Strong purifying selection at genes escaping X chromosome inactivation

Abstract

To achieve dosage balance of X-linked genes between mammalian males and females, one female X chromosome becomes inactivated. However, approximately 15% of genes on this inactivated chromosome escape X chromosome inactivation (XCI). Here, using a chromosome-wide analysis of primate X-linked orthologs, we test a hypothesis that such genes evolve under a unique selective pressure. We find that escape genes are subject to stronger purifying selection than inactivated genes and that positive selection does not significantly affect the evolution of these genes. The strength of selection does not differ between escape genes with similar versus different expression levels in males versus females. Intriguingly, escape genes possessing Y homologs evolve under the strongest purifying selection. We also found evidence of stronger conservation in gene expression levels in escape than inactivated genes. We hypothesize that divergence in function and expression between X and Y gametologs is driving such strong purifying selection for escape genes.

FIG. 1.

A comparison of K_A/K_S ratios among escape, heterogeneous, and inactivated human–chimpanzee–macaque orthologous genes. (A) All orthologs. (B) Orthologs located in the X-added region (XAR). (C) Orthologs located in the XCR. (D) All orthologs excluding genes with positively selected codons. (E) Orthologs located in XAR excluding genes with positively selected codons. (F) Orthologs located in XCR excluding genes with positively selected codons. The number of genes considered is given below each plot. In the box plots, edges and vertical dashed lines represent quartiles and range, respectively. Notches indicate standard deviations of the median. Outliers are not shown.

FIG. 2.

A comparison of K_A/K_S ratios among escape genes with Y homologs, escape genes without Y homologs, heterogeneous genes, and inactivated genes (as computed for the human–chimpanzee–macaque orthologous trios). The number of genes considered is listed below each plot.