Parental influence on human germline de novo mutations in 1,548 trios from Iceland

Abstract

The characterization of mutational processes that generate sequence diversity in the human genome is of paramount importance both to medical genetics and to evolutionary studies. To understand how the age and sex of transmitting parents affect de novo mutations, here we sequence 1,548 Icelanders, their parents, and, for a subset of 225, at least one child, to 35× genome-wide coverage. We find 108,778 de novo mutations, both single nucleotide polymorphisms and indels, and determine the parent of origin of 42,961. The number of de novo mutations from mothers increases by 0.37 per year of age (95% CI 0.32-0.43), a quarter of the 1.51 per year from fathers (95% CI 1.45-1.57). The number of clustered mutations increases faster with the mother's age than with the father's, and the genomic span of maternal de novo mutation clusters is greater than that of paternal ones. The types of de novo mutation from mothers change substantially with age, with a 0.26% (95% CI 0.19-0.33%) decrease in cytosine-phosphate-guanine to thymine-phosphate-guanine (CpG>TpG) de novo mutations and a 0.33% (95% CI 0.28-0.38%) increase in C>G de novo mutations per year, respectively. Remarkably, these age-related changes are not distributed uniformly across the genome. A striking example is a 20 megabase region on chromosome 8p, with a maternal C>G mutation rate that is up to 50-fold greater than the rest of the genome. The age-related accumulation of maternal non-crossover gene conversions also mostly occurs within these regions. Increased sequence diversity and linkage disequilibrium of C>G variants within regions affected by excess maternal mutations indicate that the underlying mutational process has persisted in humans for thousands of years. Moreover, the regional excess of C>G variation in humans is largely shared by chimpanzees, less by gorillas, and is almost absent from orangutans. This demonstrates that sequence diversity in humans results from evolving interactions between age, sex, mutation type, and genomic location.

Whole genome sequencing and mutation rate analysis of trios with paternal dioxin exposure

“…The higher mutation rate in fathers could be caused by the higher number of cell divisions in sperm development compared to the egg. The higher proportion is consistent with male driven evolution hypothesis, and previous studies (Francioli et al., ; Jonsson et al., ; Kong et al., ).…”

“…The number of point mutations corresponded to a rate of 1.42 × 10 −8 mutations per nucleotide per generation, which was consistent with previous reports (1.1 × 10 −8 to 3.8 × 10 −8 mutation per nucleotide per generation; Conrad et al., ; Jonsson et al., ; Kong et al., ). The rate of transition to transversion was 1.82, which was also similar to a previous study (Jiang et al., ).…”

“…De novo point mutations in the children. (a) Substitution pattern of de novo point mutations of this study and that of 1,548 Icelanders (Jonsson et al., ). (b) Origin of de novo point mutations.…”

Widespread transcriptional scanning in the testis modulates gene evolution rates

“…On the other side, the expressed genes of male germ cells still retain mutations that cannot be repaired by the TCR machinery 22,48 . These male germline mutations likely originate from DNA replication errors, accumulating with paternal age 49 . Thus, it would be of great interest to further analyze the observed germline mutation pattern, in particular relative to replication fork directionality 50 .…”

The contribution of environmental exposure to the etiology of autism spectrum disorder

“…While various hypotheses have been posed as to the biological mechanisms of maternal and paternal age effects, an association between advanced parental age and increasing likelihood of malign de novo mutations has been suggested [45]. This is most likely explained by a cumulating risk for mutations during spermatogenesis across the life span [46]. Indeed, de novo mutations associated with ASD are more often paternal than maternal [47], with some evidence of linked autism risk in offspring of older fathers with detected age-related DNA methylation changes in their sperm [48].…”