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1. Question-Based Collaborative Learning for Constructive Curricular Alignment

Author

Wynn-Lawrence LS, Bala L, Fletcher RJ, Wilson RK, and Sam AH

Subjects
constructive alignment, multiple choice question, Special aspects of education, LC8-6691, Medicine (General), R5-920
Abstract

Laura S Wynn-Lawrence, Laksha Bala, Rebekah J Fletcher, Rebecca K Wilson, Amir H Sam Imperial College School of Medicine, Imperial College London, London, UKCorrespondence: Amir H SamImperial College School of Medicine, London, UKEmail a.sam@imperial.ac.ukIntroduction: We designed a curriculum mapping tool which enables medical students to access intended learning outcomes (ILOs) on their iPads in the workplace. Students were encouraged to use the online curriculum map in a specially planned teaching session: question-based collaborative learning (QBCL). The aim of the session was to empower medical students to constructively align their experiential learning with the learning outcomes of the undergraduate curriculum. In doing so, our session aimed to provide students with a greater understanding of the curriculum, improve their insights into assessment and their question-writing abilities.Methods: The QBCL pre-session preparation involved reviewing a patient with a presentation that aligned to the year-specific ILOs. During a 150 minute QBCL session, students received training on how to write high quality multiple choice questions (MCQs) delivered by a faculty member of Imperial College School of Medicine. They then worked collaboratively in groups and created MCQs based on their clinical encounters. Their questions were tagged to the relevant learning objective and submitted online via the curriculum map. The student-generated MCQs were analyzed using an adjusted version of Bloom’s taxonomy. We also conducted a quantitative evaluation of the session.Results: One hundred and sixty-three questions were submitted, with 81% of questions being tagged to ILOs considered to show evidence of learning consistent with the “Apply” tier of Bloom’s taxonomy. The majority of students agreed that the session was interactive (80%), thought-provoking (77%) and improved their team-working skills (70%). It gave them a greater understanding of the undergraduate curriculum (65%), improved their question-writing and insight into assessments (76%), and provided an opportunity to learn from their peers (86%). Students agreed that this session covered a variety of cases (82%) and deepened their understanding of medical conditions and presentations (87%).Conclusion: We encouraged students to actively interact with the curriculum map. Students were able to achieve their own constructive alignment by writing assessment items based on real patients and linking them to the appropriate intended learning outcomes.Keywords: constructive alignment, multiple choice question

Published
2021

2. The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis

Author

Jones, KB, Barrott, JJ, Xie, M, Haldar, M, Jin, H, Zhu, J-F, Monument, MJ, Mosbruger, TL, Langer, EM, Randall, RL, Wilson, RK, Cairns, BR, Ding, L, and Capecchi, MR

Subjects
Genetics, Rare Diseases, Biotechnology, Human Genome, Cancer, Aetiology, 2.1 Biological and endogenous factors, Animals, Biomarkers, Tumor, Carcinogenesis, Disease Models, Animal, Genotype, Humans, Mice, Neoplasm Proteins, Oncogene Proteins, Fusion, Proto-Oncogene Proteins, Repressor Proteins, Sarcoma, Synovial, Translocation, Genetic, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Synovial sarcomas are aggressive soft-tissue malignancies that express chromosomal translocation-generated fusion genes, SS18-SSX1 or SS18-SSX2 in most cases. Here, we report a mouse sarcoma model expressing SS18-SSX1, complementing our prior model expressing SS18-SSX2. Exome sequencing identified no recurrent secondary mutations in tumors of either genotype. Most of the few mutations identified in single tumors were present in genes that were minimally or not expressed in any of the tumors. Chromosome 6, either entirely or around the fusion gene expression locus, demonstrated a copy number gain in a majority of tumors of both genotypes. Thus, by fusion oncogene coding sequence alone, SS18-SSX1 and SS18-SSX2 can each drive comparable synovial sarcomagenesis, independent from other genetic drivers. SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences overall. In direct tumorigenesis comparisons, SS18-SSX2 was slightly more sarcomagenic than SS18-SSX1, but equivalent in its generation of biphasic histologic features. Meta-analysis of human synovial sarcoma patient series identified two tumor-gentoype-phenotype correlations that were not modeled by the mice, namely a scarcity of male hosts and biphasic histologic features among SS18-SSX2 tumors. Re-analysis of human SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences, but highlighted increased native SSX2 expression in SS18-SSX1 tumors. This suggests that the translocated locus may drive genotype-phenotype differences more than the coding sequence of the fusion gene created. Two possible roles for native SSX2 in synovial sarcomagenesis are explored. Thus, even specific partial failures of mouse genetic modeling can be instructive to human tumor biology.

