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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Khurana, E; Fu, Y; Colonna, V; Mu, XJ; Kang, HM; Lappalainen, T; Sboner, A; Lochovsky, L; Chen, J; Harmanci, A; Das, J; Abyzov, A; Balasubramanian, S; Beal, K; Chakravarty, D; Challis, D; Chen, Y; Clarke, D; Clarke, L; Cunningham, F; Evani, US; Flicek, P; Fragoza, R; Garrison, E; Gibbs, R; Gümüş, ZH; Herrero, J; Kitabayashi, N; Kong, Y; Lage, K; Liluashvili, V; Lipkin, SM; MacArthur, DG; Marth, G; Muzny, D; Pers, TH; Ritchie, GRS; Rosenfeld, JA; Sisu, C; Wei, X; Wilson, M; Xue, Y; Yu, F; 1000 Genomes Project Consortium, ; Dermitzakis, ET; Yu, H; Rubin, MA; Tyler-Smith, C; Gerstein, M

Published Date

  • October 2013

Published In

Volume / Issue

  • 342 / 6154

Start / End Page

  • 1235587 -

PubMed ID

  • 24092746

Pubmed Central ID

  • PMC3947637

Electronic International Standard Serial Number (EISSN)

  • 1095-9203

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.1235587


  • eng