Abstract
The number of de novo mutations (DNMs) found in an offspring's genome increases with both paternal and maternal age. But does the rate of mutation accumulation in human gametes differ across families? Using sequencing data from 33 large, three-generation CEPH families, we observed significant variability in parental age effects on DNM counts across families, ranging from 0.19 to 3.24 DNMs per year. Additionally, we found that ~3% of DNMs originated following primordial germ cell specification in a parent, and differed from non-mosaic germline DNMs in their mutational spectra. We also discovered that nearly 10% of candidate DNMs in the second generation were post-zygotic, and present in both somatic and germ cells; these gonosomal mutations occurred at equivalent frequencies on both parental haplotypes. Our results demonstrate that rates of germline mutation accumulation vary among families with similar ancestry, and confirm that post-zygotic mosaicism is a substantial source of human DNM.
Highlights
In a 1996 lecture at the National Academy of Sciences, James Crow noted that "without mutation, evolution would be impossible" (Crow 1997)
92% (4,298 of 4,671) of de novo mutations (DNMs) observed in the second generation were single nucleotide variants (SNVs), and the remainder were small (
Using a cohort of large, multi-generational Centre d'Etude du Polymorphisme Humain (CEPH)/Utah families, we have identified a high-confidence set of germline de novo mutations that are validated by transmission to the 15
Summary
In a 1996 lecture at the National Academy of Sciences, James Crow noted that "without mutation, evolution would be impossible" (Crow 1997) His remark highlights the importance of understanding the rate at which germline mutations occur, the mechanisms that generate them, and the effects of gamete-of-origin and parental age. Numerous studies have employed this approach to analyze the mutation rate in cohorts of small, nuclear families, producing estimates nearly two-fold lower than those from phylogenetic comparison (Roach et al 2010; Kong et al 2012; Jónsson et al 2017; Goldmann et al 2016; Scally and Durbin 2012; Shendure and Akey 2015; Turner et al 2017)
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