Evolutionary divergence between homologous X-Y chromosome genes shapes sex-biased biology

Sex chromosomes are a fundamental aspect of sex-biased biology, but the extent to which homologous X–Y gene pairs (“the gametologs”) contribute to sex-biased phenotypes remains hotly-debated. Although these genes exhibit large sex differences in expression throughout the body (XX females express both X members; XY males express one X and one Y member), there is conflicting evidence regarding the degree of functional divergence between the X and Y gametologs. Here, we use co-expression fingerprint (CF) analysis to characterize functional divergence between the X and Y members of 17 gametolog gene pairs across >40 human tissues. Gametologs exhibit functional divergence between the sexes that is driven by divergence between the X vs. Y gametologs (assayed in males) and is greatest among evolutionary distant gametolog pairs. These patterns reflect that X vs. Y gametologs show coordinated patterns of asymmetric coupling with large sets of autosomal genes, which are enriched for functional pathways and gene sets implicated in sex-biased biology and disease. These findings suggest that the X and Y gametologs have diverged in function, and prioritize specific gametolog pairs for future targeted experimental studies.