Journal article
Integrative annotation of variants from 1092 humans: application to cancer genomics
Science (American Association for the Advancement of Science), Vol.342(6154), 1235587
10/04/2013
DOI: 10.1126/science.1235587
PMCID: PMC3947637
PMID: 24092746
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.
Details
- Title: Subtitle
- Integrative annotation of variants from 1092 humans: application to cancer genomics
- Creators
- Arif Harmanci - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USAJishnu Das - Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USAAlexej Abyzov - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USASuganthi Balasubramanian - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USAKathryn Beal - European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UKDimple Chakravarty - Institute for Precision Medicine and the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, NY 10065, USADaniel Challis - Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USAYuan Chen - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UKDeclan Clarke - Department of Chemistry, Yale University, New Haven, CT 06520, USALaura Clarke - European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UKFiona Cunningham - European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UKUday S Evani - Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USAPaul Flicek - European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UKRobert Fragoza - Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USAErik Garrison - Department of Biology, Boston College, Chestnut Hill, MA 02467, USARichard Gibbs - Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USAZeynep H Gümüş - Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, 10065, USAJavier Herrero - European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UKNaoki Kitabayashi - Institute for Precision Medicine and the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, NY 10065, USAYong Kong - Keck Biotechnology Resource Laboratory, Yale University, New Haven, CT 06511, USAKasper Lage - Center for Protein Research, University of Copenhagen, Copenhagen, DenmarkVaja Liluashvili - Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, 10065, USASteven M Lipkin - Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USADaniel G MacArthur - Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USAGabor Marth - Department of Biology, Boston College, Chestnut Hill, MA 02467, USADonna Muzny - Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USATune H Pers - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USAGraham R S Ritchie - European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UKJeffrey A Rosenfeld - Sackler Institute for Comparative Genomics, American Museum of Natural History, New York, NY 10024, USACristina Sisu - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USAXiaomu Wei - Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USAEkta Khurana - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USAMichael Wilson - Child Study Center, Yale University, New Haven, CT 06520, USAYao Fu - Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USAYali Xue - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UKVincenza Colonna - Institute of Genetics and Biophysics, National Research Council (CNR), 80131 Naples, ItalyFuli Yu - Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USAXinmeng Jasmine Mu - Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USAEmmanouil T Dermitzakis - Swiss Institute of Bioinformatics, 1211 Geneva, SwitzerlandHyun Min Kang - Center for Statistical Genetics, Biostatistics, University of Michigan, Ann Arbor, MI 48109, USAHaiyuan Yu - Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USATuuli Lappalainen - Swiss Institute of Bioinformatics, 1211 Geneva, SwitzerlandMark A Rubin - Institute for Precision Medicine and the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, NY 10065, USAAndrea Sboner - The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USAChris Tyler-Smith - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UKLucas Lochovsky - Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USAMark Gerstein - Department of Computer Science, Yale University, New Haven, CT 06520, USAJieming Chen - Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, CT 06520, USA1000 Genomes Project Consortium
- Contributors
- Jacob J Michaelson (Contributor) - University of Iowa, Roy J. Carver Department of Biomedical Engineering
- Resource Type
- Journal article
- Publication Details
- Science (American Association for the Advancement of Science), Vol.342(6154), 1235587
- Publisher
- United States
- DOI
- 10.1126/science.1235587
- PMID
- 24092746
- PMCID
- PMC3947637
- ISSN
- 0036-8075
- eISSN
- 1095-9203
- Grant note
- HG007000 / NHGRI NIH HHS WT090532 / Wellcome Trust R01 GM104424 / NIGMS NIH HHS R01 CA152057 / NCI NIH HHS 085532 / Wellcome Trust U01HG6513 / NHGRI NIH HHS 090532 / Wellcome Trust R01 HG002898 / NHGRI NIH HHS 095908 / Wellcome Trust U54 HG003079 / NHGRI NIH HHS CA167824 / NCI NIH HHS U01 HG006513 / NHGRI NIH HHS WT098051 / Wellcome Trust U01 HG005718 / NHGRI NIH HHS GM104424 / NIGMS NIH HHS R01 CA166661 / NCI NIH HHS G12 MD007579 / NIMHD NIH HHS G12 RR003050 / NCRR NIH HHS P20 MD006899 / NIMHD NIH HHS WT095908 / Wellcome Trust R01CA152057 / NCI NIH HHS R01 HG004719 / NHGRI NIH HHS WT085532 / Wellcome Trust U01 CA111275 / NCI NIH HHS U41 HG007000 / NHGRI NIH HHS R01HG4719 / NHGRI NIH HHS UL1 TR000457 / NCATS NIH HHS HG005718 / NHGRI NIH HHS R01 CA167824 / NCI NIH HHS 098051 / Wellcome Trust R01 GM097358 / NIGMS NIH HHS
- Language
- English
- Date published
- 10/04/2013
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Communication Sciences and Disorders; Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984070750002771
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