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Selection shapes genome evolution at the DNA sequence level, mainly manifested in changes in the primary structure of genes and other functional elements. A long-standing question in evolutionary biology is whether the organization of genes, their location in different regions of the genome, is also subject to selection (Hurst et al. 2004). A candidate case would be the genomic organization of sexually antagonistic genes, i.e., genes beneficial to one sex but either detrimental or neutral to the other (Rice 1992; Rice and Chippindale 2001; van Doorn 2009). Theoretical arguments imply that such genes are only expected to occur if the benefits accrued to one sex outweigh the disadvantages imposed to the other. However, there is an important exception to this prediction that relates to the special mode of inheritance and organization of sex chromosomes, and to cost-benefit scenarios associated with sex-linkage. For example, as far as partially or fully dominant mutations are considered, theory predicts that it should be easier for an antagonistic gene favorable to one sex to evolve on a sex chromosome that is more often present in that sex than in the other, since net selection will then be positive (Rice 1984; Charlesworth et al. 1987). This leads to the expectation that female-beneficial genes should be over-represented, and male-beneficial genes under-represented, on the X-chromosome in male-heterogametic organisms. In practice, it is difficult on a large scale to determine whether genes are or have been sexually antagonistic. Several investigators have therefore used sex-biased gene expression as a proxy for sexual antagonism (see Ellegren and Parsch 2007); sex-biased gene expression may potentially represent the resolution of past sexual antagonism (e.g., Mank and Ellegren 2009). This line of thinking has been integrated with several observations of a non-random genomic distribution of genes with sex-biased expression. In Drosophila, male-biased genes are under-represented on the X (Parisi et al. 2003; Sturgill et al. 2007; Vicoso and Charlesworth 2009). If this is translated into an under-representation of male-beneficial genes on X, it would be consistent with theory for partly or fully dominant mutations (Rice 1984). In Caenorhabditis elegans, sperm-enriched genes are nearly absent from the X-chromosome (Reinke et al. 2000). In mammals, the picture is more complex. Female-biased genes expressed in ovary and placenta are over-represented on the mouse X-chromosome (Khil et al. 2004), also as expected for dominant mutations. However, male-biased genes expressed in early stages of spermatogenesis are in excess on the mouse X as well (Khil et al. 2004), although genes expressed later during male meiosis are, in fact, under-represented on the X (Khil et al. 2004). Several alternative explanations to the non-random distribution of sex-biased genes have therefore been suggested (Rogers et al. 2003; Meisel et al. 2009), including escape from meiotic sex chromosome inactivation (MSCI) by genes needed to be expressed during spermatogenesis (Hense et al. 2007; Potrzebowski et al. 2008; Vibranovski et al. 2009a). A limitation in the abovementioned empirical studies is that they survey the overall present-day gene content of different chromosomal categories rather than specifically focusing on the characteristics of those new genes that evolved in different regions of the genome (cf. Zhang et al. 2010). However, the arguments for the probability of evolution of sexually antagonistic alleles in different chromosomal categories can also be applied to different scenarios of movement of genes between sex chromosomes and autosomes (Moyle et al. 2010). Relevant in this context are empirical data on traffic of retrogenes between autosomes and the X-chromosome in mammals and Drosophila (Betran et al. 2002; Emerson et al. 2004; Vibranovski et al. 2009b), in particular, a pattern that has been referred to as “out-of-X movement.” It has been noted that many retrotransposed gene copies moving from the X-chromosome to autosomes have acquired sex-biased gene expression and are mainly expressed in testis (Bradley et al. 2004). In the seminal study by Emerson et al. (2004), it was hypothesized that natural selection has favored the preservation of genes with male-biased function that move from the X-chromosome to autosomes: “One model of sexual antagonism (Wu and Yujun Xu 2003) predicts that gene copies that benefit males at a cost to females would be more likely found on the autosomes than on the X-chromosome.” Note again that sex-biased gene expression is taken as a proxy for sexual antagonism. A potentially interesting contrast in testing an adaptive scenario for the genomic distribution of new sex-biased genes is to study organisms with female heterogamety (males ZZ, females ZW). In this case, male-beneficial genes in which new mutations are at least partly dominant may be expected to accumulate on the Z-chromosome, rather than on autosomes, because Z is two-thirds of the time in males. With the same argument, female-beneficial genes would be expected to become less abundant on the Z-chromosome. These opposing predictions compared to systems of male heterogamety are helpful for the general argument because they allow distinguishing the expected effects of heterogamety from any other difference that pertain to autosomes and sex chromosomes. Female heterogamety is found in a diverse range of organisms. All birds are female heterogametic, and the same applies to all butterflies. A ZW sex chromosome system is also present in individual lineages of reptiles, amphibians, fishes, and crustaceans. Although draft genome sequences of a few female heterogametic bird species (chicken, Gallus gallus [International Chicken Genome Sequencing Consortium 2004]; zebra finch, Taeniopygia guttata [Warren et al. 2010]; and turkey [Dalloul et al. 2010]) and one moth (silkworm, Bombyx mori [Mita et al. 2004; Xia et al. 2004]) have been reported, the coverage of the Z-chromosome has generally not been sufficient for a comprehensive analysis of gene content. However, the recent sequencing to near completion of the chicken Z-chromosome (Bellott et al. 2010) provides a framework for a test of the emergence of new genes on sex chromosomes in a female heterogametic system. The chicken Z-chromosome is 80 Mb in size and contains about 1000 genes. The female-specific W-chromosome is less well characterized, but it is considerably smaller, mostly non-recombining, and contains a limited number of paralogs (gametologs) to Z-linked genes as well as some female-specific genes (Ellegren 2000; International Chicken Genome Sequencing Consortium 2004). The avian ZW and the mammalian XY sex chromosomes evolved independently from different pairs of autosomes present in a vertebrate ancestor (Fridolfsson et al. 1998; Nanda et al. 1999; Bellott et al. 2010). They thereby offer parallel biological replicates to the study of sex chromosome evolution and the associated question of genome organization potentially driven by selectively favorable gene acquisitions.

