Drivers of systemic male-female allele frequency divergence in humans

Allele frequency differences between males and females in genetic studies have been interpreted as suggestive of sex differences in natural selection. However, systemic differences may also arise through sex differences in study participation as well as bioinformatic artifacts. To mitigate these confounding effects, we performed a meta-analysis of sex differences in allele frequencies across three genetic studies. We identify twelve concordant genes with cross-study evidence of sex differences in allele frequency. We propose four hypotheses for how and when sex differences in allele frequencies arise and point out the plausible hypotheses for subsets of the twelve candidates. For example, beyond candidates that plausibly reflect sex differences in viability selection, we also find candidate loci potentially under X/Y-differential selection in sperm populations. Taken together, our results offer clearer delineation of the factors driving sex differences in allele frequencies, including the timing and mechanisms of natural selection.