Integrative Annotation of Variants from 1092 Humans: Application to Cancer Genomics

Author:

Khurana Ekta12,Fu Yao1,Colonna Vincenza34,Mu Xinmeng Jasmine1,Kang Hyun Min5,Lappalainen Tuuli678,Sboner Andrea910,Lochovsky Lucas1,Chen Jieming111,Harmanci Arif12,Das Jishnu1213,Abyzov Alexej12,Balasubramanian Suganthi12,Beal Kathryn14,Chakravarty Dimple9,Challis Daniel15,Chen Yuan3,Clarke Declan16,Clarke Laura14,Cunningham Fiona14,Evani Uday S.15,Flicek Paul14,Fragoza Robert1317,Garrison Erik18,Gibbs Richard15,Gümüş Zeynep H.1019,Herrero Javier14,Kitabayashi Naoki9,Kong Yong220,Lage Kasper2122232425,Liluashvili Vaja1019,Lipkin Steven M.26,MacArthur Daniel G.2227,Marth Gabor18,Muzny Donna15,Pers Tune H.242829,Ritchie Graham R. S.14,Rosenfeld Jeffrey A.303132,Sisu Cristina12,Wei Xiaomu1326,Wilson Michael133,Xue Yali3,Yu Fuli15,Dermitzakis Emmanouil T.678,Yu Haiyuan1213,Rubin Mark A.9,Tyler-Smith Chris3,Gerstein Mark1234,

Affiliation:

1. Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.

2. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.

3. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.

4. Institute of Genetics and Biophysics, National Research Council (CNR), 80131 Naples, Italy.

5. Center for Statistical Genetics, Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.

6. Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva Switzerland.

7. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland.

8. Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland.

9. 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.

10. The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA.

11. Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, CT 06520, USA.

12. Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA.

13. Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.

14. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.

15. Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USA.

16. Department of Chemistry, Yale University, New Haven, CT 06520, USA.

17. Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.

18. Department of Biology, Boston College, Chestnut Hill, MA 02467, USA.

19. Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, 10065, USA.

20. Keck Biotechnology Resource Laboratory, Yale University, New Haven, CT 06511, USA.

21. Pediatric Surgical Research Laboratories, MassGeneral Hospital for Children, Massachusetts General Hospital, Boston, MA 02114, USA.

22. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.

23. Harvard Medical School, Boston, MA 02115, USA.

24. Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.

25. Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.

26. Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.

27. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA.

28. Division of Endocrinology and Center for Basic and Translational Obesity Research, Children’s Hospital, Boston, MA 02115, USA.

29. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

30. Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, USA.

31. IST/High Performance and Research Computing, Rutgers University Newark, NJ 07101, USA.

32. Sackler Institute for Comparative Genomics, American Museum of Natural History, New York, NY 10024, USA.

33. Child Study Center, Yale University, New Haven, CT 06520, USA.

34. Department of Computer Science, Yale University, New Haven, CT 06520, USA.

Abstract

Identifying Important Identifiers Each of us has millions of sequence variations in our genomes. Signatures of purifying or negative selection should help identify which of those variations is functionally important. Khurana et al. ( 1235587 ) used sequence polymorphisms from 1092 humans across 14 populations to identify patterns of selection, especially in noncoding regulatory regions. Noncoding regions under very strong negative selection included binding sites of some chromatin and general transcription factors (TFs) and core motifs of some important TF families. Positive selection in TF binding sites tended to occur in network hub promoters. Many recurrent somatic cancer variants occurred in noncoding regulatory regions and thus might indicate mutations that drive cancer.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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