We investigated the correlation between the chromosomal location and age distribution of new male-biased genes formed by duplications via DNA intermediates (DNA-level) or by de novo origination in Drosophila. Our genome-wide analysis revealed an excess of young X-linked male-biased genes. The proportion of X-linked male-biased genes then diminishes through time, leading to an autosomal excess of male-biased genes. The switch between X-linked and autosomal enrichment of male-biased genes was also present in the distribution of both protein-coding genes on the D. pseudoobscura neo-X chromosome and microRNA genes of D. melanogaster. These observations revealed that the evolution of male-biased genes is more complicated than the previously detected one-step X→A gene traffic and the enrichment of the male-biased genes on autosomes. The pattern we detected suggests that the interaction of various evolutionary forces such as the meiotic sex chromosome inactivation (MSCI), faster-X effect, and sexual antagonism in the male germline might have shaped the chromosomal distribution of male-biased genes on different evolutionary time scales.

Past demographic changes can produce distortions in patterns of genetic variation that can mimic the appearance of natural selection unless the demographic effects are explicitly removed. Here we fit a detailed model of human demography that incorporates divergence, migration, admixture, and changes in population size to directly sequenced data from 13,400 protein coding genes from 20 European-American and 19 African-American individuals. Based on this demographic model, we use several new and established statistical methods for identifying genes with extreme patterns of polymorphism likely to be caused by Darwinian selection, providing the first genome-wide analysis of allele frequency distributions in humans based on directly sequenced data. The tests are based on observations of excesses of high frequency–derived alleles, excesses of low frequency–derived alleles, and excesses of differences in allele frequencies between populations. We detect numerous new genes with strong evidence of selection, including a number of genes related to psychiatric and other diseases. We also show that microRNA controlled genes evolve under extremely high constraints and are more likely to undergo negative selection than other genes. Furthermore, we show that genes involved in muscle development have been subject to positive selection during recent human history. In accordance with previous studies, we find evidence for negative selection against mutations in genes associated with Mendelian disease and positive selection acting on genes associated with several complex diseases.

