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De novo structural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families

View ORCID ProfileJonathan R. Belyeu, View ORCID ProfileHarrison Brand, Harold Wang, View ORCID ProfileXuefang Zhao, View ORCID ProfileBrent S. Pedersen, View ORCID ProfileJulie Feusier, Meenal Gupta, Thomas J. Nicholas, Lisa Baird, View ORCID ProfileBernie Devlin, View ORCID ProfileStephan J. Sanders, View ORCID ProfileLynn B. Jorde, View ORCID ProfileMichael E. Talkowski, View ORCID ProfileAaron R. Quinlan
doi: https://doi.org/10.1101/2020.10.06.329011
Jonathan R. Belyeu
1Department of Human Genetics, University of Utah, Salt Lake City, UT
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  • ORCID record for Jonathan R. Belyeu
Harrison Brand
2Center for Genomic Medicine, Massachusetts General Hospital, Boston MA
3Department of Neurology, Harvard Medical School, Boston MA
4Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge MA
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Harold Wang
2Center for Genomic Medicine, Massachusetts General Hospital, Boston MA
3Department of Neurology, Harvard Medical School, Boston MA
4Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge MA
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Xuefang Zhao
2Center for Genomic Medicine, Massachusetts General Hospital, Boston MA
3Department of Neurology, Harvard Medical School, Boston MA
4Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge MA
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Brent S. Pedersen
1Department of Human Genetics, University of Utah, Salt Lake City, UT
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Julie Feusier
5Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
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Meenal Gupta
1Department of Human Genetics, University of Utah, Salt Lake City, UT
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Thomas J. Nicholas
1Department of Human Genetics, University of Utah, Salt Lake City, UT
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Lisa Baird
1Department of Human Genetics, University of Utah, Salt Lake City, UT
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Bernie Devlin
6Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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  • ORCID record for Bernie Devlin
Stephan J. Sanders
7Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
8Institute for Human Genetics, University of California, San Francisco, CA, USA
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Lynn B. Jorde
1Department of Human Genetics, University of Utah, Salt Lake City, UT
10Utah Center for Genetic Discovery, University of Utah, Salt Lake City, UT
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Michael E. Talkowski
2Center for Genomic Medicine, Massachusetts General Hospital, Boston MA
3Department of Neurology, Harvard Medical School, Boston MA
4Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge MA
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  • For correspondence: aaronquinlan@gmail.com
Aaron R. Quinlan
1Department of Human Genetics, University of Utah, Salt Lake City, UT
9Department of Biomedical Informatics, University of Utah, Salt Lake City, UT
10Utah Center for Genetic Discovery, University of Utah, Salt Lake City, UT
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  • ORCID record for Aaron R. Quinlan
  • For correspondence: aaronquinlan@gmail.com
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Abstract

Each human genome includes de novo mutations that arose during gametogenesis. While these germline mutations represent a fundamental source of new genetic diversity, they can also create deleterious alleles that impact fitness. The germline mutation rate for single nucleotide variants and factors that significantly influence this rate, such as parental age, are now well established. However, far less is known about the frequency, distribution, and features that impact de novo structural mutations. We report a large, family-based study of germline mutations, excluding aneuploidy, that affect genome structure among 572 genomes from 33 families in a multigenerational CEPH-Utah cohort and 2,363 cases of non-familial autism spectrum disorder (ASD), 1,938 unaffected siblings, and both parents (9,599 genomes in total). We find that de novo structural mutations detected by alignment-based, short-read WGS occurred at an overall rate of at least 0.160 events per genome in unaffected individuals and was significantly higher (0.206 per genome) in ASD cases. In both probands and unaffected samples, nearly 73% of de novo structural mutations arose in paternal gametes, and predict most de novo structural mutations to be caused by mutational mechanisms that do not require sequence homology. After multiple testing correction we did not observe a statistically significant correlation between parental age and the rate of de novo structural variation in offspring. These results highlight that a spectrum of mutational mechanisms contribute to germline structural mutations, and that these mechanisms likely have markedly different rates and selective pressures than those leading to point mutations.

Competing Interest Statement

The authors have declared no competing interest.

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 October 08, 2020.
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De novo structural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families
Jonathan R. Belyeu, Harrison Brand, Harold Wang, Xuefang Zhao, Brent S. Pedersen, Julie Feusier, Meenal Gupta, Thomas J. Nicholas, Lisa Baird, Bernie Devlin, Stephan J. Sanders, Lynn B. Jorde, Michael E. Talkowski, Aaron R. Quinlan
bioRxiv 2020.10.06.329011; doi: https://doi.org/10.1101/2020.10.06.329011
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De novo structural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families
Jonathan R. Belyeu, Harrison Brand, Harold Wang, Xuefang Zhao, Brent S. Pedersen, Julie Feusier, Meenal Gupta, Thomas J. Nicholas, Lisa Baird, Bernie Devlin, Stephan J. Sanders, Lynn B. Jorde, Michael E. Talkowski, Aaron R. Quinlan
bioRxiv 2020.10.06.329011; doi: https://doi.org/10.1101/2020.10.06.329011

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