Implications of sex‐specific selection for the genetic basis of disease

Mutation and selection are thought to shape the underlying genetic basis of many common human diseases. However, both processes depend on the context in which they occur, such as environment, genetic background, or sex. Sex has widely known effects on phenotypic expression of genotype, but an analysis of how it influences the evolutionary dynamics of disease‐causing variants has not yet been explored. We develop a simple population genetic model of disease susceptibility and evaluate it using a biologically plausible empirically based distribution of fitness effects among contributing mutations. The model predicts that alleles under sex‐differential selection, including sexually antagonistic alleles, will disproportionately contribute to genetic variation for disease predisposition, thereby generating substantial sexual dimorphism in the genetic architecture of complex (polygenic) diseases. This is because such alleles evolve into higher population frequencies for a given effect size, relative to alleles experiencing equally strong purifying selection in both sexes. Our results provide a theoretical justification for expecting a sexually dimorphic genetic basis for variation in complex traits such as disease. Moreover, they suggest that such dimorphism is interesting – not merely something to control for – because it reflects the action of natural selection in molding the evolution of common disease phenotypes.