Browsing by Author "Wilson, R. K."

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Open Access
Building and improving reference genome assemblies
(IEEE, 2017-01) Steinberg, K. M.; Schneider, V. A.; Alkan, Can; Montague, M. J.; Warren, W. C.; Church, D. M.; Wilson, R. K.
A genome sequence assembly provides the foundation for studies of genotypic and phenotypic variation, genome structure, and evolution of the target organism. In the past four decades, there has been a surge of new sequencing technologies, and with these developments, computational scientists have developed new algorithms to improve genome assembly. Here we discuss the relationship between sequencing technology improvements and assembly algorithm development and how these are applied to extend and improve human and nonhuman genome assemblies. © 1963-2012 IEEE.
Open Access
Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication
(Proceedings of the National Academy of Sciences, 2014-12-02) Montague, M. J.; Li, G.; Gandolfi, B.; Khan, R.; Aken, B. L.; Marques Bonet, T.; Alkan C.; Thomas, G. W. C.; Warren, W. C.; Searle, S. M. J.; Minx, M.; Hilliera, LaDeana W.; Koboldt, D. C.; Davis, B. W.; Driscoll, C. A.; Barr, C. S.; Blackistone, K.; Quilez, J.; Lorente-Galdos, B.; Marques Bonet, T.; Hahnj, M. W.; Menotti-Raymond, M.; O’Brien, S. J.; Wilson, R. K.; Lyons, L. A.; Murphy, W. J.
Little is known about the genetic changes that distinguish domestic cat populations from their wild progenitors. Here we describe a high-quality domestic cat reference genome assembly and comparative inferences made with other cat breeds, wildcats, and other mammals. Based upon these comparisons, we identified positively selected genes enriched for genes involved in lipid metabolism that underpin adaptations to a hypercarnivorous diet. We also found positive selection signals within genes underlying sensory processes, especially those affecting vision and hearing in the carnivore lineage. We observed an evolutionary tradeoff between functional olfactory and vomeronasal receptor gene repertoires in the cat and dog genomes, with an expansion of the feline chemosensory system for detecting pheromones at the expense of odorant detection. Genomic regions harboring signatures of natural selection that distinguish domestic cats from their wild congeners are enriched in neural crest-related genes associated with behavior and reward in mouse models, as predicted by the domestication syndrome hypothesis. Our description of a previously unidentified allele for the gloving pigmentation pattern found in the Birman breed supports the hypothesis that cat breeds experienced strong selection on specific mutations drawn from random bred populations. Collectively, these findings provide insight into how the process of domestication altered the ancestral wildcat genome and build a resource for future disease mapping and phylogenomic studies across all members of the Felidae.
Open Access
A global reference for human genetic variation
(Nature Publishing Group, 2015) Auton, A.; Abecasis, G. R.; Altshuler, D. M.; Durbin, R. M.; Bentley, D. R.; Chakravarti, A.; Clark, A. G.; Donnelly, P.; Eichler, E. E.; Flicek, P.; Gabriel, S. B.; Gibbs, R. A.; Green, E. D.; Hurles, M. E.; Knoppers, B. M.; Korbel, J. O.; Lander, E. S.; Lee, C.; Lehrach, H.; Mardis, E. R.; Marth, G. T.; McVean, G. A.; Nickerson, D. A.; Schmidt, J. P.; Sherry, S. T.; Wang, J.; Wilson, R. K.; Boerwinkle, E.; Doddapaneni, H.; Han, Y.; Korchina, V.; Kovar, C.; Lee, S.; Muzny, D.; Reid, J. G.; Zhu, Y.; Chang, Y.; Feng, Q.; Fang, X.; Guo, X.; Jian, M.; Jiang, H.; Jin, X.; Lan, T.; Li, G.; Li, J.; Li, Y.; Liu, S.; Liu, X.; Lu, Y.; Ma, X.; Tang, M.; Wang, B.; Wang, G.; Wu, H.; Wu, R.; Xu, X.; Yin, Y.; Zhang, D.; Zhang, W.; Zhao, J.; Zhao, M.; Zheng, X.; Gupta, N.; Gharani, N.; Toji, L. H.; Gerry, N. P.; Resch, A. M.; Barker, J.; Clarke, L.; Gil, L.; Hunt, S. E.; Kelman, G.; Kulesha, E.; Leinonen, R.; McLaren, W. M.; Radhakrishnan, R.; Roa, A.; Smirnov, D.; Smith, R. E.; Streeter, I.; Thormann, A.; Toneva, I.; Vaughan, B.; Zheng-Bradley, X.; Grocock, R.; Humphray, S.; James, T.; Kingsbury, Z.; Sudbrak, R.; Albrecht, M. W.; Amstislavskiy, V. S.; Borodina, T. A.; Lienhard, M.; Mertes, F.; Sultan, M.; Timmermann, B.; Yaspo, Marie-Laure; Fulton, L.; Ananiev, V.; Belaia, Z.; Beloslyudtsev, D.; Bouk, N.; Chen, C.; Church, D.; 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.; Zhang, H.; Balasubramaniam, S.; Burton, J.; Danecek, P.; Keane, T. M.; Kolb-Kokocinski, A.; McCarthy, S.; Stalker, J.; Quail, M.; Davies, C. J.; Gollub, J.; Webster, T.; Wong, B.; Zhan, Y.; Campbell, C. L.; Kong, Y.; Marcketta, A.; Yu, F.; Antunes, L.; Bainbridge, M.; Sabo, A.; Huang, Z.; Coin, L. J. M.; Fang, L.; Li, Q.; Li, Z.; Lin, H.; Liu, B.; Luo, R.; Shao, H.; Xie, Y.; Ye, C.; Yu, C.; Zhang, F.; Zheng, H.; Zhu, H.; Alkan, C.; Dal, E.; Kahveci, F.; Garrison, E. P.; Kural, D.; Lee, W. P.; Leong, W. F.; Stromberg, M.; Ward, A. N.; Wu, J.; Zhang, M.; Daly, M. J.; DePristo, M. A.; Handsaker, R. E.; Banks, E.; Bhatia, G.; Del Angel, G.; Genovese, G.; Li, H.; Kashin, S.; McCarroll, S. A.; Nemesh, J. C.; Poplin, R. E.; Yoon, S. C.; Lihm, J.; Makarov, V.; Gottipati, S.; Keinan, A.; Rodriguez-Flores, J. L.; Rausch, T.; Fritz, M. H.; Stütz, A. M.; Beal, K.; Datta, A.; Herrero, J.; Ritchie, G. R. S.; Zerbino, D.; Sabeti, P. C.; Shlyakhter, I.; Schaffner, S. F.; Vitti, J.; Cooper, D. N.; Ball, E. V.; Stenson, P. D.; Barnes, B.; Bauer, M.; Cheetham, R. K.; Cox, A.; Eberle, M.; Kahn, S.; Murray, L.; Peden, J.; Shaw, R.; Kenny, E. E.; Batzer, M. A.; Konkel, M. K.; Walker, J. A.; MacArthur, D. G.; Lek, M.; Herwig, R.; Ding, L.; Koboldt, D. C.; Larson, D.; Ye, K.; Gravel, S.; Swaroop, A.; Chew, E.; Lappalainen, T.; Erlich, Y.; Gymrek, M.; Willems, T. F.; Simpson, J. T.; Shriver, M. D.; Rosenfeld, J. A.; Bustamante, C. D.; Montgomery, S. B.; De La Vega, F. M.; Byrnes, J. K.; Carroll, A. W.; DeGorter, M. K.; Lacroute, P.; Maples, B. K.; Martin, A. R.; Moreno-Estrada, A.; Shringarpure, S. S.; Zakharia, F.; Halperin, E.; Baran, Y.; Cerveira, E.; Hwang, J.; Malhotra, A.; Plewczynski, D.; Radew, K.; Romanovitch, M.; Zhang, C.; Hyland, F. C. L.; Craig, D. W.; Christoforides, A.; Homer, N.; Izatt, T.; Kurdoglu, A. A.; Sinari, S. A.; Squire, K.; Xiao, C.; Sebat, J.; Antaki, D.; Gujral, M.; Noor, A.; Ye, K.; Burchard, E. G.; Hernandez, R. D.; Gignoux, C. R.; Haussler, D.; Katzman, S. J.; Kent, W. J.; Howie, B.; Ruiz-Linares, A.; Dermitzakis, E. T.; Devine, S. E.; Kang, H. M.; Kidd, J. M.; Blackwell, T.; Caron, S.; Chen, W.; Emery, S.; Fritsche, L.; Fuchsberger, C.; Jun, G.; Li, B.; Lyons, R.; Scheller, C.; Sidore, C.; Song, S.; Sliwerska, E.; Taliun, D.; Tan, A.; Welch, R.; Wing, M. K.; Zhan, X.; Awadalla, P.; Hodgkinson, A.; Li, Y.; Shi, X.; Quitadamo, A.; Lunter, G.; Marchini, J. L.; Myers, S.; Churchhouse, C.; Delaneau, O.; Gupta-Hinch, A.; Kretzschmar, W.; Iqbal, Z.; Mathieson, I.; Menelaou, A.; Rimmer, A.; Xifara, D. K.; Oleksyk, T. K.; Fu, Y.; Liu, X.; Xiong, M.; Jorde, L.; Witherspoon, D.; Xing, J.; Browning, B. L.; Browning, S. R.; Hormozdiari, F.; Sudmant, P. H.; Khurana, E.; Tyler-Smith, C.; Albers, C. A.; Ayub, Q.; Chen, Y.; Colonna, V.; Jostins, L.; Walter, K.; Xue, Y.; Gerstein, M. B.; Abyzov, A.; Balasubramanian, S.; Chen, J.; Clarke, D.; Fu, Y.; Harmanci, A. O.; Jin, M.; Lee, D.; Liu, J.; Mu, X. J.; Zhang, J.; Zhang, Y.; Hartl, C.; Shakir, K.; Degenhardt, J.; Meiers, S.; Raeder, B.; Casale, F. P.; Stegle, O.; Lameijer, E. W.; Hall, I.; Bafna, V.; Michaelson, J.; Gardner, E. J.; Mills, R. E.; Dayama, G.; Chen, K.; Fan, X.; Chong, Z.; Chen, T.; Chaisson, M. J.; Huddleston, J.; Malig, M.; Nelson, B. J.; Parrish, N. F.; Blackburne, B.; Lindsay, S. J.; Ning, Z.; Zhang, Y.; Lam, H.; Sisu, C.; Challis, D.; Evani, U. S.; Lu, J.; Nagaswamy, U.; Yu, J.; Li, W.; Habegger, L.; Yu, H.; Cunningham, F.; Dunham, I.; Lage, K.; Jespersen, J. B.; Horn, H.; Kim, D.; Desalle, R.; Narechania, A.; Sayres, M. A. W.; Mendez, F. L.; Poznik, G. D.; Underhill, P. A.; Mittelman, D.; Banerjee, R.; Cerezo, M.; Fitzgerald, T. W.; Louzada, S.; Massaia, A.; Yang, F.; Kalra, D.; Hale, W.; Dan, X.; Barnes, K. C.; Beiswanger, C.; Cai, H.; Cao, H.; Henn, B.; Jones, D.; Kaye, J. S.; Kent, A.; Kerasidou, A.; Mathias, R.; Ossorio, P. N.; Parker, M.; Rotimi, C. N.; Royal, C. D.; Sandoval, K.; Su, Y.; Tian, Z.; Tishkoff, S.; Via, M.; Wang, Y.; Yang, H.; Yang, L.; Zhu, J.; Bodmer, W.; Bedoya, G.; Cai, Z.; Gao, Y.; Chu, J.; Peltonen, L.; Garcia-Montero, A.; Orfao, A.; Dutil, J.; Martinez-Cruzado, J. C.; Mathias, R. A.; Hennis, A.; Watson, H.; McKenzie, C.; Qadri, F.; LaRocque, R.; Deng, X.; Asogun, D.; Folarin, O.; Happi, C.; Omoniwa, O.; Stremlau, M.; Tariyal, R.; Jallow, M.; Joof, F. S.; Corrah, T.; Rockett, K.; Kwiatkowski, D.; Kooner, J.; Hien, T. T.; Dunstan, S. J.; ThuyHang, N.; Fonnie, R.; Garry, R.; Kanneh, L.; Moses, L.; Schieffelin, J.; Grant, D. S.; Gallo, C.; Poletti, G.; Saleheen, D.; Rasheed, A.; Brooks, L. D.; Felsenfeld, A. L.; McEwen, J. E.; Vaydylevich, Y.; Duncanson, A.; Dunn, M.; Schloss, J. A.
The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies. © 2015 Macmillan Publishers Limited. All rights reserved.
