The ‘faulty male’ hypothesis for sex-biased mutation and disease

Biological differences between males and females lead to many differences in physiology, disease, and overall health. One of the most prominent disparities is in the number of germline mutations passed to offspring: human males transmit three times as many mutations as do females. While the classic explanation for this pattern invokes differences in post-puberty germline replication between the sexes, recent whole-genome evidence in humans and other mammals has cast doubt on this mechanism. Here, we review recent work that is inconsistent with a replication-driven model of male-biased mutation, and propose an alternative, 'faulty male' hypothesis. This model proposes that males are less able to repair and/or protect DNA from damage compared to females. Importantly, we suggest that this new model for male-biased mutation may also help to explain several pronounced differences between the sexes in cancer, aging, and DNA repair. Although the detailed contributions of genetic, epigenetic, and hormonal influences of biological sex on mutation remain to be fully understood, a reconsideration of the mechanisms underlying these differences will lead to a deeper understanding of evolution and disease.