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

Overlooked roles of DNA damage and maternal age in generating human germline mutations

View ORCID ProfileZiyue Gao, Priya Moorjani, View ORCID ProfileGuy Amster, View ORCID ProfileMolly Przeworski
doi: https://doi.org/10.1101/327098
Ziyue Gao
1Howard Hughes Medical Institute & Department of Genetics, Stanford University.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ziyue Gao
  • For correspondence: ziyuegao@stanford.edu mp3284@columbia.edu
Priya Moorjani
2Department of Molecular and Cell Biology, University of California, Berkeley.
3Center for Computational Biology, University of California, Berkeley.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Guy Amster
4Department of Biological Sciences, Columbia University.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Guy Amster
Molly Przeworski
4Department of Biological Sciences, Columbia University.
5Department of Systems Biology, Columbia University.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Molly Przeworski
  • For correspondence: ziyuegao@stanford.edu mp3284@columbia.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Human germline mutations are primarily paternal in origin and their total number increases linearly with the age of the father, observations that are thought to support the textbook view that germline point mutations stem primarily from DNA replication errors. Analyzing large germline mutation datasets for humans, we uncovered two lines of evidence that call this understanding into question. First, despite the drastic increase in the ratio of male to female germ cell divisions after the onset of spermatogenesis, the ratio of paternal to maternal mutations is already 3:1 by puberty and barely increases with the age of the parents, pointing to a substantial contribution of damage-induced mutations. Supporting this hypothesis, C to G transversions and CpG transitions, which together constitute about a 1/3 of point mutations, show sex-specific age dependencies indicative of double-strand break repair and methylation-associated damage, respectively. Second, the age of a mother influences not only the number of mutations that her child inherits on the maternal genome, but also the number of mutations on the paternal genome, as expected if children of older mothers accumulate more mutations in embryogenesis. Together, these findings reveal that, rather than arising predominantly from pre-zygotic replication errors, the parental age effects on germline mutations reflect a combination of higher damage rates in males and a maternal age effect on early development.

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 May 21, 2018.
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.
Overlooked roles of DNA damage and maternal age in generating human germline mutations
(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
Overlooked roles of DNA damage and maternal age in generating human germline mutations
Ziyue Gao, Priya Moorjani, Guy Amster, Molly Przeworski
bioRxiv 327098; doi: https://doi.org/10.1101/327098
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Overlooked roles of DNA damage and maternal age in generating human germline mutations
Ziyue Gao, Priya Moorjani, Guy Amster, Molly Przeworski
bioRxiv 327098; doi: https://doi.org/10.1101/327098

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

  • Genetics
Subject Areas
All Articles
  • Animal Behavior and Cognition (4685)
  • Biochemistry (10362)
  • Bioengineering (7682)
  • Bioinformatics (26343)
  • Biophysics (13534)
  • Cancer Biology (10694)
  • Cell Biology (15446)
  • Clinical Trials (138)
  • Developmental Biology (8501)
  • Ecology (12824)
  • Epidemiology (2067)
  • Evolutionary Biology (16867)
  • Genetics (11402)
  • Genomics (15484)
  • Immunology (10621)
  • Microbiology (25226)
  • Molecular Biology (10225)
  • Neuroscience (54482)
  • Paleontology (402)
  • Pathology (1669)
  • Pharmacology and Toxicology (2897)
  • Physiology (4345)
  • Plant Biology (9254)
  • Scientific Communication and Education (1587)
  • Synthetic Biology (2558)
  • Systems Biology (6781)
  • Zoology (1466)