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

TitleIntegrative annotation of variants from 1092 humans: application to cancer genomics.
Publication TypeJournal Article
Year of Publication2013
AuthorsKhurana E, Fu Y, Colonna V, Mu XJasmine, Kang HMin, 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, Gümüs 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, Dermitzakis ET, Yu H, Rubin MA, Tyler-Smith C, Gerstein M
Corporate Authors1000 Genomes Project Consortium
JournalScience
Volume342
Issue6154
Pagination1235587
Date Published2013 Oct 4
ISSN1095-9203
KeywordsBinding Sites, Genetic Variation, Genome, Human, Genomics, Humans, Kruppel-Like Transcription Factors, Molecular Sequence Annotation, Mutation, Neoplasms, Polymorphism, Single Nucleotide, Population, RNA, Untranslated, Selection, Genetic
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.

DOI10.1126/science.1235587
Alternate JournalScience
PubMed ID24092746
PubMed Central IDPMC3947637
Grant List085532 / / Wellcome Trust / United Kingdom
090532 / / Wellcome Trust / United Kingdom
095908 / / Wellcome Trust / United Kingdom
098051 / / Wellcome Trust / United Kingdom
098051 / / Wellcome Trust / United Kingdom
CA167824 / CA / NCI NIH HHS / United States
G12 MD007579 / MD / NIMHD NIH HHS / United States
G12 RR003050 / RR / NCRR NIH HHS / United States
GM104424 / GM / NIGMS NIH HHS / United States
HG005718 / HG / NHGRI NIH HHS / United States
HG007000 / HG / NHGRI NIH HHS / United States
R01 CA166661 / CA / NCI NIH HHS / United States
R01 HG002898 / HG / NHGRI NIH HHS / United States
R01CA152057 / CA / NCI NIH HHS / United States
R01HG4719 / HG / NHGRI NIH HHS / United States
U01 CA111275 / CA / NCI NIH HHS / United States
U01 CA111275 / CA / NCI NIH HHS / United States
U01 HG005718 / HG / NHGRI NIH HHS / United States
U01HG6513 / HG / NHGRI NIH HHS / United States
U41 HG007000 / HG / NHGRI NIH HHS / United States
U54 HG003079 / HG / NHGRI NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
WT085532 / / Wellcome Trust / United Kingdom
WT095908 / / Wellcome Trust / United Kingdom
Research Reference: 
Gene Annotation