Is faster-X adaptation due to large-effect mutations? An empirical test of a new theory

Abstract

A widespread observation in molecular evolution is that X-linked genes evolve faster--and often adapt faster--than autosomal genes. Three main ideas have been put forward to explain "faster-X" adaptation. The first is that new beneficial mutations are typically partially recessive with respect to fitness, leading to more efficient selection in hemizygous males. The second is that sex differences in recombination, or sex differences in variance in reproductive success, enhance the effective population size on the X chromosome relative to autosomes. Both ideas have limitations: the first conflicts with theories of dominance, in which beneficial mutations are proposed to be partially dominant, while the second only applies to some taxa. Here we tested a third, newly-proposed theory, in which mutations with large "scaled phenotypic effects" (i.e., large effects relative to the distance to a phenotypic optimum) experience more positive selection on the X. Specifically, we used three proxies for scaled phenotypic effects--amino-acid dissimilarity, sequence conservation, and gene age--and estimated X and autosomal rates of adaptation of nonsynonymous mutations across effect-size classes. We did this in three lineages with a well-documented faster-X: Drosophila melanogaster, Mus musculus, and Homo sapiens. As expected, we found that large-effect mutations were more likely to be under purifying selection and less likely to be under positive selection than small-effect mutations. However, contrary to the new theory, faster-X adaptation was not enriched among large-effect mutations. Overall, our results highlight an unresolved gap between patterns of sex chromosome evolution and theories of dominance, and the need for more direct empirical data on the dominance of new beneficial mutations. Significance statementIn many species, genes on the X chromosome undergo more adaptation than autosomal genes, but it is not clear why this pattern of "faster-X" occurs. One possibility is that recessive beneficial mutations drive the effect, but theories of dominance propose instead that beneficial mutations should be dominant. Meanwhile, alternative explanations (e.g., sex differences in recombination or sex differences in variance in reproductive success) can only apply to some taxa. Here we tested a new idea, which proposes that the effect is driven by mutations with large effects. However, data from fruit flies, humans and mice did not provide support for the new theory. Our work highlights an unresolved gap between patterns of sex chromosome evolution and theories of dominance.