Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 19, Pages 9491-9500Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1901259116
Keywords
germline mutation; male mutation bias; DNA replication; DNA damage and repair; maternal age effect
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Funding
- Burroughs Wellcome Fund Career Award at the Scientific Interface
- NIH [R01GM122975, R01GM059290, R01GM104390, R35GM118335, T32GM007464, U01HG009431, R01HG008140]
- NIH National Human Genome Research Institute [R01HG006693, R01HG009141]
- National Institute of General Medical Sciences [R01GM124355]
- National Cancer Institute [U24CA209999]
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The textbook view that most germline mutations in mammals arise from replication errors is indirectly supported by the fact that there are both more mutations and more cell divisions in the male than in the female germline. When analyzing large de novo mutation datasets in humans, we find multiple lines of evidence that call that view into question. Notably, despite the drastic increase in the ratio of male to female germ cell divisions after the onset of spermatogenesis, even young fathers contribute three times more mutations than young mothers, and this ratio barely increases with parental age. This surprising finding points to a substantial contribution of damage-induced mutations. Indeed, C-to-G transversions and CpG transitions, which together constitute over one-fourth of all base substitution mutations, show genomic distributions and sex-specific age dependencies indicative of double-strand break repair and methylation-associated damage, respectively. Moreover, we find evidence that maternal age at conception influences the mutation rate both because of the accumulation of damage in oocytes and potentially through an influence on the number of postzygotic mutations in the embryo. These findings reveal underappreciated roles of DNA damage and maternal age in the genesis of human germline mutations.
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