Open Access
Great ape genetic diversity and population history
(Nature Publishing Group, 2013) Prado-Martinez, J.; Eichler, E. E.; Marques-Bonet, T.; Sudmant, P. H.; Kidd, J. M.; Li, H.; Kelley, J. L.; Lorente-Galdos, B.; Veeramah, K. R.; Woerner, A. E.; O’Connor, T. D.; Santpere, G.; Cagan, A.; Theunert, C.; Casals, F.; Laayouni, H.; Munch, K.; Hobolth, A.; Halager, A. E.; Malig, M.; Hernandez-Rodriguez, J.; Hernando-Herraez, I.; Prüfer, K.; Pybus, M.; Johnstone, L.; Lachmann, M.; Alkan C.; Twig, D.; Petit, N.; Baker, C.; Hormozdiari, F.; Fernandez-Callejo, M.; Dabad, M.; Wilson, M. L.; Stevison, L.; Camprubí, C.; Carvalho, T.; RuizHerrera, A.; Vives, L.; Mele, M.; Abello, T.; Kondova, I.; Bontrop, R. E.; Pusey, A.; Lankester, F.; Kiyang, J. A.; Bergl, R. A.; Lonsdorf, E.; Myers, S.; Ventura, M.; Gagneux, P.; Comas, D.; Siegismund, H.; Blanc, J.; Agueda-Calpena, L.; Gut, M.; Fulton, L.; Tishkoff, S. A.; Mullikin, J. C.; Wilson, R. K.; Gut, I. G.; Gonder, M K.; Ryder, O. A.; Hahn, B. H.; Navarro, A.; Akey, J. M.; Bertranpetit, J.; Reich, D.; Mailund, T.; Schierup, M. H.; Hvilsom, C.; Andrés, A. M.; Wall, J. D.; Bustamante, C. D.; Hammer, M. F.
Most great ape genetic variation remains uncharacterized(1,2); however, its study is critical for understanding population history(3-6), recombination(7), selection(8) and susceptibility to disease(9,10). Here we sequence to high coverage a total of 79 wild-and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria-Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.
Open Access
Oncogenic signaling pathways in the Cancer Genome Atlas
(Cell Press, 2018) Sanchez-Vega, F.; Mina, M.; Armenia, J.; Chatila, W. K.; Luna, A.; La, K. C.; Dimitriadoy, S.; Liu, D. L.; Kantheti, H. S.; Saghafinia, S.; Chakravarty, D.; Daian, F.; Gao, Q.; Bailey, M. H.; Liang, W. -W.; Foltz, S. M.; Shmulevich, I.; Ding, L.; Heins, Z.; Ochoa, A.; Gross, B.; Gao, J.; Zhang, H.; Kundra, R.; Kandoth, C.; Bahceci, I.; Dervishi, L.; Doğrusöz, Uğur; Zhou, W.; Shen, H.; Laird, P. W.; Way, G. P.; Greene, C. S.; Liang, H.; Xiao, Y.; Wang, C.; Iavarone, A.; Berger, A. H.; Bivona, T. G.; Lazar, A. J.; Hammer, G. D.; Giordano, T.; Kwong, L. N.; McArthur, G.; Huang, C.; Tward, A. D.; Frederick, M. J.; McCormick, F.; Meyerson, M.; Caesar-Johnson, S. J.; Demchok, J. A.; Felau, I.; Kasapi, M.; Ferguson, M. L.; Hutter, C. M.; Sofia, H. J.; Tarnuzzer, R.; Wang, Z.; Yang, L.; Zenklusen, J. C.; Zhang, J. J.; Chudamani, S.; Liu, J.; Lolla, L.; Naresh, R.; Pihl, T.; Sun, Q.; Wan, Y.; Wu, Y.; Cho, J.; DeFreitas, T.; Frazer, S.; Gehlenborg, N.; Getz, G.; Heiman, D. I.; Kim, J.; Lawrence, M. S.; Lin, P.; Meier, S.; Noble, M. S.; Saksena, G.; Voet, D.; Zhang, H.; Bernard, B.; Chambwe, N.; Dhankani, V.; Knijnenburg, T.; Kramer, R.; Leinonen, K.; Liu, Y.; Miller, M.; Reynolds, S.; Shmulevich, I.; Thorsson, V.; Zhang, W.; Akbani, R.; Broom, B. M.; Hegde, A. M.; Ju, Z.; Kanchi, R. S.; Korkut, A.; Li, J.; Liang, H.; Ling, S.; Liu