RT Journal Article SR Electronic T1 Overlooked roles of DNA damage and maternal age in generating human germline mutations JF bioRxiv FD Cold Spring Harbor Laboratory SP 327098 DO 10.1101/327098 A1 Gao, Ziyue A1 Moorjani, Priya A1 Sasani, Thomas A1 Pedersen, Brent A1 Quinlan, Aaron A1 Jorde, Lynn A1 Amster, Guy A1 Przeworski, Molly YR 2018 UL http://biorxiv.org/content/early/2018/10/11/327098.abstract AB 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.