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

DNA mutations (alteration of a nucleotide base) can occur in the germline or somewhere in the body other than the germ cells (spermatozoa and ova). The former are called germ cell mutations, and the latter somatic cell mutations. It has long been known, or at least strongly suspected, that mutations in germ cells will increase as a function of age –– meaning that a 50-year-old is more likely to have had a detrimental mutation in a germ cell than a 20-year-old. Years ago, I remember that Leonid Kruglyak had estimated that, just from ionizing background radiation, a child will have on average ~320 de novo mutations that neither parent carries. 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 age and sex of transmitting parents affect de novo mutations in their offspring, authors [see attached article] performed whole-genome sequencing (WGS) on 1,548 Icelanders, their parents –– and, for a subset of 225, at least one child. They found 108,778 de novo mutations, both single nucleotide polymorphisms (SNPs) and insertions/deletions (indels), and they determined the parent of origin in 42,961 of these mutations. The number of de novo mutations from mothers increased by ~0.37 per year of age, which was only one-fourth of the number of mutations from fathers (~1.51 per year). The number of clustered mutations increased faster with the mother’s age than with the father’s age, 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 changed substantially with age, with a 0.26% decrease in cytosine–phosphate–guanine to thymine–phosphate–guanine (CpG>TpG) de novo mutations, and a 0.33% 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 (20-Mb) region on chromosome 8p, with a maternal C>G mutation rate that is as much as 50-fold greater than the rest of the genome. 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. These really cool findings demonstrate that sequence diversity in humans results from evolving interactions between age, sex, mutation type, and genomic location.

Nature October 2o17; doi:10.1038/nature24018 [ePub]

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