Abstract
Whole genome sequencing (WGS) studies have estimated the human germline mutation rate per basepair per generation (~1.2 × 10−8) to be higher than in mice (3.5–5.4 × 10−9). In humans, most germline mutations are paternal in origin and numbers of mutations per offspring increase with paternal and maternal age. Here we estimate germline mutation rates and spectra in six multi-sibling mouse pedigrees and compare to three multi-sibling human pedigrees. In both species we observe a paternal mutation bias, a parental age effect, and a highly mutagenic first cell division contributing to the embryo. We also observe differences between species in mutation spectra, in mutation rates per cell division, and in the parental bias of mutations in early embryogenesis. These differences between species likely result from both species-specific differences in cellular genealogies of the germline, as well as biological differences within the same stage of embryogenesis or gametogenesis.
Highlights
IntroductionTo characterise mutation rates, timing and spectra in the murine germline, we analyse the patterns of de novo mutations (DNMs) sharing among offspring and parental tissues in six large mouse pedigrees (Fig. 1), using a combination of whole-genome sequencing (WGS), deep targeted sequencing and an analytical workflow described previously[3]
Whole genome sequencing (WGS) studies have estimated the human germline mutation rate per basepair per generation (~1.2 × 10−8) to be higher than in mice (3.5–5.4 × 10−9)
Some of the differences we observed between mice and humans are attributable to the differences in cellular genealogies of the germline, for example, the greater proportion of germline replications occurring during early embryogenesis in mice, leading to greater germline mosaicism and sharing of mutations between siblings
Summary
To characterise mutation rates, timing and spectra in the murine germline, we analyse the patterns of DNM sharing among offspring and parental tissues in six large mouse pedigrees (Fig. 1), using a combination of whole-genome sequencing (WGS), deep targeted sequencing and an analytical workflow described previously[3]. We compare these murine patterns with equivalent, previously published, human data on three multi-sibling families[3]. We find that mutation rates in SSC cell divisions are lower in humans than in mice
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