We report a comprehensive analysis of gene expression differences between sexes in multiple somatic tissues of 334 mice derived from an intercross between inbred mouse strains C57BL/6J and C3H/HeJ. The analysis of a large number of individuals provided the power to detect relatively small differences in expression between sexes, and the use of an intercross allowed analysis of the genetic control of sexually dimorphic gene expression. Microarray analysis of 23,574 transcripts revealed that the extent of sexual dimorphism in gene expression was much greater than previously recognized. Thus, thousands of genes showed sexual dimorphism in liver, adipose, and muscle, and hundreds of genes were sexually dimorphic in brain. These genes exhibited highly tissue-specific patterns of expression and were enriched for distinct pathways represented in the Gene Ontology database. They also showed evidence of chromosomal enrichment, not only on the sex chromosomes, but also on several autosomes. Genetic analyses provided evidence of the global regulation of subsets of the sexually dimorphic genes, as the transcript levels of a large number of these genes were controlled by several expression quantitative trait loci (eQTL) hotspots that exhibited tissue-specific control. Moreover, many tissue-specific transcription factor binding sites were found to be enriched in the sexually dimorphic genes.

X chromosomes are preferentially transmitted through females, which may favor the accumulation of X-linked alleles/genes with female-beneficial effects. Numerous studies have shown that genes with sex-biased expression are under- or over-represented on the X chromosomes of a wide variety of organisms. The patterns, however, vary between different animal species, and the causes of these differences are unresolved. Additionally, genes with sex-biased expression tend to be narrowly expressed in a limited number of tissues, and narrowly expressed genes are also non-randomly X-linked in a taxon-specific manner. It is therefore unclear whether the unique gene content of the X chromosome is the result of selection on genes with sex-biased expression, narrowly expressed genes, or some combination of the two. To address this problem, we measured sex-biased expression in multiple Drosophila species and at different developmental time points. These data were combined with available expression measurements from Drosophila melanogaster and mouse to reconcile the inconsistencies in X-chromosome content among taxa. Our results suggest that most of the differences between Drosophila and mammals are confounded by disparate data collection/analysis approaches as well as the correlation between sex bias and expression breadth. Both the Drosophila and mouse X chromosomes harbor an excess of genes with female-biased expression after controlling for the confounding factors, suggesting that the asymmetrical transmission of the X chromosome favors the accumulation of female-beneficial mutations in X-linked genes. However, some taxon-specific patterns remain, and we provide evidence that these are in part a consequence of constraints imposed by the dosage compensation mechanism in Drosophila.

Theoretical work predicts natural selection to be more efficient in the fixation of beneficial mutations in X-linked genes than in autosomal genes. This “fast-X effect” should be evident by an increased ratio of nonsynonymous to synonymous substitutions (dN/dS) for sex-linked genes; however, recent studies have produced mixed support for this expectation. To make an independent test of the idea of fast-X evolution, we focused on birds, which have female heterogamety (males ZZ, females ZW), where analogous arguments would predict a fast-Z effect. We aligned 2.8 Mb of orthologous protein-coding sequence of zebra finch and chicken from 172 Z-linked and 4848 autosomal genes. Zebra finch data were in the form of EST sequences from brain cDNA libraries, while chicken genes were from the draft genome sequence. The dN/dS ratio was significantly higher for Z-linked (0.110) than for all autosomal genes (0.085; P = 0.002), as well as for genes linked to similarly sized autosomes 1–10 (0.0948; P = 0.04). This pattern of fast-Z was evident even after we accounted for the nonrandom distribution of male-biased genes. We also examined the nature of standing variation in the chicken protein-coding regions. The ratio of nonsynonymous to synonymous polymorphism (pN/pS) did not differ significantly between genes on the Z chromosome (0.104) and on the autosomes (0.0908). In conjunction, these results suggest that evolution proceeds more quickly on the Z chromosome, where hemizygous exposure of beneficial nondominant mutations increases the rate of fixation.