Strong male-driven evolution of DNA sequences in humans and apes

Studies of human genetic diseases have suggested a higher mutation rate in males than in females1 and the male-to-female ratio (α) of mutation rate has been estimated from DNA sequence and microsatellite data to be about 4–6 in higher primates2,3,4,5. Two recent studies, however, claim that α is only about 2 in humans6,7. This is even smaller than the estimates (α > 4) for carnivores and birds8,9; humans should have a higher α than carnivores and birds because of a longer generation time and a larger sex difference in the number of germ cell cycles. To resolve this issue, we sequenced a noncoding fragment on Y of about 10.4 kilobases (kb) and a homologous region on chromosome 3 in humans, greater apes, and lesser apes. Here we show that our estimate of α from the internal branches of the phylogeny is 5.25 (95% confidence interval (CI) 2.44 to ∞), similar to the previous estimates2,3,4,5, but significantly higher than the two recent ones6,7. In contrast, for the external (short, species-specific) branches, α is only 2.23 (95% CI: 1.47–3.84). We suggest that closely related species are not suitable for estimating α, because of ancient polymorphism and other factors. Moreover, we provide an explanation for the small estimate of α in a previous study12. Our study reinstates a high α in hominoids and supports the view that DNA replication errors are the primary source of germline mutation.