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

Sex chromosomes are subject to sex-specific selective evolutionary forces1,2. One model predicts that genes with sex-biased expression should be enriched on the X chromosome2,3,4,5. In agreement with Rice's hypothesis3, spermatogonial genes are over-represented on the X chromosome of mice6 and sex- and reproduction-related genes are over-represented on the human X chromosome7,8. Male-biased genes are under-represented on the X chromosome in worms and flies9,10,11, however. Here we show that mouse spermatogenesis genes are relatively under-represented on the X chromosome and female-biased genes are enriched on it. We used Spo11−/− mice blocked in spermatogenesis early in meiosis12 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.