biostudies-literatureYuan RNIGMS NIH HHSevaf207https://www.ebi.ac.uk/biostudies/studies/S-EPMC12629233biostudies-literatureUnknown17(11)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 hGenome biology and evolutionTesting the Mother's Curse Hypothesis in Human Mitochondrial Genome Evolution.PMC12629233R35 GM139484Zhang JYuan RfalseTesting 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 h2025-01-01T00:00:00Z2025 Oct2026-06-06T06:40:47.536Z2026-06-06T03:07:04.531ZS-EPMC126292334120601310.1093/gbe/evaf207