The “faulty male” hypothesis: implications for evolution and disease

Abstract

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. Importantly, we suggest that the 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.

Re-evaluating the driving force behind mutations

“…As oocytes stop dividing in childhood once they are fully formed, this suggests that heritable mutations are caused by age-related damage, not replication errors. Despite being typically harder to observe in males, heritable mutations transmitted from the paternal parent have also recently been shown to be consistent with the age-related hypothesis ( Hahn et al, 2023 ). To test the two hypotheses in plants (right panel), Satake et al calculated the number of somatic mutations per metre of growth in two evolutionary related tropical trees: a slow-growing (blue) and a fast-growing (green) species that were of similar heights but different ages.…”