly and Presgraves 2007). tein coding vs. cis-regulatory (i.e., noncoding sequences that The prediction of faster X evolution has been tested re- affect local gene expression). These contrasts have generated peatedly by comparing between-species divergence at X-linked substantial interest because they are tied directly to basic ques- and autosomal genes (Meisel and Connallon 2013). The tions about adaptive evolution. most popular approach calculates the relative rate of sub- The fate of a beneficial mutation should depend on its stitution at nonsynonymous and synonymous sites, reason- mode of inheritance. This idea motivates comparisons ing that nonsynonymous changes will often be targeted by between rates of adaptive evolution on the X chromosome selection. A flurry of studies featuring Drosophila revealed and the autosomes. Recent, low-frequency recessive muta- a range of support for faster X evolution (Betancourt et al. tions are immediately exposed to selection in males when 2002; Thornton and Long 2002; Counterman et al. 2004; X-linked and are mostly hidden from selection (in hetero- Musters et al. 2006; Thornton et al. 2006; Begun et al. 2007; zygotes) when autosomal. If beneficial mutations are at Presgraves 2008; Singh et al. 2008; Vicoso et al. 2008; Grath least partially recessive on average, they will fixfasteron and Parsch 2012; Zhou and Bachtrog 2012). A recent compa- rison between high-quality genomes sequences of Drosophila simulans and D. melanogaster found faster X evolution at Copyright © 2014 by the Genetics Society of America nonsynonymous sites, UTRs, and long introns (Hu et al. doi: 10.1534/genetics.113.160648 2013). This pattern is expected if beneficial substitutions Manuscript received January 28, 2014; accepted for publication February 2, 2014 Address for correspondence: Genetics/Biotechnology 2428, 425-G Henry Mall, are recessive on average, though the authors suggest it is University of Wisconsin, Madison, WI 53706. E-mail: [email protected] more likely due to differences in gene content between the X Genetics, Vol. 196, 931–935 April 2014 931 chromosome and the autosomes. Human–chimpanzee house mice, and Mus famulus, are combined with the existing divergence (Lu and Wu 2005; Nielsen et al. 2005; Chimpanzee rat genome sequence to describe patterns of polymorphism Sequencing and Analysis Consortium 2005; Hvilsom et al. and divergence genome-wide. In this issue of Genetics, 2012), human–mouse divergence (Torgerson and Singh Kousathanas et al. translate these patterns into conclusions 2003), and mouse–rat divergence (Baines and Harr about faster X evolution, whereas Halligan et al. (2013) use 2007) support faster X, mostly for genes biased toward them to examine the relative roles of protein-coding and cis- male expression. The bird Z chromosome (the analog of regulatory variation in adaptation. the X) also shows elevated rates of protein evolution Kousathanas et al. (2014) analyze variation at 700 (Borge et al. 2005; Mank et al. 2007; Ellegren 2009) but X-linked genes and 18,110 autosomal genes. The authors com- this elevation might not be caused by selection (Mank bine two approaches to measure adaptive evolution (Eyre- et al. 2010). Walker and Keightley 2009). First, they analyze the site The divergence-based tests described above cannot frequency spectrum, fitting a demographic model to synony- discriminate between adaptive,neutral,anddeleterious mous variants (which are presumed neutral) and a selection substitutions. But the faster X prediction is strongest for model to nonsynonymous variants (Keightley and Eyre- adaptive substitutions (mildly deleterious mutations can Walker 2007). The resulting distribution of fitness effects is also fix faster due to the smaller effective population size used to calculate the average fixation probability of deleteri- of the X chromosome). All substitutions pass through a ous and neutral nonsynonymous mutations relative to neutral polymorphic stage, and combining divergence with intra- synonymous changes. Second, the authors count the numbers specific polymorphism generates a much richer portrait of of divergent nonsynonymous and synonymous sites between selection. The fraction of substitutions fixed by positive M. musculus castaneus and the outgroup species. They com- selection can be estimated by comparing polymorphism and bine divergence counts with fixation probabilities to estimate divergence at nonsynonymous and synonymous sites, allow- the proportion of substitutions that are adaptive (a; Fay ing an improved test of faster X. This approach has so far et al. 2001) and the relative rate of adaptive substitution yielded strong evidence for faster X in Drosophila (Langley (w; Gossmann et al. 2010). This mode of inference accounts et al. 2012; Mackay et al. 2012; Campos et al. 2014) and for effects of mildly deleterious mutations and demography. chimpanzees (Hvilsom et al. 2012) with mixed results for Kousathanas et al. (2014) categorize genes as male-specific rabbits (Carneiro et al. 2012). (expressed only in testis or prostate), female-specific (expressed Another salient question about the genetics of adaptation only in ovary or uterus), or non-sex-specific,basedonpublished concerns the location of causative mutations within genes: Do expression datasets for mice. they primarily fall in protein-coding regions or cis-regulatory X-linked genes exhibit higher values of a and w than elements? If cis-regulatory mutations more easily allow autosomal genes, providing clear evidence for more adap- functional fine tuning (Jacob and Monod 1961; Stern tive evolution on the X chromosome. The signal is driven by 2000; Wilkins 2002; Carroll et al. 2004) and/or are less male-specific genes—neither female-specific nor non-sex- pleiotropic than protein-coding changes (Stern 2000; specific genes differ based on whether they are X-linked or Wilkins 2002; Wray et al. 2003), the former might dispro- autosomal—as expected if exposure of recessive mutations portionately drive adaptation (Carroll 2005; Wray 2007). to selection in males is responsible (Charlesworth et al. Mutations responsible for adaptive phenotypic differences 1987). have been identified in both protein-coding and cis-regulatory Using the relative rates of adaptive evolution on the X sequences, but the issue of whether these two classes of chromosome and the autosomes, Kousanthanas et al. (2014) changes differ generally in their evolutionary properties [as estimate the average dominance of a new beneficial muta- famously proposed by King and Wilson (1975)] remains un- tion to be #0.2. The authors emphasize that the calculation resolved (Hoekstra and Coyne 2007; Wray 2007; Stern and requires many assumptions (Charlesworth et al. 1987; Con- Orgogozo 2008). nallon et al. 2012). One assumption unlikely to be met in As in the case of faster X, patterns of molecular evolution house mice is that equal numbers of males and females can help address this question. Many studies have docu- breed in nature. mented adaptive divergence in proteins; there is also good Kousathanas et al. (2014) raise another wrinkle with the evidence for adaptive evolution of putative cis-regulatory dominance explanation for faster X. Before the first meiotic sequences in Drosophila (Andolfatto 2005), humans (Torgerson division in spermatogenesis, cells are diploid: recessive X- et al. 2009), and house mice (Halligan et al. 2011; Kousathanas linked mutations are expressed but recessive autosomal et al.
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