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

Abstract

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. Keywords: germline mutation, male mutation bias, DNA replication, DNA damage and repair, maternal age effect