The mouse X chromosome is enriched for sex-biased genes not subject to selection by meiotic sex chromosome inactivation

Abstract

Sex chromosomes are subject to sex-specific selective evolutionary forces 1,2 . One model predicts that genes with sexbiased expression should be enriched on the X chromosome 2-5 . In agreement with Rice's hypothesis 3 , spermatogonial genes are over-represented on the X chromosome of mice 6 and sex-and reproduction-related genes are over-represented on the human X chromosome 7,8 . Male-biased genes are under-represented on the X chromosome in worms and flies 9-11 , however. Here we show that mouse spermatogenesis genes are relatively underrepresented on the X chromosome and female-biased genes are enriched on it. We used Spo11 -/-mice blocked in spermatogenesis early in meiosis 12 to evaluate the temporal pattern of gene expression in sperm development. Genes expressed before the Spo11 block are enriched on the X chromosome, whereas those expressed later in spermatogenesis are depleted. Inactivation of the X chromosome in male meiosis may be a universal driving force for X-chromosome demasculinization.To investigate the genomic distribution of mouse genes with patterns of sex-biased expression, we analyzed the chromosomal distribution of genes expressed in sexually dimorphic tissues. We consider genes that are preferentially expressed in such tissues as testis, ovary and placenta to be sex-biased genes. We used two approaches to define the tissue specificity of genes expressed in mice: analysis of large-scale microarray-based gene expression data and analysis of the distribution of expressed-sequence tags (ESTs) in different cDNA libraries. Instead of focusing on transcripts restricted to a single tissue, our analysis targeted the identification of tissue-enriched transcripts using a 'preferential expression measure' (PEM) 13 . As an uniform source of expression data, we used publicly available data sets of mouse RNA samples representing 49 tissues hybridized to Affymetrix mouse U74A microarrays (GNF data set) 14 and 20 tissues analyzed with RIKEN cDNA microarrays (RIKEN data set) 15 .In the GNF data set 14 , expression of 624 genes (∼7% of all analyzed) in testis was three times greater than the median expression in other tissues, and expression of 361 genes in testis was five times greater (PEM values >1.58 and >2.32, respectively). These genes are considered testis-enriched genes. The chromosomal distribution of testisenriched genes was significantly different from uniform (χ 2 = 30.8, P = 0.05; Fig. 1a and Supplementary Table 1 online). The most significant deviation from the average gene density was on the X chromosome, where testis-enriched genes were 2.5 times less dense (the ratio of the density of testis-enriched genes on the X chromosome to the average density on all chromosomes, ρ X , was 0.40; χ 2 = 7.7, P = 0.006). The depletion of testis-enriched genes on the X chromosome was independent of the cut-off (three or five times greater expression) used in the selection process (Table 1). In addition, genes that were expressed most highly in testis and all the genes detected in testis were underrepresen...

Demasculinization of X chromosomes in the Drosophila genus

“…Our data strongly support the idea that the X chromosome has an unusual distribution of genes with male-biased expression 4,5,[16][17][18] . Although there is compelling evidence that precocious X chromosome inactivation occurs in at least some species, and that this may contribute to the reduced density of genes with male-biased expression on X chromosomes 4,5 , our data indicate that this is not a major contributor to the pattern in the Drosophila genus.…”

“…We observe the same under-representation on the neo-X of D. pseudoobscura. It has been suggested that precocious meiotic silencing of the X chromosome accounts for reduced X chromosome male-biased expression in nematodes 4 , mammals 5 and Drosophila 6 . We show that X chromosome genes with male-biased expression are under-represented in somatic cells and in mitotic male germ cells.…”

No amicable divorce? Challenging the notion that sexual antagonism drives sex chromosome evolution

“…Profiles of genome expression indicate enrichment of female-limited genes on the X chromosome of D. melanogaster [66], Drosophila simulans [67] and the mouse [68] and of malelimited genes on the Z chromosome of the chicken [65]. However, genes with male-biased expression are underrepresented on the X chromosomes of Drosophila and Caenorhabditis elegans [66,67,69] and on the Z chromosome of the chicken [65].…”

The role of spermatogonially expressed germ cell-specific genes in mammalian meiosis

“…When 36 germ cell-specific genes were identified from mouse spermatogonia in a systematic genomic screen (Table 1), nearly one-third of these genes were X-linked, demonstrating that early spermatogenesis genes are enriched on the X chromosome in mouse (Wang et al 2001). [Such enrichment is also substantiated by genomic studies of the mouse Spo11 mutant and human germ cell-restricted genes (Khil et al 2004, Koslowski et al 2006]. To date, 13 out of these 36 genes (Sycp1,Sycp2,Sycp3,Sall4,Figla,Stra8,Tex14,Ddx4,Rnf17,Piwil2,Dazl,Tdrd1, and Taf 7l) have been characterized by targeted inactivation in mice (Table 1).…”

“…Topoisomerase SPO11 is required for homologous recombination and its loss causes meiotic arrest prior to the pachytene stage in mouse (Baudat et al 2000, Romanienko & CameriniOtero 2000. Expression profiling of Spo11-deficient testes showed that genes expressed before the Spo11 block are enriched on the X chromosome, whereas those expressed after the block are under-represented (Khil et al 2004). It has been hypothesized that male beneficial genes (for example, genes expressed in early spermatogenesis) tend to accumulate on the X chromosome during evolution because of its hemizygosity in males (Rice 1984).…”