Published
2016

3. Correction: Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.

Author

Bis, JC, Jian, X, Kunkle, BW, Chen, Y, Hamilton-Nelson, KL, Bush, WS, Salerno, WJ, Lancour, D, Ma, Y, Renton, AE, Marcora, E, Farrell, JJ, Zhao, Y, Qu, L, Ahmad, S, Amin, N, Amouyel, P, Beecham, GW, Below, JE, Campion, D, Cantwell, L, Charbonnier, C, Chung, J, Crane, PK, Cruchaga, C, Cupples, LA, Dartigues, J-F, Debette, S, Deleuze, J-F, Fulton, L, Gabriel, SB, Genin, E, Gibbs, RA, Goate, A, Grenier-Boley, B, Gupta, N, Haines, JL, Havulinna, AS, Helisalmi, S, Hiltunen, M, Howrigan, DP, Ikram, MA, Kaprio, J, Konrad, J, Kuzma, A, Lander, ES, Lathrop, M, Lehtimäki, T, Lin, H, Mattila, K, Mayeux, R, Muzny, DM, Nasser, W, Neale, B, Nho, K, Nicolas, G, Patel, D, Pericak-Vance, MA, Perola, M, Psaty, BM, Quenez, O, Rajabli, F, Redon, R, Reitz, C, Remes, AM, Salomaa, V, Sarnowski, C, Schmidt, H, Schmidt, M, Schmidt, R, Soininen, H, Thornton, TA, Tosto, G, Tzourio, C, van der Lee, SJ, van Duijn, CM, Valladares, O, Vardarajan, B, Wang, L-S, Wang, W, Wijsman, E, Wilson, RK, Witten, D, Worley, KC, Zhang, X, Alzheimer’s Disease Sequencing Project, Bellenguez, C, Lambert, J-C, Kurki, MI, Palotie, A, Daly, M, Boerwinkle, E, Lunetta, KL, Destefano, AL, Dupuis, J, Martin, ER, Schellenberg, GD, Seshadri, S, Naj, AC, Fornage, M, Farrer, LA, Bis, JC, Jian, X, Kunkle, BW, Chen, Y, Hamilton-Nelson, KL, Bush, WS, Salerno, WJ, Lancour, D, Ma, Y, Renton, AE, Marcora, E, Farrell, JJ, Zhao, Y, Qu, L, Ahmad, S, Amin, N, Amouyel, P, Beecham, GW, Below, JE, Campion, D, Cantwell, L, Charbonnier, C, Chung, J, Crane, PK, Cruchaga, C, Cupples, LA, Dartigues, J-F, Debette, S, Deleuze, J-F, Fulton, L, Gabriel, SB, Genin, E, Gibbs, RA, Goate, A, Grenier-Boley, B, Gupta, N, Haines, JL, Havulinna, AS, Helisalmi, S, Hiltunen, M, Howrigan, DP, Ikram, MA, Kaprio, J, Konrad, J, Kuzma, A, Lander, ES, Lathrop, M, Lehtimäki, T, Lin, H, Mattila, K, Mayeux, R, Muzny, DM, Nasser, W, Neale, B, Nho, K, Nicolas, G, Patel, D, Pericak-Vance, MA, Perola, M, Psaty, BM, Quenez, O, Rajabli, F, Redon, R, Reitz, C, Remes, AM, Salomaa, V, Sarnowski, C, Schmidt, H, Schmidt, M, Schmidt, R, Soininen, H, Thornton, TA, Tosto, G, Tzourio, C, van der Lee, SJ, van Duijn, CM, Valladares, O, Vardarajan, B, Wang, L-S, Wang, W, Wijsman, E, Wilson, RK, Witten, D, Worley, KC, Zhang, X, Alzheimer’s Disease Sequencing Project, Bellenguez, C, Lambert, J-C, Kurki, MI, Palotie, A, Daly, M, Boerwinkle, E, Lunetta, KL, Destefano, AL, Dupuis, J, Martin, ER, Schellenberg, GD, Seshadri, S, Naj, AC, Fornage, M, and Farrer, LA

