A re-evaluation of Muller’s sheltering hypothesis for the evolution of sex chromosome gene content

The first influential hypothesis for sex chromosome evolution was proposed in 1914 by H. J. Muller, who argued that once recombination was suppressed between the X and Y chromosomes, Y-linked genes become “sheltered” from selection, leading to accumulation of recessive loss-of-function (LOF) mutations and decay of Y-linked genes. The hypothesis fell out of favour in the 1970s because early mathematical models failed to support it and data on the dominance of lethal mutations were viewed as incompatible with the hypothesis. We reevaluate the main arguments against Muller’s hypothesis and find that they do not conclusively exclude a role for sheltering in sex chromosome evolution. By relaxing restrictive assumptions of earlier models, we show that sheltering promotes fixation of LOF mutations with sexually dimorphic fitness effects, resulting in decay of X-linked genes that are exclusively expressed by males and Y-linked genes that are primarily, though not necessarily exclusively, expressed by females. We further show that drift and other processes contributing to Y degeneration (i.e., selective interference and regulatory evolution) expand conditions of Y-linked gene loss by sheltering. The actual contribution of sheltering to sex chromosome evolution hinges upon the distribution of dominance and sex-specific fitness effects of LOF mutations, which we discuss.