Testing the Mother's Curse Hypothesis in Human Mitochondrial Genome Evolution

In species where mitochondrial DNA (mtDNA) is maternally inherited such as vertebrates, mtDNA mutations harming males only are not subject to purifying selection and thus can spread in a population, especially when these mutations benefit females. Therefore, the mother's curse hypothesis (MCH) posits a greater mtDNA mutation load in males than in females. MCH is potentially important for human health, disease, and evolution, but a systematic test that considers the vast human mtDNA variation is lacking. Analyzing the genotypic and phenotypic data of approximately 0.5 million British participants in the UK Biobank, we estimate the reproductive fitness of mtDNA variants in each sex. Contradicting MCH, a positive intersexual correlation in the number of offspring exists across mitochondrial haplogroups. While a significant variation in the number of opposite-sex sexual partners-a proxy for reproductive fitness in premodern societies-is present among mitochondrial haplogroups, no significant intersexual correlation in this quantity is detected. The frequencies of a few mtDNA variants differ significantly between males and females, suggesting that these variants differentially affect the survival in the two sexes, but the number of such variants with lower male frequencies is not significantly different from that with lower female frequencies. Analysis of disease associations also finds no enrichment of male disease-associated mtDNA variants despite the discovery of multiple sex-biased disease associations. Together, these findings provide no genomic support to MCH in humans and suggest no difference in mtDNA mutation load between the two sexes that is detectable in the UK Biobank.