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

Excess of Deleterious Mutations around HLA Genes Reveals Evolutionary Cost of Balancing Selection

Tobias L. Lenz, Victor Spirin, Daniel M. Jordan, Shamil R. Sunyaev
doi: https://doi.org/10.1101/053793
Tobias L. Lenz
1Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
2Evolutionary Immunogenomics, Department of Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, 24306 Plön, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: lenz@post.harvard.edu ssunyaev@rics.bwh.harvard.edu
Victor Spirin
1Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel M. Jordan
1Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shamil R. Sunyaev
1Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
3DProgram in Medical and Population Genetics, The Broad Institute, Cambridge, MA 02142, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: lenz@post.harvard.edu ssunyaev@rics.bwh.harvard.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Deleterious mutations are expected to evolve under negative selection and are usually purged from the population. However, deleterious alleles segregate in the human population and some disease-associated variants are maintained at considerable frequencies. Here we test the hypothesis that balancing selection may counteract purifying selection in neighboring regions and thus maintain deleterious variants at higher frequency than expected from their detrimental fitness effect. We first show in realistic simulations that balancing selection reduces the density of polymorphic sites surrounding a locus under balancing selection, but at the same time markedly increases the population frequency of the remaining variants, including even substantially deleterious alleles. To test the predictions of our simulations empirically, we then use whole exome sequencing data from 6,500 human individuals and focus on the most established example for balancing selection in the human genome, the major histocompatibility complex (MHC). Our analysis shows an elevated frequency of putatively deleterious coding variants in non-HLA genes localized in the MHC region. The mean frequency of these variants declined with physical distance from the classical HLA genes, indicating dependency on genetic linkage. These results reveal an indirect cost of the genetic diversity maintained by balancing selection, which has hitherto been perceived as mostly advantageous, and have implications both for the evolution of recombination and also for the epidemiology of various MHC-associated diseases.

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.
Back to top
PreviousNext
Posted June 15, 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.
Excess of Deleterious Mutations around HLA Genes Reveals Evolutionary Cost of Balancing Selection
(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
Excess of Deleterious Mutations around HLA Genes Reveals Evolutionary Cost of Balancing Selection
Tobias L. Lenz, Victor Spirin, Daniel M. Jordan, Shamil R. Sunyaev
bioRxiv 053793; doi: https://doi.org/10.1101/053793
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Excess of Deleterious Mutations around HLA Genes Reveals Evolutionary Cost of Balancing Selection
Tobias L. Lenz, Victor Spirin, Daniel M. Jordan, Shamil R. Sunyaev
bioRxiv 053793; doi: https://doi.org/10.1101/053793

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

  • Evolutionary Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3513)
  • Biochemistry (7358)
  • Bioengineering (5334)
  • Bioinformatics (20290)
  • Biophysics (10032)
  • Cancer Biology (7753)
  • Cell Biology (11323)
  • Clinical Trials (138)
  • Developmental Biology (6442)
  • Ecology (9962)
  • Epidemiology (2065)
  • Evolutionary Biology (13340)
  • Genetics (9363)
  • Genomics (12594)
  • Immunology (7717)
  • Microbiology (19055)
  • Molecular Biology (7452)
  • Neuroscience (41085)
  • Paleontology (300)
  • Pathology (1232)
  • Pharmacology and Toxicology (2140)
  • Physiology (3169)
  • Plant Biology (6867)
  • Scientific Communication and Education (1275)
  • Synthetic Biology (1899)
  • Systems Biology (5320)
  • Zoology (1089)