TY - JOUR T1 - Large, three-generation CEPH families reveal post-zygotic mosaicism and variability in germline mutation accumulation JF - bioRxiv DO - 10.1101/552117 SP - 552117 AU - Thomas A. Sasani AU - Brent S. Pedersen AU - Ziyue Gao AU - Lisa Baird AU - Molly Przeworski AU - Lynn B. Jorde AU - Aaron R. Quinlan Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/07/09/552117.abstract N2 - 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. ER -