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

被引：273

作者：

Khurana, Ekta ^{[1
,2
]}

Fu, Yao ^{[1
]}

Colonna, Vincenza ^{[3
,4
]}

Mu, Xinmeng Jasmine ^{[1
]}

Kang, Hyun Min ^{[5
]}

Lappalainen, Tuuli ^{[6
,7
,8
]}

Sboner, Andrea ^{[9
,10
,11
,12
]}

Lochovsky, Lucas ^{[1
]}

Chen, Jieming ^{[1
,13
]}

Harmanci, Arif ^{[1
,2
]}

Das, Jishnu ^{[14
,15
]}

Abyzov, Alexej ^{[1
,2
]}

Balasubramanian, Suganthi ^{[1
,2
]}

Beal, Kathryn ^{[16
]}

Chakravarty, Dimple ^{[9
,10
,11
]}

Challis, Daniel ^{[17
]}

Chen, Yuan ^{[3
]}

Clarke, Declan ^{[18
]}

Clarke, Laura ^{[16
]}

Cunningham, Fiona ^{[16
]}

Evani, Uday S. ^{[17
]}

Flicek, Paul ^{[16
]}

Fragoza, Robert ^{[15
,19
]}

Garrison, Erik ^{[20
]}

Gibbs, Richard ^{[17
]}

Gumus, Zeynep H. ^{[12
,21
]}

Herrero, Javier ^{[16
]}

Kitabayashi, Naoki ^{[9
,10
,11
]}

Kong, Yong ^{[2
,22
]}

Lage, Kasper ^{[23
,24
,25
,26
,27
]}

Liluashvili, Vaja ^{[12
,21
]}

Lipkin, Steven M. ^{[28
]}

MacArthur, Daniel G. ^{[24
,29
]}

Marth, Gabor ^{[20
]}

Muzny, Donna ^{[17
]}

Pers, Tune H. ^{[26
,30
,31
,32
]}

Ritchie, Graham R. S. ^{[16
]}

Rosenfeld, Jeffrey A. ^{[33
,34
]}

Sisu, Cristina ^{[1
,2
]}

Wei, Xiaomu ^{[15
,28
]}

Wilson, Michael ^{[1
,35
]}

Xue, Yali ^{[3
]}

Yu, Fuli ^{[17
]}

Dermitzakis, Emmanouil T. ^{[6
,7
,8
]}

Yu, Haiyuan ^{[14
,15
]}

Rubin, Mark A. ^{[9
,10
,11
]}

Tyler-Smith, Chris ^{[3
]}

Gerstein, Mark ^{[1
,2
,36
]}

机构：

[1] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA

[2] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA

[3] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England

[4] CNR, Inst Genet & Biophys, I-80131 Naples, Italy

[5] Univ Michigan, Ctr Stat Genet, Biostat, Ann Arbor, MI 48109 USA

[6] Univ Geneva, Med Sch, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland

[7] Univ Geneva, iGE3, CH-1211 Geneva, Switzerland

[8] Swiss Inst Bioinformat, CH-1211 Geneva, Switzerland

[9] Weill Cornell Med Coll, Inst Precis Med, New York, NY 10065 USA

[10] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA

[11] New York Presbyterian Hosp, New York, NY 10065 USA

[12] Weill Cornell Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10021 USA

[13] Yale Univ, Integrated Grad Program Phys & Engn Biol, New Haven, CT 06520 USA

[14] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY 14853 USA

[15] Cornell Univ, Weill Inst Cell & Mol Biol, Ithaca, NY 14853 USA

[16] European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England

[17] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[18] Yale Univ, Dept Chem, New Haven, CT 06520 USA

[19] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA

[20] Boston Coll, Dept Biol, Chestnut Hill, MA 02467 USA

[21] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA

[22] Yale Univ, Keck Biotechnol Resource Lab, New Haven, CT 06511 USA

[23] Massachusetts Gen Hosp, MassGen Hosp Children, Pediat Surg Res Labs, Boston, MA USA

[24] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[25] Harvard Med Sch, Boston, MA USA

[26] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, Lyngby, Denmark

[27] Univ Copenhagen, Ctr Prot Res, Copenhagen, Denmark

[28] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA

[29] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA

[30] Childrens Hosp, Div Endocrinol, Boston, MA USA

[31] Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA

[32] Broad Inst MIT & Harvard, Cambridge, MA USA

[33] Univ Med & Dent New Jersey, Dept Med, Newark, NJ 07101 USA

[34] Univ Med & Dent New Jersey, IST High Performance & Res Comp, Newark, NJ 07101 USA

[35] Yale Univ, Ctr Child Study, New Haven, CT 06520 USA

[36] Yale Univ, Dept Comp Sci, New Haven, CT 06520 USA

来源：

SCIENCE | 2013年 / 342卷 / 6154期

基金：

英国惠康基金;

关键词：

TERT PROMOTER MUTATIONS; NATURAL-SELECTION; POSITIVE SELECTION; COPY NUMBER; ELEMENTS; NETWORK; REGIONS;

D O I：

10.1126/science.1235587

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 similar to 90 cancer genomes reveals nearly a hundred candidate noncoding drivers.

引用

页码：84 / +

页数：10

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