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

ABSTRACT: 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.

SUBMITTER: Gao Z

PROVIDER: S-EPMC6511033 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Gao Ziyue Z Moorjani Priya P Sasani Thomas A TA Pedersen Brent S BS Quinlan Aaron R AR Jorde Lynn B LB Amster Guy G Przeworski Molly M

Proceedings of the National Academy of Sciences of the United States of America 20190424 19

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 cont ...[more]

PMID: 31019089

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Project description:Genomic imprinting is an epigenetic marking process that results in the monoallelic expression of a subset of genes. Many of these 'imprinted' genes in mice and humans are involved in embryonic and extraembryonic growth and development, and some have life-long impacts on metabolism. During mammalian development, the genome undergoes waves of (re)programming of DNA methylation and other epigenetic marks. Disturbances in these events can cause imprinting disorders and compromise development. Multi-locus imprinting disturbance (MLID) is a condition by which imprinting defects touch more than one locus. Although most cases with MLID present with clinical features characteristic of one imprinting disorder. Imprinting defects also occur in 'molar' pregnancies-which are characterized by highly compromised embryonic development-and in other forms of reproductive compromise presenting clinically as infertility or early pregnancy loss. Pathogenic variants in some of the genes encoding proteins of the subcortical maternal complex (SCMC), a multi-protein complex in the mammalian oocyte, are responsible for a rare subgroup of moles, biparental complete hydatidiform mole (BiCHM), and other adverse reproductive outcomes which have been associated with altered imprinting status of the oocyte, embryo and/or placenta. The finding that defects in a cytoplasmic protein complex could have severe impacts on genomic methylation at critical times in gamete or early embryo development has wider implications beyond these relatively rare disorders. It signifies a potential for adverse maternal physiology, nutrition, or assisted reproduction to cause epigenetic defects at imprinted or other genes. Here, we review key milestones in DNA methylation patterning in the female germline and the embryo focusing on humans. We provide an overview of recent findings regarding DNA methylation deficits causing BiCHM, MLID, and early embryonic arrest. We also summarize identified SCMC mutations with regard to early embryonic arrest, BiCHM, and MLID.

Dataset Information

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

Publications

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

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