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

View ORCID ProfileZiyue Gao, Priya Moorjani, Thomas Sasani, Brent Pedersen, Aaron Quinlan, Lynn Jorde, View ORCID ProfileGuy Amster, View ORCID ProfileMolly Przeworski
doi: https://doi.org/10.1101/327098
Ziyue Gao
1Howard Hughes Medical Institute & Department of Genetics, Stanford University.
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  • For correspondence: ziyuegao@stanford.edu mp3284@columbia.edu
Priya Moorjani
2Department of Molecular and Cell Biology, University of California, Berkeley.
3Center for Computational Biology, University of California, Berkeley.
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Thomas Sasani
4Department of Human Genetics, University of Utah School of Medicine.
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Brent Pedersen
4Department of Human Genetics, University of Utah School of Medicine.
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Aaron Quinlan
4Department of Human Genetics, University of Utah School of Medicine.
5Department of Biomedical Informatics, University of Utah School of Medicine.
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Lynn Jorde
4Department of Human Genetics, University of Utah School of Medicine.
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Guy Amster
6Department of Biological Sciences, Columbia University.
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Molly Przeworski
6Department of Biological Sciences, Columbia University.
7Department of Systems Biology, Columbia University.
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  • For correspondence: ziyuegao@stanford.edu mp3284@columbia.edu
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Abstract

Although the textbook view is that most germline mutations arise from replication errors, when analyzing large de novo mutation datasets in humans, we find multiple lines of evidence that call that understanding 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 ages. This surprising finding points to a substantial contribution of damage-induced mutations. Indeed, C to G transversions and CpG transitions, which together constitute one third of all mutations, show genomic distributions and sex-specific age dependencies indicative of doublestrand break repair and methylation-associated damage, respectively. Moreover, the data indicate 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.

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Posted October 11, 2018.
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Overlooked roles of DNA damage and maternal age in generating human germline mutations
Ziyue Gao, Priya Moorjani, Thomas Sasani, Brent Pedersen, Aaron Quinlan, Lynn Jorde, Guy Amster, Molly Przeworski
bioRxiv 327098; doi: https://doi.org/10.1101/327098
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Overlooked roles of DNA damage and maternal age in generating human germline mutations
Ziyue Gao, Priya Moorjani, Thomas Sasani, Brent Pedersen, Aaron Quinlan, Lynn Jorde, Guy Amster, Molly Przeworski
bioRxiv 327098; doi: https://doi.org/10.1101/327098

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