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PMID: 37989088 Published · ppublish English Review Journal Article Research Support, N.I.H., Extramural

The 'faulty male' hypothesis for sex-biased mutation and disease.

Current biology : CB ·Vol. 33 ·No. 22 ·2023-00-20 ·Pages R1166-R1172

Hahn MW, Peña-Garcia Y, Wang RJ

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. 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.

MeSH Terms
Female Animals Male Humans Mutation Genome Germ Cells Mammals/genetics Aging
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Hahn Matthew W
Department of Biology, Indiana University, 1001 E. 3(rd) Street, Bloomington, IN 47405, USA; Department of Computer Science, 700 N. Woodlawn Avenue, Bloomington, IN 47405, USA. Electronic address: [email protected].
Peña-Garcia Yadira
Department of Biology, Indiana University, 1001 E. 3(rd) Street, Bloomington, IN 47405, USA.
Wang Richard J
Department of Biology, Indiana University, 1001 E. 3(rd) Street, Bloomington, IN 47405, USA; Department of Computer Science, 700 N. Woodlawn Avenue, Bloomington, IN 47405, USA.
Conflict of Interest

Declaration of interests The authors declare no competing interests.

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Article Info
Journal
Current biology : CB
Abbr.
Curr Biol
ISSN
1879-0445
DOI
10.1016/j.cub.2023.09.028
Email
[email protected]
Published
2023-00-20
Pages
R1166-R1172
Language
English
Region
England
NLM ID
9107782
PMCID
PMC11795531
Subset
IM
Grants
NICHD NIH HHS · R01 HD107120 · United States
External Links
PubMed source DOI: 10.1016/j.cub.2023.09.028 PMC Full Text View journal details
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