Abstract
The number of de novo mutations (DNMs) found in an offspring's genome is known to increase with both paternal and maternal age. But does the rate of mutation accumulation in parental gametes differ across families? To answer this question, we analyzed DNMs in 33 large, three-generation families collected in Utah by the Centre d'Etude du Polymorphisme Humain (CEPH) consortium. We observed significant variability in parental age effects on DNM counts across families, ranging from 0.24 to 3.33 additional DNMs per year. Using up to 14 grandchildren in these families, we find that 3% of DNMs originated following primordial germ cell specification (PGCS) in a parent, and differ from non-mosaic germline DNMs in their mutational spectra. We also identify a median of 3 gonosomal mutations per sample in the F1 generation, which, along with post-PGCS DNMs, occur at equivalent frequencies on the paternal and maternal haplotypes. These results demonstrate that the rate of germline mutation accumulation varies among families with similar ancestry, and confirm that parental mosaicism is a substantial source of de novo mutations in children.