Abstract

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

4. Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry

Author

Patel, D, Mez, J, Vardarajan, BN, Staley, L, Chung, J, Zhang, XK, Ahmad, Shahzad, Amin, Najaf, Ikram, Arfan, van der Lee, Sven, Duijn, Cornelia, van der Spek, Ashley, Waligorski, J, Wilson, RK, Patel, D, Mez, J, Vardarajan, BN, Staley, L, Chung, J, Zhang, XK, Ahmad, Shahzad, Amin, Najaf, Ikram, Arfan, van der Lee, Sven, Duijn, Cornelia, van der Spek, Ashley, Waligorski, J, and Wilson, RK

Published
2019

5. Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Author

Lazar, AJ, McLellan, MD, Bailey, MH, Miller, CA, Appelbaum, EL, Cordes, MG, Fronick, CC, Fulton, LA, Fulton, RS, Mardis, ER, Schmidt, HK, Wong, W, Wilson, RK, Yellapantula, V, Radenbaugh, AJ, Hoadley, KA, Hayes, DN, Parker, JS, Wilkerson, MD, Auman, JT, Balu, S, Bodenheimer, T, Hoyle, AP, Jefferys, SR, Jones, CD, Lehmann, K-V, Meng, S, Mieczkowski, PA, Mose, LE, Perou, CM, Roach, J, Senbabaoglu, Y, Shi, Y, Simons, JV, Skelly, T, Soloway, MG, Tan, D, Veluvolu, U, Davis, IJ, Hepperla, AJ, Brohl, AS, Kasaian, K, Mungall, K, Sadeghi, S, Barthel, FP, Verhaak, R, Hu, X, Chibon, F, Cherniack, AD, Shih, J, Beroukhim, R, Meyerson, M, Cibulskis, C, Gabriel, SB, Saksena, G, Schumacher, SE, Gao, Q, Wyczalkowski, M, Bowlby, R, Robertson, AG, Ally, A, Balasundaram, M, Brooks, D, Carlsen, R, Chuah, E, Dhalla, N, Holt, RA, Jones, SJM, Lee, D, Li, I, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Schein, JE, Sipahimalani, P, Tam, A, Thiessen, N, Wong, T, Danilova, L, Cope, L, Baylin, SB, Bootwalla, MS, Lai, PH, Laird, PW, Maglinte, DT, Van Den Berg, DJ, Weisenberger, DJ, Wrangle, J, Drill, E, Shen, R, Iype, L, Reynolds, SM, Shmulevich, I, Yau, C, Armenia, J, Liu, EM, Benz, C, Pastore, A, Sanchez-Vega, F, Schultz, N, Akbani, R, Hegde, AM, Liu, W, Lu, Y, Mills, GB, Weinstein, JN, Roszik, J, Anur, P, Spellman, P, Abeshouse, A, Chen, H-W, Gao, J, Heins, Z, Kundra, R, Larsson, E, Ochoa, A, Sander, C, Socci, N, Zhang, H, Noble, MS, Heiman, DI, Kim, J, Chin, L, Getz, G, Cho, J, Defreitas, T, Frazer, S, Gehlenborg, N, Lawrence, MS, Lin, P, Meier, S, Voet, D, Byers, L, Diao, L, Gay, CM, Wang, J, Newton, Y, Cooper, LAD, Gutman, DA, Lee, S, Nalisnik, M, Bowen, J, Gastier-Foster, JM, Gerken, M, Helsel, C, Hobensack, S, Leraas, KM, Lichtenberg, TM, Ramirez, NC, Wise, L, Zmuda, E, Anderson, ML, Castro, P, Ittmann, M, Gordienko, E, Paklina, O, Setdikova, G, Raut, CP, Karlan, BY, Lester, J, Belyaev, D, Fulidou, V, Potapova, O, Voronina, O, Demetri, GD, Ramalingam, SS, Behera, M, Delman, K, Owonikoko, TK, Sica, GL, Boyd, J, Magliocco, A, Salner, A, Bennett, J, Iacocca, M, Swanson, P, Dottino, P, Kalir, T, Pereira, E, Akeredolu, T, Crain, D, Curley, E, Gardner, J, Mallery, D, Morris, S, Paulauskis, J, Penny, R, Shelton, C, Shelton, T, Thompson, E, Hoon, DB, Parfitt, J, Birrer, M, Karseladze, A, Mariamidze, A, Dao, F, Levine, DA, Olvera, N, Maki, RG, Bartlett, J, Eschbacher, J, Dubina, M, Mozgovoy, E, Fedosenko, K, Manikhas, G, Sekhon, H, Ramirez, N, Ingram, DR, Torres, KE, DiSaia, P, Godwin, AK, Godwin, EM, Kuo, H, Madan, R, Reilly, C, Adebamowo, C, Adebamowo, SN, Bocklage, T, Higgins, K, Martinez, C, Boice, L, Grilley-Olson, JE, Huang, M, Perou, AH, Thorne, LB, Rathmell, WK, Gutmann, DH, Singer, S, Chudamani, S, Liu, J, Lolla, L, Naresh, R, Pihl, T, Sun, Q, Wan, Y, Wu, Y, Felau, I, Zenklusen, JC, Demchok, JA, Ferguson, ML, Hutter, CM, Sofia, HJ, Tarnuzzer, R, Wang, Z, Yang, L, Zhang, JJ, Demicco, EG, Doyle, LA, Hornick, JL, Rubin, BP, de Rijn, MV, Baker, L, Riedel, RF, Ding, L, Ladanyi, M, Novak, JE, Van Tine, BA, Davis, LE, Grilley-Olsen, JE, Pollock, RE, Jones, KB, Martignetti, JA, Tong, P, and Network, CGAR

