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

Zh, Gümüs; Yu, J.; Yu, H.; Yu, Fuli; Yu, Haiyuan; Khurana, Ekta; Fu, Yao; Colonna, Vincenza; Chen, J.; Chen, Y.; Mu, Xinmeng Jasmine; Kang, Hyun Min; Xj, Mu; Hm, Kang; Us, Evani; Sm, Lipkin; Lappalainen, Tuuli; Dg, MacArthur; Th, Pers; Gr, Ritchie; Ja, Rosenfeld; Sboner, Andrea; Consortium, Genomes Project; Dm, Altshuler; Rm, Durbin; Harmanci, Arif; Lochovsky, Lucas; Gr, Abecasis; Dr, Bentley; Ag, Clark; Ee, Eichler; Yu, F.; Sb, Gabriel; Ra, Gibbs; Altshuler, D. M.; Ed, Green; Das, Jishnu; Durbin, R. M.; Me, Hurles; Chakravarti, A.; Abecasis, G. R.; Bm, Knoppers; Jo, Korbel; Abyzov, Alexej; Bentley, D. R.; Donnelly, P.; Es, Lander; Clark, A. G.; Balasubramanian, Suganthi; Hans Lehrach, H.; Eichler, E. E.; Er, Mardis; Zhang, W.; Gabriel, S. B.; Zhao, J.; Gt, Marth; Zhao, M.; Beal, Kathryn; Zheng, X.; Green, E. D.; Zhou, Y.; Hurles, M. E.; Ga, McVean; Zheng Bradley, X.; Knoppers, B. M.; Chakravarty, Dimple; Lee, C.; Da, Nickerson; Korbel, J. O.; Jp, Schmidt; Lander, E. S.; St, Sherry; Challis, Daniel; Lehrach, H.; Rk, Wilson; Mardis, E. R.; McVean, G. A.; Nickerson, D. A.; Schmidt, J. P.; Wang, J.; Sherry, S. T.; Clarke, Declan; Gümüş, Zeynep H.; Dinh, H.; Wilson, R. K.; Kovar, C.; Zhan, Y.; Lee, S.; Chen, Jieming; Lewis, L.; Clarke, Laura; Reid, J.; Wang, M.; Fang, X.; Guo, X.; Cunningham, Fiona; Jian, M.; Jiang, H.; Jin, X.; Li, G.; Garrison, Erik; Li, J.; Zhang, F.; Ma, X.; Li, Y.; Zheng, H.; Li, Z.; Zhu, H.; Liu, X.; Evani, Uday S.; Gibbs, Richard; Lu, Y.; Flicek, Paul; Su, Z.; Zhang, M.; Gibbs, Richard A.; Tai, S.; Tang, M.; von Grotthuss, M.; Wang, B.; Re, Smith; Zhang, C.; Fragoza, Robert; Wang, G.; Wu, H.; Wu, R.; Yin, Y.; del Angel, G.; Ritchie, Graham-R.-S.; Mw, Albrecht; Vs, Amstislavskiy; Gupta, N.; Ta, Borodina; Leinonen, R.; Sudbrack, R.; Grocock, R.; Smith, R. E.; Humphray, S.; James, T.; Ml, Yaspo; Kingsbury, Z.; Herrero, Javier; Sudbrak, R.; Albrecht, M. W.; Lienhard, M.; Gm, Weinstock; Amstislavskiy, V. S.; Mertes, F.; Kitabayashi, Naoki; Borodina, T. A.; Sultan, M.; Tm, Keane; Timmermann, Bernd; Marth, Gabor T.; Fulton, L.; Yaspo, M. L.; Kong, Yong; Fulton, R.; Marth, Gabor; Balasubramaniam, S.; Cj, Davies; Weinstock, G. M.; Burton, J.; Lage, Kasper; Danecek, P.; Zakharia, F.; Kolb Kokocinski, A.; McCarthy, S.; Keane, T. M.; Liluashvili, Vaja; Stalker, J.; Quail, M.; Gollub, J.; Davies, C. J.; Webster, T.; Lj, Coin; Wong, B.; Auton, A.; Lipkin, Steven M.; Bainbridge, M.; Chen, Yuan; Lu, J.; Nagaswamy, U.; Sabo, A.; MacArthur, Daniel G.; Wang, Y.; Fang, L.; Coin, L. J.; Li, Q.; Muzny, Donna; Lin, H.; Ep, Garrison; Liu, B.; Luo, R.; Wp, Lee; Qin, N.; Wf, Leong; Shao, H.; An, Ward; Xie, Y.; Ye, C.; Ch, Hsieh; Yu, C.; Re, Mills; Pers, Tune H.; Kural, D.; Lee, W. P.; Mj, Daly; Wu, J.; Ma, DePristo; Leong, W. F.; Sisu, Cristina; Ward, A. N.; Mo, Carneiro; Griffin, L.; Rosenfeld, Jeffrey A.; Zhang, Q.; Re, Handsaker; Hsieh, C. H.; Wei, Xiaomu; Shi, X.; Mills, R. E.; Zhang, Y.; Sa, McCarroll; Garrison, Erik P.; Jc, Nemesh; Wilson, Michael; Banks, E.; Re, Poplin; Daly, M. J.; Bhatia, G.; DePristo,; Sf, Schaffner; Sc, Yoon; Xue, Yali; Genovese, G.; Carneiro, M. O.; Hartl, C.; Handsaker, R. E.; McCarroll, S. A.; Kc, Kim; Nemesh, J. C.; Shakir, K.; Poplin, R. E.; Gerstein, Mark; Wm, McLaren; Lihm, J.; Schaffner, S. F.; Kim, W.; Makarov, V.; Jl, Rodriguez Flores; Yoon, S. C.; Pc, Sabeti; Jin, H.; Dermitzakis, Emmanouil T.; Rausch, T.; Sr, Grossman; Kim, K. C.; Zhang, H.; Dn, Cooper; Gottipati, S.; McLaren, W. M.; Ev, Ball; Keinan, A.; Pd, Stenson; Rodriguez-Flores, J. L.; Tabrizi, S.; Rubin, Mark A.; Tariyal, R.; Sabeti, P. C.; Grossman,; Tyler-Smith, Chris; Cooper, D. N.; Barnes, B.; Ball, E.; Bauer, M.; Stenson, P. D.; Zhu, J.; Cheetham, R.; Cox, T.; Eberle, M.; Ma, Batzer; Kahn, S.; Murray, L.; Mk, Konkel; Peden, J.; Ja, Walker; Shaw, R.; Ye, K.; Md, Shriver; Cd, Bustamante; Batzer,; Gumus, Zeynep H.; Lek, M.; Jk, Byrnes; Konkel, M. K.; Walker, J. A.; Herwig, R.; Ee, Kenny; Shriver,; Bustamante, C. D.; Byrnes, J. K.; Gravel, S.; Jm, Kidd; De La Vega, M.; Bk, Maples; Kenny, E. E.; Kidd, J. M.; Lacroute, P.; Maples, B. K.; Moreno Estrada, A.; Dw, Craig; Halperin, E.; Baran, Y.; Christoforides, A.; Aa, Kurdoglu; Craig, D. W.; Homer, N.; Sa, Sinari; Izatt, T.; Kurdoglu, A. A.; Squire, K.; Sinari, S. A.; Xiao, C.; Ritchie, Graham R. S.; Eg, Burchard; Sebat, J.; Bafna, V.; Rd, Hernandez; Burchard, E. G.; Cr, Gignoux; Sj, Katzman; Hernandez, R. D.; Haussler, D.; Gignoux, C. R.; Kent, W.; Katzman, S. J.; Howie, B.; Et, Dermitzakis; Ruiz Linares, A.; Se, Devine; Maroo, A.; Devine, S. E.; Lj, Tallon; Tallon, L. J.; Harmanci, Arif O.; Lp, Michelson; Michelson, L. P.; Anderson, P.; Angius, A.; Bigham, A.; Blackwell, T.; Busonero, F.; Cucca, F.; Fuchsberger, C.; Jones, C.; Jun, G.; Lyons, R.; Maschio, A.; Porcu, E.; Reinier, F.; Sanna, S.; Schlessinger, D.; Sidore, C.; Tan, A.; Mk, Trost; Trost, M. K.; Awadalla, P.; Hodgkinson, A.; Lunter, G.; Marchini, J. L.; Myers, S.; Jl, Marchini; Churchhouse, C.; Delaneau, O.; Gupta