RT Journal Article
SR Electronic
T1 Large, three-generation CEPH families reveal post-zygotic mosaicism and variability in germline mutation accumulation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 552117
DO 10.1101/552117
A1 Thomas A. Sasani
A1 Brent S. Pedersen
A1 Ziyue Gao
A1 Lisa Baird
A1 Molly Przeworski
A1 Lynn B. Jorde
A1 Aaron R. Quinlan
YR 2019
UL http://biorxiv.org/content/early/2019/07/09/552117.abstract
AB 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, with estimates ranging from 0.19 to 3.24 DNMs per year. Additionally, we found that approximately 3% of DNMs originated following primordial germ cell specification (PGCS) 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 the rate of germline mutation accumulation varies among families with similar ancestry, and confirm that post-zygotic mosaicism is a substantial source of de novo mutations in humans.Data and code availability. Code used for statistical analysis and figure generation has been deposited on GitHub as a collection of annotated Jupyter Notebooks: https://github.com/quinlan-lab/ceph-dnm-manuscript. Data files containing high-confidence de novo mutations, as well as the gonosomal and post-primordial germ cell specification (PGCS) mosaic mutations, are included with these Notebooks. To mitigate compatibility issues, we have also made all notebooks available in a Binder environment, accessible at the above GitHub repository.