Large, three-generation human families reveal post-zygotic mosaicism and variability in germline mutation accumulation

• DOI: 10.7554/elife.46922
• Publication Date: 2019-09-24T00:00:16Z
• Authors: Thomas A Sasani; Brent S Pedersen; Ziyue Gao; Lisa Baird; Molly Przeworski; Lynn B Jorde; Aaron R Quinlan
• Keywords: Germline mosaicism; Mutation Accumulation

The number of de novo mutations (DNMs) found in an offspring's genome increases with both paternal and maternal age. But does the rate mutation accumulation human gametes differ across families? Using sequencing data from 33 large, three-generation CEPH families, we observed significant variability parental age effects on DNM counts ranging 0.19 to 3.24 DNMs per year. Additionally, that ~3% originated following primordial germ cell specification a parent, differed non-mosaic germline their mutational spectra. We also discovered nearly 10% candidate second generation were post-zygotic, present somatic cells; these gonosomal occurred at equivalent frequencies haplotypes. Our results demonstrate rates vary among families similar ancestry, confirm post-zygotic mosaicism is substantial source DNM.