Integrative annotation of variants from 1092 humans: application to cancer genomics.
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Khurana E
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
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Fu Y
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
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Colonna V
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.
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Mu XJ
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
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Kang HM
Center for Statistical Genetics, Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
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Lappalainen T
Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.
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Sboner A
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, USA.
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Lochovsky L
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
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Chen J
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
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Harmanci A
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
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Das J
Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA.
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Abyzov A
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
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Balasubramanian S
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
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Beal K
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
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Chakravarty D
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, USA.
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Challis D
Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USA.
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Chen Y
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.
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Clarke D
Department of Chemistry, Yale University, New Haven, CT 06520, USA.
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Clarke L
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
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Cunningham F
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
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Evani US
Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USA.
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Flicek P
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
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Fragoza R
Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.
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Garrison E
Department of Biology, Boston College, Chestnut Hill, MA 02467, USA.
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Gibbs R
Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USA.
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Gümüş ZH
The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA.
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Herrero J
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
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Kitabayashi N
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, USA.
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Kong Y
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
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Lage K
Pediatric Surgical Research Laboratories, MassGeneral Hospital for Children, Massachusetts General Hospital, Boston, MA 02114, USA.
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Liluashvili V
The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA.
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Lipkin SM
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
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MacArthur DG
Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
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Marth G
Department of Biology, Boston College, Chestnut Hill, MA 02467, USA.
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Muzny D
Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USA.
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Pers TH
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
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Ritchie GRS
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
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Rosenfeld JA
Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, USA.
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Sisu C
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
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Wei X
Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.
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Wilson M
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
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Xue Y
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.
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Yu F
Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USA.
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Dermitzakis ET
Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA.
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Yu H
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, USA.
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Rubin MA
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.
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Tyler-Smith C
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
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Gerstein M
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Published in:
- Science (New York, N.Y.). - 2013
English
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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Open access status
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green
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Persistent URL
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https://sonar.ch/global/documents/192012
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