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

View ORCID ProfileThomas A. Sasani, View ORCID ProfileBrent S. Pedersen, View ORCID ProfileZiyue Gao, Lisa Baird, View ORCID ProfileMolly Przeworski, Lynn B. Jorde, View ORCID ProfileAaron R. Quinlan
doi: https://doi.org/10.1101/552117
Thomas A. Sasani
1Department of Human Genetics, University of Utah. Salt Lake City, UT
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Brent S. Pedersen
1Department of Human Genetics, University of Utah. Salt Lake City, UT
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Ziyue Gao
4Howard Hughes Medical Institute & Department of Genetics, Stanford University, Stanford, CA
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Lisa Baird
1Department of Human Genetics, University of Utah. Salt Lake City, UT
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Molly Przeworski
5Department of Biological Sciences, Columbia University, New York City, NY
6Department of Systems Biology, Columbia University, New York City, NY
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Lynn B. Jorde
1Department of Human Genetics, University of Utah. Salt Lake City, UT
3USTAR Center for Genetic Discovery, University of Utah. Salt Lake City, UT
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  • For correspondence: lbj@genetics.utah.edu aaronquinlan@gmail.com
Aaron R. Quinlan
1Department of Human Genetics, University of Utah. Salt Lake City, UT
2Department of Biomedical Informatics, University of Utah. Salt Lake City, UT
3USTAR Center for Genetic Discovery, University of Utah. Salt Lake City, UT
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  • For correspondence: lbj@genetics.utah.edu aaronquinlan@gmail.com
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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, 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.

Footnotes

  • The manuscript has been revised to include improved methods for detecting post-zygotic mutations in the CEPH/Utah individuals, in addition to more minor textual changes and updates. The precise numbers of germline and post-zygotic mutations identified in both the second and third generations have been updated, though the major results of the manuscript remain very similar to those in the original version. Supplementary files (including IGV screenshots of representative mutations) have been updated accordingly.

  • https://github.com/quinlan-lab/ceph-dnm-manuscript

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 09, 2019.
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Large, three-generation CEPH families reveal post-zygotic mosaicism and variability in germline mutation accumulation
Thomas A. Sasani, Brent S. Pedersen, Ziyue Gao, Lisa Baird, Molly Przeworski, Lynn B. Jorde, Aaron R. Quinlan
bioRxiv 552117; doi: https://doi.org/10.1101/552117
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Large, three-generation CEPH families reveal post-zygotic mosaicism and variability in germline mutation accumulation
Thomas A. Sasani, Brent S. Pedersen, Ziyue Gao, Lisa Baird, Molly Przeworski, Lynn B. Jorde, Aaron R. Quinlan
bioRxiv 552117; doi: https://doi.org/10.1101/552117

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