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

Probabilities of Fitness Consequences for Point Mutations Across the Human Genome

Brad Gulko, Ilan Gronau, Melissa J. Hubisz, Adam Siepel
doi: https://doi.org/10.1101/006825
Brad Gulko
1Graduate Field of Computer Science, Cornell University, Ithaca, NY 14853, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ilan Gronau
2Dept. of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Melissa J. Hubisz
2Dept. of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Adam Siepel
2Dept. of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: acs4@cornell.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Abstract

The identification of noncoding functional elements based on high-throughput genomic data remains an important open problem. Here we describe a novel computational approach for estimating the probability that a point mutation at each nucleotide position in a genome will influence organismal fitness. These fitness consequence (fitCons) scores can be interpreted as an evolution-based measure of potential genomic function. We first partition the genome into clusters of positions having distinct functional genomic “fingerprints,” based on cell-type-specific DNase-seq, RNA-seq, and histone modification data. Then we estimate the probability of fitness consequences for each cluster from associated patterns of genetic polymorphism and divergence using a recently developed probabilistic method called INSIGHT. We have generated fitCons scores for three human cell types based on publicly available genomic data and made them available as UCSC Genome Browser tracks. Like conventional evolutionary conservation scores, fitCons scores are clearly elevated in known coding and noncoding functional elements, but they show considerably better sensitivity than conservation scores for many noncoding elements. In addition, they perform exceptionally well in distinguishing ChIP-seq-supported transcription factor binding sites, expression quantitative trait loci, and predicted enhancers from putatively nonfunctional sequences. The fitCons scores indicate that 4.2–7.5% of nucleotide positions in the human genome have influenced fitness since the human-chimpanzee divergence. In contrast to several recent studies, they suggest that recent evolutionary turnover has had a relatively modest impact on the functional content of the genome. Our approach provides a unique new measure of genomic function that complements measures based on evolutionary conservation or functional genomics alone and is particularly well suited for characterizing turnover and evolutionary novelty.

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 July 02, 2014.
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.
Probabilities of Fitness Consequences for Point Mutations Across the Human Genome
(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
Probabilities of Fitness Consequences for Point Mutations Across the Human Genome
Brad Gulko, Ilan Gronau, Melissa J. Hubisz, Adam Siepel
bioRxiv 006825; doi: https://doi.org/10.1101/006825
Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Probabilities of Fitness Consequences for Point Mutations Across the Human Genome
Brad Gulko, Ilan Gronau, Melissa J. Hubisz, Adam Siepel
bioRxiv 006825; doi: https://doi.org/10.1101/006825

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 (2517)
  • Biochemistry (4964)
  • Bioengineering (3469)
  • Bioinformatics (15181)
  • Biophysics (6885)
  • Cancer Biology (5380)
  • Cell Biology (7711)
  • Clinical Trials (138)
  • Developmental Biology (4518)
  • Ecology (7135)
  • Epidemiology (2059)
  • Evolutionary Biology (10210)
  • Genetics (7497)
  • Genomics (9767)
  • Immunology (4822)
  • Microbiology (13179)
  • Molecular Biology (5129)
  • Neuroscience (29367)
  • Paleontology (203)
  • Pathology (835)
  • Pharmacology and Toxicology (1460)
  • Physiology (2129)
  • Plant Biology (4734)
  • Scientific Communication and Education (1008)
  • Synthetic Biology (1337)
  • Systems Biology (4002)
  • Zoology (768)