Integrative Annotation of Variants from 1092 Humans: Application to Cancer Genomics
Name
nihms-545446.pdf
Description
Accepted version
Size
2.99 MB
Format
Adobe PDF
Checksum (MD5)
268403ac513a8a4a66051e474f7e302a
Author(s)
Khurana, Ekta
Fu, Yao
Colonna, Vincenza
Mu, Xinmeng Jasmine
Kang, Hyun Min
Lappalainen, Tuuli
Sboner, Andrea
Lochovsky, Lucas
Chen, Jieming
Harmanci, Arif
Date Issued
October 2013
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Khurana, Ekta et al. "Research Article Integrative Annotation of Variants from 1092 Humans: Application to Cancer Genomics." Science 342, 6154 (October 2013): 1235587 © 2013 American Association for the Advancement of Science
Version
Author's final manuscript
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.
MIT Department
Broad Institute of MIT and Harvard
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1126/science.1235587
