Gene survival and death on the human Y chromosome

Abstract

Y chromosomes have long been dismissed as "graveyards of genes," but there is still much to be learned from the genetic relics of genes that were once functional on the human Y. We identified human X-linked genes whose gametologs have been pseudogenized or completely lost from the Y chromosome and inferred which evolutionary forces may be acting to retain genes on the Y. Although gene loss appears to be largely correlated with the suppression of recombination, we observe that X-linked genes with functional Y homologs evolve under stronger purifying selection and are expressed at higher levels than X-linked genes with nonfunctional Y homologs. Additionally, we support and expand upon the hypothesis that X inactivation is primarily driven by gene loss on the Y. Using linear discriminant analysis, we show that X-inactivation status can successfully classify 90% of X-linked genes into those with functional or nonfunctional Y homologs.

Fig. 1.

Pairwise synonymous substitution rate across chromosome X. The pairwise X_gene–Y_gene and X_gene–Y_pseudogene synonymous substitution rates (dS) are plotted across the entire X chromosome in 10 Mb sliding windows, sliding by 1 Mb. We observe a trend from smaller dS values to larger dS values as we move from the short arm of the X chromosome (where the newest strata are located) to the end of the long arm (where the oldest strata are located) but do not identify strict boundaries using this method. For reference, the dS of X-linked genes with functional Y homologs (excluding the XTR) are plotted separately in red.

Fig. 2.

Schematic of ancestral versus derived dosage of sex-linked genes. Ancestrally, it is expected that all genes were expressed in two copies in females (from both X chromosomes) and in two copies in males (from the ancestral X and Y chromosomes). The derived condition, resulting from loss of gene content and expression in males on the Y chromosome, is expression of many sex-linked genes in a single copy in males, and so inactivation evolved to silence one copy of the gene in females (on the inactive X chromosome, X_I) and resulted in expression of only one copy of the sex-linked gene in females (from the active X chromosome, X_A). Filled rectangles represent expressed genes, whereas empty white rectangles represent silenced (inactivated) genes.

Fig. 3.

Average proportion of cell lines (out of nine assayed in [Carrel and Willard 2005]) for which an X-linked gene escapes inactivation. Boxplots representing the number of cell lines for which a gene escapes X-chromosome inactivation are shown for the sets X-linked genes with functional, pseudogenized, or absent (lost) Y-linked gametologs. P values testing for significant differences between each pairwise class of X-linked genes (with functional, pseudogenized, and lost Y gametologs) from permutation tests with 10,000 replicates are labeled at the top of the figures for the entire X (whole X), the XAR, and the XCR. P values that are significant after correction for multiple testing are shown in bold, and the number of genes assayed in each set is shown below each boxplot. The mean and median number of cell lines for which a gene escapes X-chromosome inactivation are reported in supplementary table S5, Supplementary Material online.