Overlooked roles of DNA damage and maternal age in generating human germline mutations

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 l...

Full description

Saved in:
Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 116; no. 19; pp. 9491 - 9500
Main Authors Gao, Ziyue, Moorjani, Priya, Sasani, Thomas A., Pedersen, Brent S., Quinlan, Aaron R., Jorde, Lynn B., Amster, Guy, Przeworski, Molly
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 07.05.2019
SeriesPNAS Plus
Subjects
Adolescent
Adult
Age
Biological Sciences
CpG islands
Damage accumulation
Databases, Nucleic Acid
Deoxyribonucleic acid
DNA
DNA Breaks, Double-Stranded
DNA damage
DNA Repair
Double-strand break repair
Embryos
Female
Germ-Line Mutation
Humans
Male
Maternal Age
Methylation
Middle Aged
Mutation
Mutation rates
Oocytes
PNAS Plus
Pregnancy
Spermatogenesis
Spermatogenesis - genetics
male mutation bias
DNA replication
DNA damage and repair
germline mutation
maternal age effect
Online AccessGet full text

Cover

More Information
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Edited by James A. Birchler, University of Missouri, Columbia, MO, and approved April 2, 2019 (received for review January 23, 2019)
Author contributions: Z.G., P.M., G.A., and M.P. designed research; Z.G., P.M., T.A.S., B.S.P., A.R.Q., L.B.J., G.A., and M.P. performed research; Z.G., P.M., T.A.S., B.S.P., G.A., and M.P. analyzed data; A.R.Q. and L.B.J. revised the paper; and Z.G., P.M., G.A., and M.P. wrote the paper.
2G.A. and M.P. contributed equally to this work.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1901259116