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.