Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Estimating the Selective Effect of Heterozygous Protein Truncating Variants from Human Exome Data

View ORCID ProfileChristopher A. Cassa, Donate Weghorn, Daniel J. Balick, Daniel M. Jordan, David Nusinow, Kaitlin E. Samocha, Anne O'Donnell Luria, Daniel G. MacArthur, Mark J. Daly, David R. Beier, Shamil R. Sunyaev
doi: https://doi.org/10.1101/075523
Christopher A. Cassa
1Brigham and Women’s Hospital, Division of Genetics, Harvard Medical School, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Christopher A. Cassa
Donate Weghorn
1Brigham and Women’s Hospital, Division of Genetics, Harvard Medical School, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel J. Balick
1Brigham and Women’s Hospital, Division of Genetics, Harvard Medical School, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel M. Jordan
3Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David Nusinow
1Brigham and Women’s Hospital, Division of Genetics, Harvard Medical School, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kaitlin E. Samocha
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
5Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anne O'Donnell Luria
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
6Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel G. MacArthur
2Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark J. Daly
2Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David R. Beier
7Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, WA, USA
8Dept. of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: ssunyaev@rics.bwh.harvard.edu David.Beier@seattlechildrens.org
Shamil R. Sunyaev
1Brigham and Women’s Hospital, Division of Genetics, Harvard Medical School, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: ssunyaev@rics.bwh.harvard.edu David.Beier@seattlechildrens.org
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

The dispensability of individual genes for viability has interested generations of geneticists. For some genes it is essential to maintain two functional chromosomal copies, while other genes may tolerate the loss of one or both copies. Exome sequence data from 60,706 individuals provide sufficient observations of rare protein truncating variants (PTVs) to make genome-wide estimates of selection against heterozygous loss of gene function. The cumulative frequency of rare deleterious PTVs is primarily determined by the balance between incoming mutations and purifying selection rather than genetic drift. This enables the estimation of the genome-wide distribution of selection coefficients for heterozygous PTVs and corresponding Bayesian estimates for individual genes. The strength of selection can help discriminate the severity, age of onset, and mode of inheritance in Mendelian exome sequencing cases. We find that genes under the strongest selection are enriched in embryonic lethal mouse knockouts, putatively cell-essential genes inferred from human tumor cells, Mendelian disease genes, and regulators of transcription. Using an essentiality screen, we find a large set of genes under strong selection that are likely to have critical function but that have not yet been studied extensively.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted September 16, 2016.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Estimating the Selective Effect of Heterozygous Protein Truncating Variants from Human Exome Data
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Estimating the Selective Effect of Heterozygous Protein Truncating Variants from Human Exome Data
Christopher A. Cassa, Donate Weghorn, Daniel J. Balick, Daniel M. Jordan, David Nusinow, Kaitlin E. Samocha, Anne O'Donnell Luria, Daniel G. MacArthur, Mark J. Daly, David R. Beier, Shamil R. Sunyaev
bioRxiv 075523; doi: https://doi.org/10.1101/075523
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Estimating the Selective Effect of Heterozygous Protein Truncating Variants from Human Exome Data
Christopher A. Cassa, Donate Weghorn, Daniel J. Balick, Daniel M. Jordan, David Nusinow, Kaitlin E. Samocha, Anne O'Donnell Luria, Daniel G. MacArthur, Mark J. Daly, David R. Beier, Shamil R. Sunyaev
bioRxiv 075523; doi: https://doi.org/10.1101/075523

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Genomics
Subject Areas
All Articles
  • Animal Behavior and Cognition (4235)
  • Biochemistry (9136)
  • Bioengineering (6784)
  • Bioinformatics (24001)
  • Biophysics (12129)
  • Cancer Biology (9534)
  • Cell Biology (13778)
  • Clinical Trials (138)
  • Developmental Biology (7636)
  • Ecology (11702)
  • Epidemiology (2066)
  • Evolutionary Biology (15513)
  • Genetics (10644)
  • Genomics (14326)
  • Immunology (9483)
  • Microbiology (22839)
  • Molecular Biology (9090)
  • Neuroscience (48995)
  • Paleontology (355)
  • Pathology (1482)
  • Pharmacology and Toxicology (2570)
  • Physiology (3846)
  • Plant Biology (8331)
  • Scientific Communication and Education (1471)
  • Synthetic Biology (2296)
  • Systems Biology (6192)
  • Zoology (1301)