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

A survey of rare epigenetic variation in 23,116 human genomes identifies disease-relevant epivariations and novel CGG expansions

Paras Garg, Bharati Jadhav, Oscar L. Rodriguez, Nihir Patel, Alejandro Martin-Trujillo, Miten Jain, Sofie Metsu, Hugh Olsen, Benedict Paten, Beate Ritz, R. Frank Kooy, View ORCID ProfileJozef Gecz, Andrew J. Sharp
doi: https://doi.org/10.1101/2020.03.25.007864
Paras Garg
1Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount, Hess Center for Science and Medicine, New York, NY 10029
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bharati Jadhav
1Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount, Hess Center for Science and Medicine, New York, NY 10029
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Oscar L. Rodriguez
1Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount, Hess Center for Science and Medicine, New York, NY 10029
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nihir Patel
1Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount, Hess Center for Science and Medicine, New York, NY 10029
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alejandro Martin-Trujillo
1Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount, Hess Center for Science and Medicine, New York, NY 10029
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Miten Jain
2UC Santa Cruz Genomics Institute, University of California, Santa Cruz, California, 95064
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sofie Metsu
4Department of Medical Genetics, University of Antwerp, 2000 Antwerp, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hugh Olsen
2UC Santa Cruz Genomics Institute, University of California, Santa Cruz, California, 95064
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Benedict Paten
2UC Santa Cruz Genomics Institute, University of California, Santa Cruz, California, 95064
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Beate Ritz
3Department of Epidemiology, Fielding School of Public Health, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, 90095
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
R. Frank Kooy
4Department of Medical Genetics, University of Antwerp, 2000 Antwerp, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jozef Gecz
5Adelaide Medical School and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5005, Australia
6Women and Kids, South Australian Health and Medical Research Institute, Adelaide, SA 5005, Australia
7Genetics and Molecular Pathology, SA Pathology, Adelaide SA 5006, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jozef Gecz
Andrew J. Sharp
1Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount, Hess Center for Science and Medicine, New York, NY 10029
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: andrew.sharp@mssm.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

ABSTRACT

There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals using the Illumina 450k array. Using a robust outlier approach, we identified 4,452 unique autosomal epivariations, including potentially inactivating promoter methylation events at 384 genes linked to human disease. For example, we observed promoter hypermethylation of BRCA1 and LDLR at population frequencies of ~1 in 3,000 and ~1 in 6,000 respectively, suggesting that epivariations may underlie a fraction of human disease which would be missed by purely sequence-based approaches. Using expression data, we confirmed that many epivariations are associated with outlier gene expression. Analysis of SNV data and monozygous twin pairs suggests that approximately two thirds of epivariations segregate in the population secondary to underlying sequence mutations, while one third are likely sproradic events that occur post-zygotically. We identified 25 loci where rare hypermethylation coincided with the presence of an unstable CGG tandem repeat, and validated the presence of novel CGG expansions at several of these, identifying the molecular defect underlying most of the known folate-sensitive fragile sites in the genome. Our study provides a catalog of rare epigenetic changes in the human genome, gives insight into the underlying origins and consequences of epivariations, and identifies many novel hypermethylated CGG repeat expansions.

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 March 26, 2020.
Download PDF
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.
A survey of rare epigenetic variation in 23,116 human genomes identifies disease-relevant epivariations and novel CGG expansions
(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
A survey of rare epigenetic variation in 23,116 human genomes identifies disease-relevant epivariations and novel CGG expansions
Paras Garg, Bharati Jadhav, Oscar L. Rodriguez, Nihir Patel, Alejandro Martin-Trujillo, Miten Jain, Sofie Metsu, Hugh Olsen, Benedict Paten, Beate Ritz, R. Frank Kooy, Jozef Gecz, Andrew J. Sharp
bioRxiv 2020.03.25.007864; doi: https://doi.org/10.1101/2020.03.25.007864
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
A survey of rare epigenetic variation in 23,116 human genomes identifies disease-relevant epivariations and novel CGG expansions
Paras Garg, Bharati Jadhav, Oscar L. Rodriguez, Nihir Patel, Alejandro Martin-Trujillo, Miten Jain, Sofie Metsu, Hugh Olsen, Benedict Paten, Beate Ritz, R. Frank Kooy, Jozef Gecz, Andrew J. Sharp
bioRxiv 2020.03.25.007864; doi: https://doi.org/10.1101/2020.03.25.007864

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 (3514)
  • Biochemistry (7367)
  • Bioengineering (5346)
  • Bioinformatics (20324)
  • Biophysics (10045)
  • Cancer Biology (7776)
  • Cell Biology (11352)
  • Clinical Trials (138)
  • Developmental Biology (6453)
  • Ecology (9980)
  • Epidemiology (2065)
  • Evolutionary Biology (13356)
  • Genetics (9373)
  • Genomics (12612)
  • Immunology (7725)
  • Microbiology (19103)
  • Molecular Biology (7465)
  • Neuroscience (41153)
  • Paleontology (301)
  • Pathology (1235)
  • Pharmacology and Toxicology (2142)
  • Physiology (3178)
  • Plant Biology (6880)
  • Scientific Communication and Education (1276)
  • Synthetic Biology (1900)
  • Systems Biology (5328)
  • Zoology (1091)