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Integrative annotation of variants from 1092 humans: application to cancer genomics.

Authors
  • Khurana, Ekta
  • Fu, Yao
  • Colonna, Vincenza
  • Mu, Xinmeng Jasmine
  • Kang, Hyun Min
  • Lappalainen, Tuuli
  • Sboner, Andrea
  • Lochovsky, Lucas
  • Chen, Jieming
  • Harmanci, Arif
  • Das, Jishnu
  • Abyzov, Alexej
  • Balasubramanian, Suganthi
  • Beal, Kathryn
  • Chakravarty, Dimple
  • Challis, Daniel
  • Chen, Yuan
  • Clarke, Declan
  • Clarke, Laura
  • Cunningham, Fiona
  • And 28 more
Type
Published Article
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Publication Date
Oct 04, 2013
Volume
342
Issue
6154
Pages
1235587–1235587
Identifiers
DOI: 10.1126/science.1235587
PMID: 24092746
Source
Medline
License
Unknown

Abstract

Interpreting variants, especially noncoding ones, in the increasing number of personal genomes is challenging. We used patterns of polymorphisms in functionally annotated regions in 1092 humans to identify deleterious variants; then we experimentally validated candidates. We analyzed both coding and noncoding regions, with the former corroborating the latter. We found regions particularly sensitive to mutations ("ultrasensitive") and variants that are disruptive because of mechanistic effects on transcription-factor binding (that is, "motif-breakers"). We also found variants in regions with higher network centrality tend to be deleterious. Insertions and deletions followed a similar pattern to single-nucleotide variants, with some notable exceptions (e.g., certain deletions and enhancers). On the basis of these patterns, we developed a computational tool (FunSeq), whose application to ~90 cancer genomes reveals nearly a hundred candidate noncoding drivers.

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