W.; Lu, Y.; Mills, G. B.; Ng, K. -S.; Rao, A.; Ryan, M.; Wang, J.; Weinstein, J. N.; Zhang, J.; Abeshouse, A.; Armenia, J.; Chakravarty, D.; Chatila, W. K.; de, Bruijn, I.; Gao, J.; Gross, B. E.; Heins, Z. J.; Kundra, R.; La, K.; Ladanyi, M.; Luna, A.; Nissan, M. G.; Ochoa, A.; Phillips, S. M.; Reznik, E.; Sanchez-Vega, F.; Sander, C.; Schultz, N.; Sheridan, R.; Sumer, S. O.; Sun, Y.; Taylor, B. S.; Wang, J.; Zhang, H.; Anur, P.; Peto, M.; Spellman, P.; Benz, C.; Stuart, J. M.; Wong, C. K.; Yau, C.; Hayes, D. N.; Parker, J. S.; Wilkerson, M. D.; Ally, A.; Balasundaram, M.; Bowlby, R.; Brooks, D.; Carlsen, R.; Chuah, E.; Dhalla, N.; Holt, R.; Jones, S. J. M.; Kasaian, K.; Lee, D.; Ma, Y.; Marra, M. A.; Mayo, M.; Moore, R. A.; Mungall, A. J.; Mungall, K.; Robertson, A. G.; Sadeghi, S.; Schein, J. E.; Sipahimalani, P.; Tam, A.; Thiessen, N.; Tse, K.; Wong, T.; Berger, A. C.; Beroukhim, R.; Cherniack, A. D.; Cibulskis, C.; Gabriel, S. B.; Gao, G. F.; Ha, G.; Meyerson, M.; Schumacher, S. E.; Shih, J.; Kucherlapati, M. H.; Kucherlapati, R. S.; Baylin, S.; Cope, L.; Danilova, L.; Bootwalla, M. S.; Lai, P. H.; Maglinte, D. T.; Van, Den, Berg, D. J.; Weisenberger, D. J.; Auman, J. T.; Balu, S.; Bodenheimer, T.; Fan, C.; Hoadley, K. A.; Hoyle, A. P.; Jefferys, S. R.; Jones, C. D.; Meng, S.; Mieczkowski, P. A.; Mose, L. E.; Perou, A. H.; Perou, C. M.; Roach, J.; Shi, Y.; Simons, J. V.; Skelly, T.; Soloway, M. G.; Tan, D.; Veluvolu, U.; Fan, H.; Hinoue, T.; Laird, P. W.; Shen, H.; Zhou, W.; Bellair, M.; Chang, K.; Covington, K.; Creighton, C. J.; Dinh, H.; Doddapaneni, H.; Donehower, L. A.; Drummond, J.; Gibbs, R. A.; Glenn, R.; Hale, W.; Han, Y.; Hu, J.; Korchina, V.; Lee, S.; Lewis, L.; Li, W.; Liu, X.; Morgan, M.; Morton, D.; Muzny, D.; Santibanez, J.; Sheth, M.; Shinbrot, E.; Wang, L.; Wang, M.; Wheeler, D. A.; Xi, L.; Zhao, F.; Hess, J.; Appelbaum, E. L.; Bailey, M.; Cordes, M. G.; Ding, L.; Fronick, C. C.; Fulton, L. A.; Fulton, R. S.; Kandoth, C.; Mardis, E. R.; McLellan, M. D.; Miller, C. A.; Schmidt, H. K.; Wilson, R. K.; Crain, D.; Curley, E.; Gardner, J.; Lau, K.; Mallery, D.; Morris, S.; Paulauskis, J.; Penny, R.; Shelton, C.; Shelton, T.; Sherman, M.; Thompson, E.; Yena, P.; Bowen, J.; Gastier-Foster, J. M.; Gerken, M.; Leraas, K. M.; Lichtenberg, T. M.; Ramirez, N. C.; Wise, L.; Zmuda, E.; Corcoran, N.; Costello, T.; Hovens, C.; Carvalho, A. L.; de, Carvalho, A. C.; Fregnani, J. H.; Longatto-Filho, A.; Reis, R. M.; Scapulatempo-Neto, C.; Silveira, H. C. S.; Vidal, D. O.; Burnette, A.; Eschbacher, J.; Hermes, B.; Noss, A.; Singh, R.; Anderson, M. L.; Castro, P. D.; Ittmann, M.; Huntsman, D.; Kohl, B.; Le, X.; Thorp, R.; Andry, C.; Duffy, E. R.; Lyadov, V.; Paklina, O.; Setdikova, G.; Shabunin, A.; Tavobilov, M.; McPherson, C.; Warnick, R.; Berkowitz, R.; Cramer, D.; Feltmate, C.; Horowitz, N.; Kibel, A.; Muto, M.; Raut, C. P.; Malykh, A.; Barnholtz-Sloan, J. S.; Barrett, W.; Devine, K.; Fulop, J.; Ostrom, Q. T.; Shimmel, K.; Wolinsky, Y.; Sloan, A. E.; De, Rose, A.; Giuliante, F.; Goodman, M.; Karlan, B. Y.; Hagedorn, C. H.; Eckman, J.; Harr, J.; Myers, J.; Tucker, K.; Zach, L. A.; Deyarmin, B.; Hu, H.; Kvecher, L.; Larson, C.; Mural, R. J.; Somiari, S.; Vicha, A.; Zelinka, T.; Bennett, J.; Iacocca, M.; Rabeno, B.; Swanson, P.; Latour, M.; Lacombe, L.; Têtu, B.; Bergeron, A.; McGraw, M.; Staugaitis, S. M.; Chabot, J.; Hibshoosh, H.; Sepulveda, A.; Su, T.; Wang, T.; Potapova, O.; Voronina, O.; Desjardins, L.; Mariani, O.; Roman-Roman, S.; Sastre, X.; Stern, M. -H.; Cheng, F.; Signoretti, S.; Berchuck, A.; Bigner, D.; Lipp, E.; Marks, J.; McCall, S.; McLendon, R.; Secord, A.; Sharp, A.; Behera, M.; Brat, D. J.; Chen, A.; Delman, K.; Force, S.; Khuri, F.; Magliocca, K.; Maithel, S.; Olson, J. J.; Owonikoko, T.; Pickens, A.; Ramalingam, S.; Shin, D. M.; Sica, G.; Van, Meir, E. G.; Zhang, H.; Eijckenboom, W.; Gillis, A.; Korpershoek, E.; Looijenga, L.; Oosterhuis, W.; Stoop, H.; van, Kessel, K. E.; Zwarthoff, E. C.; Calatozzolo, C.; Cuppini, L.; Cuzzubbo, S.; DiMeco, F.; Finocchiaro, G.; Mattei, L.; Perin, A.; Pollo, B.; Chen, C.; Houck, J.; Lohavanichbutr, P.; Hartmann, A.; Stoehr, C.; Stoehr, R.; Taubert, H.; Wach, S.; Wullich, B.; Kycler, W.; Murawa, D.; Wiznerowicz, M.; Chung, K.; Edenfield, W. J.; Martin, J.; Baudin, E.; Bubley, G.; Bueno, R.; De, Rienzo, A.; Richards, W. G.; Kalkanis, S.; Mikkelsen, T.; Noushmehr, H.; Scarpace, L.; Girard, N.; Aymerich, M.; Campo, E.; Giné, E.; Guillermo, A. L.; Van, Bang, N.; Hanh, P. T.; Phu, B. D.; Tang, Y.; Colman, H.; Evason, K.; Dottino, P. R.; Martignetti, J. A.; Gabra, H.; Juhl, H.; Akeredolu, T.; Stepa, S.; Hoon, D.; Ahn, K.; Kang, K. J.; Beuschlein, F.; Breggia, A.; Birrer, M.; Bell, D.; Borad, M.; Bryce, A. H.; Castle, E.; Chandan, V.; Cheville, J.; Copland, J. A.; Farnell, M.; Flotte, T.; Giama, N.; Ho, T.; Kendrick, M.; Kocher, J. -P.; Kopp, K.; Moser, C.; Nagorney, D.; O'Brien, D.; O'Neill, B. P.; Patel, T.; Petersen, G.; Que, F.; Rivera, M.; Roberts, L.; Smallridge, R.; Smyrk, T.; Stanton, M.; Thompson, R. H.; Torbenson, M.; Yang, J. D.; Zhang, L.; Brimo, F.; Ajani, J. A.; Gonzalez, A. M. A.; Behrens, C.; Bondaruk, J.; Broaddus, R.; Czerniak, B.; Esmaeli, B.; Fujimoto, J.; Gershenwald, J.; Guo, C.; Lazar, A. J.; Logothetis, C.; Meric-Bernstam, F.; Moran, C.; Ramondetta, L.; Rice, D.; Sood, A.; Tamboli, P.; Thompson, T.; Troncoso, P.; Tsao, A.; Wistuba, I.; Carter, C.; Haydu, L.; Hersey, P.; Jakrot, V.; Kakavand, H.; Kefford, R.; Lee, K.; Long, G.; Mann, G.; Quinn, M.; Saw, R.; Scolyer, R.; Shannon, K.; Spillane, A.; Stretch, J.; Synott, M.; Thompson, J.; Wilmott, J.; Al-Ahmadie, H.; Chan, T. A.; Ghossein, R.; Gopalan, A.; Levine, D. A.; Reuter, V.; Singer, S.; Singh, B.; Tien, N. V.; Broudy, T.; Mirsaidi, C.; Nair, P.; Drwiega, P.; Miller, J.; Smith, J.; Zaren, H.; Park, J. -W.; Hung, N. P.; Kebebew, E.; Linehan, W. M.; Metwalli, A. R.; Pacak, K.; Pinto, P. A.; Schiffman, M.; Schmidt, L. S.; Vocke, C. D.; Wentzensen, N.; Worrell, R.; Yang, H.; Moncrieff, M.; Goparaju, C.; Melamed, J.; Pass, H.; Botnariuc, N.; Caraman, I.; Cernat, M.; Chemencedji, I.; Clipca, A.; Doruc, S.; Gorincioi, G.; Mura, S.; Pirtac, M.; Stancul, I.; Tcaciuc, D.; Albert, M.; Alexopoulou, I.; Arnaout, A.; Bartlett, J.; Engel, J.; Gilbert, S.; Parfitt, J.; Sekhon, H.; Thomas, G.; Rassl, D. M.; Rintoul, R. C.; Bifulco, C.; Tamakawa, R.; Urba, W.; Hayward, N.; Timmers, H.; Antenucci, A.; Facciolo, F.; Grazi, G.; Marino, M.; Merola, R.; de, Krijger, R.; Gimenez-Roqueplo, A. -P.; Piché, A.; Chevalier, S.; McKercher, G.; Birsoy, K.; Barnett, G.; Brewer, C.; Farver, C.; Naska, T.; Pennell, N. A.; Raymond, D.; Schilero, C.; Smolenski, K.; Williams, F.; Morrison, C.; Borgia, J. A.; Liptay, M. J.; Pool, M.; Seder, C. W.; Junker, K.; Omberg, L.; Dinkin, M.; Manikhas, G.; Alvaro, D.; Bragazzi, M. 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Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.
Open Access
Reconstructing complex regions of genomes using long-read sequencing technology
(Cold Spring Harbor Laboratory Press, 2014) Huddleston, J.; Ranade, S.; Malig, M.; Antonacci, F.; Chaisson, M.; Hon, L.; Sudmant, P. H.; Alkan C.; Eichler, E. E.; Graves, T. A.; Dennis, M. Y.; Wilson, R. K.; Turner, S. W.; Korlach, J.
Obtaining high-quality sequence continuity of complex regions of recent segmental duplication remains one of the major challenges of finishing genome assemblies. In the human and mouse genomes, this was achieved by targeting large-insert clones using costly and laborious capillary-based sequencing approaches. Sanger shotgun sequencing of clone inserts, however, has now been largely abandoned, leaving most of these regions unresolved in newer genome assemblies generated primarily by next-generation sequencing hybrid approaches. Here we show that it is possible to resolve regions that are complex in a genome-wide context but simple in isolation for a fraction of the time and cost of traditional methods using long-read single molecule, real-time (SMRT) sequencing and assembly technology from Pacific Biosciences (PacBio). We sequenced and assembled BAC clones corresponding to a 1.3-Mbp complex region of chromosome 17q21.31, demonstrating 99.994% identity to Sanger assemblies of the same clones. We targeted 44 differences using Illumina sequencing and find that PacBio and Sanger assemblies share a comparable number of validated variants, albeit with different sequence context biases. Finally, we targeted a poorly assembled 766-kbp duplicated region of the chimpanzee genome and resolved the structure and organization for a fraction of the cost and time of traditional finishing approaches. Our data suggest a straightforward path for upgrading genomes to a higher quality finished state.