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

Mar 8, 2021

Contributor: Jonathan R Belyeu,Harrison Brand,Harold Wang,Xuefang Zhao,Brent S Pedersen,Julie Feusier,Meenal Gupta,Thomas J Nicholas,Joseph Brown,Lisa Baird,Bernie Devlin,Stephan J Sanders,Lynn B Jorde,Michael E Talkowski,Aaron R Quinlan

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

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. Whereas the rate and patterns of point mutations in the human germline are now well understood, far less is known about the frequency and features that impact de novo structural variants (dnSVs). We report a family-based study of germline mutations among 9,599 human genomes from 33 multigenerational CEPH-Utah families and 2,384 families from the Simons Foundation Autism Research Initiative. We find that de novo structural mutations detected by alignment-based, short-read WGS occur at an overall rate of at least 0.160 events per genome in unaffected individuals, and we observe a significantly higher rate (0.206 per genome) in ASD-affected individuals. In both probands and unaffected samples, nearly 73% of de novo structural mutations arose in paternal gametes, and we 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 most likely have markedly different rates and selective pressures than those leading to point mutations.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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About The Expert

Jonathan R Belyeu

Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.

Harrison Brand

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02114, USA.

Harold Wang

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02114, USA.

Xuefang Zhao

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02114, USA.

Brent S Pedersen

Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.

Julie Feusier

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

Meenal Gupta

Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.

Thomas J Nicholas

Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.

Joseph Brown

Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.

Lisa Baird

Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.

Bernie Devlin

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

Stephan J Sanders

Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.

Lynn B Jorde

Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA; Utah Center for Genetic Discovery, University of Utah, Salt Lake City, UT 84112, USA.

Michael E Talkowski

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02114, USA. Electronic address: mtalkowski@mgh.harvard.edu.

Aaron R Quinlan

Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA; Department of Biomedical Informatics, University of Utah, Salt Lake City, UT 84112, USA; Utah Center for Genetic Discovery, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: aaronquinlan@gmail.com.

References

PubMed