Hinch, A.; Iqbal, Z.; Mathieson, I.; Rimmer, A.; Xifara, D. K.; Oleksyk, T. K.; Xiong, M.; Dk, Xifara; Jorde, L.; Tk, Oleksyk; Witherspoon, D.; Xing, J.; Browning, B. L.; Alkan, C.; Hajirasouliha, I.; Hormozdiari, F.; Bl, Browning; Chen, K.; Ko, A.; Sudmant, P. H.; Chinwalla, A.; De La Vega, F. M.; Ph, Sudmant; Ding, L.; Dooling, D.; Koboldt, D. C.; McLellan,; Wallis, J. W.; Dc, Koboldt; Wendl, M. C.; Md, McLellan; Albers, C. A.; Jw, Wallis; Ayub, Q.; Mc, Wendl; Coffey, A. J.; Ca, Albers; Huang, N.; Jostins, L.; Aj, Coffey; Li, H.; Scally, A.; Walter, K.; Habegger, L.; Mb, Gerstein; Jin, M.; Degenhardt, J.; Ao, Harmanci; Stütz, A. M.; Church, D.; Am, Stütz; Michaelson, J. J.; Blackburne, B.; Jj, Michaelson; Lindsay, S. J.; Ning, Z.; Sj, Lindsay; Frankish, A.; Harrow, J.; Kalra, D.; Fm, De La Vega; Hale, W.; Fowler, G.; Barker, J.; Kelman, G.; Kulesha, E.; Radhakrishnan, R.; Roa, A.; Smirnov, D.; Streeter, I.; Gerstein, Mark B.; Toneva, I.; Vaughan, B.; Ananiev, V.; Belaia, Z.; Beloslyudtsev, D.; Bouk, N.; Chen, C.; Cohen, R.; Cook, C.; Garner, J.; Hefferon, T.; Kimelman, M.; Liu, C.; Lopez, J.; Meric, P.; O'Sullivan, C.; Ostapchuk, Y.; Phan, L.; Ponomarov, S.; Schneider, V.; Shekhtman, E.; Sirotkin, K.; Slotta, D.; Kc, Barnes; Barnes, K. C.; Beiswanger, C.; Burchard, E.; Cai, H.; Cao, H.; Gharani, N.; Js, Kaye; Henn, B.; Jones, D.; Kaye, J. S.; Kent, A.; Kerasidou, A.; Pn, Ossorio; Mathias, R.; McVean, G.; Ossorio, P. N.; Parker, M.; Cn, Rotimi; Reich, D.; Cd, Royal; Rotimi, C. N.; Royal, C. D.; Sandoval, K.; Su, Y.; Tian, Z.; Lh, Toji; Tishkoff, S.; Toji, L. H.; Via, M.; Yang, H.; Yang, L.; Cz, Ming; Bodmer, W.; Bedoya, G.; Cj, You; Ming, C. Z.; Yang, G.; You, C. J.; Peltonen, L.; Garcia Montero, A.; Jc, Martinez Cruzado; Orfao, A.; Ld, Brooks; Dutil, J.; Al, Felsenfeld; Martinez-Cruzado, J. C.; Je, McEwen; Brooks, L. D.; Nc, Clemm; Felsenfeld, A. L.; McEwen, J. E.; Clemm, N. C.; Duncanson, A.; Ms, Guyer; Dunn, M.; Jl, Peterson; Guyer,; Ma, Rubin; Peterson, J. L.

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American Association for the Advancement of Science, Science, 6154(342), 2013

DOI: 10.1126/science.1235587

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

Journal article published in 2013 by Gümüs Zh, J. Yu, H. Yu, Fuli Yu, Haiyuan Yu, Ekta Khurana, Yao Fu, Vincenza Colonna, J. Chen, Y. Chen, Xinmeng Jasmine Mu, Hyun Min Kang, Mu Xj, Kang Hm, Evani Us and other authors.

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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.

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

Abstract