Subjects
0301 basic medicine, Leiomyosarcoma, Adult, Epigenomics, DNA Copy Number Variations, Genomics, Biology, General Biochemistry, Genetics and Molecular Biology, Undifferentiated Pleomorphic Sarcoma, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, medicine, Cluster Analysis, Humans, ATRX, Aged, Comparative genomics, Aged, 80 and over, Genome, Human, Sarcoma, Middle Aged, medicine.disease, Synovial sarcoma, 030104 developmental biology, 030220 oncology & carcinogenesis, Immunology, DNA methylation, Mutation, Cancer research, Genome-Wide Association Study
Abstract

Summary Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes ( TP53 , ATRX , RB1 ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.

Published
2017
Full Text
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6. Integrated genomic characterization of oesophageal carcinoma

Author

Kim, J, Bowlby, R, Mungall, AJ, Robertson, AG, Odze, RD, Cherniack, AD, Shih, J, Pedamallu, CS, Cibulskis, C, Dunford, A, Meier, SR, Raphael, BJ, Wu, H-T, Wong, AM, Willis, JE, Bass, AJ, Derks, S, Garman, K, McCall, SJ, Wiznerowicz, M, Pantazi, A, Parfenov, M, Thorsson, V, Shmulevich, I, Dhankani, V, Miller, M, Sakai, R, Wang, K, Schultz, N, Shen, R, Arora, A, Weinhold, N, Sanchez-Vega, F, Kelsen, DP, Zhang, J, Felau, I, Demchok, J, Rabkin, CS, Camargo, MC, Zenklusen, JC, Bowen, J, Leraas, K, Lichtenberg, TM, Curtis, C, Seoane, JA, Ojesina, AI, Beer, DG, Gulley, ML, Pennathur, A, Luketich, JD, Zhou, Z, Weisenberger, DJ, Akbani, R, Lee, J-S, Liu, W, Mills, GB, Zhang, W, Reid, BJ, Hinoue, T, Laird, PW, Shen, H, Piazuelo, MB, Schneider, BG, McLellan, M, Taylor-Weiner, A, Lawrence, M, Cibulskis, K, Stewart, C, Getz, G, Lander, E, Gabriel, SB, Ding, L, McLellan, MD, Miller, CA, Appelbaum, EL, Cordes, MG, Fronick, CC, Fulton, LA, Mardis, ER, Wilson, RK, Schmidt, HK, Fulton, RS, Ally, A, Balasundaram, M, Carlsen, R, Chuah, E, Dhalla, N, Holt, RA, Jones, SJM, Kasaian, K, Brooks, D, Li, HI, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, KL, Schein, JE, Sipahimalani, P, Tam, A, Thiessen, N, Wong, T, Beroukhim, R, Bullman, S, Murray, BA, Saksena, G, Schumacher, SE, Gabriel, S, Meyerson, M, Hadjipanayis, A, Kucherlapati, R, Ren, X, Park, PJ, Lee, S, Kucherlapati, M, Yang, L, Baylin, SB, Hoadley, KA, Bootwalla, MS, Lai, PH, Van den Berg, DJ, Berrios, M, Holbrook, A, