%0 Journal Article %1 gao2019overlooked %A Gao, Ziyue %A Moorjani, Priya %A Sasani, Thomas A. %A Pedersen, Brent S. %A Quinlan, Aaron R. %A Jorde, Lynn B. %A Amster, Guy %A Przeworski, Molly %D 2019 %I National Academy of Sciences %J Proceedings of the National Academy of Sciences %K human_genome mutation_rate mutation_spectrum %N 19 %P 9491--9500 %R 10.1073/pnas.1901259116 %T Overlooked roles of DNA damage and maternal age in generating human germline mutations %U https://www.pnas.org/content/116/19/9491 %V 116 %X More than three-fourths of human germline mutations are paternal in origin and their total number increases with the father’s age at conception. These observations are thought to support the textbook view that germline point mutations stem mostly from DNA replication errors. Analyzing large germline mutation datasets for humans, we find that this understanding cannot explain the observed patterns of new mutations. Instead, we show that the male mutation bias is not driven by spermatogenesis. We further find evidence that a substantial fraction of mutations are not replicative in origin and uncover a potential effect of a mother’s age on the number of mutations that happen early in the development of the embryo.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.

@article{gao2019overlooked, abstract = {More than three-fourths of human germline mutations are paternal in origin and their total number increases with the father{\textquoteright}s age at conception. These observations are thought to support the textbook view that germline point mutations stem mostly from DNA replication errors. Analyzing large germline mutation datasets for humans, we find that this understanding cannot explain the observed patterns of new mutations. Instead, we show that the male mutation bias is not driven by spermatogenesis. We further find evidence that a substantial fraction of mutations are not replicative in origin and uncover a potential effect of a mother{\textquoteright}s age on the number of mutations that happen early in the development of the embryo.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.}, added-at = {2019-10-01T22:22:59.000+0200}, author = {Gao, Ziyue and Moorjani, Priya and Sasani, Thomas A. and Pedersen, Brent S. and Quinlan, Aaron R. and Jorde, Lynn B. and Amster, Guy and Przeworski, Molly}, biburl = {https://www.bibsonomy.org/bibtex/20c7092778cea4a638b5f403350ad6091/peter.ralph}, doi = {10.1073/pnas.1901259116}, eprint = {https://www.pnas.org/content/116/19/9491.full.pdf}, interhash = {44ce2f6b0a99b7e52a9ffdd2b039e409}, intrahash = {0c7092778cea4a638b5f403350ad6091}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, keywords = {human_genome mutation_rate mutation_spectrum}, number = 19, pages = {9491--9500}, publisher = {National Academy of Sciences}, timestamp = {2019-10-01T22:22:59.000+0200}, title = {Overlooked roles of {DNA} damage and maternal age in generating human germline mutations}, url = {https://www.pnas.org/content/116/19/9491}, volume = 116, year = 2019 }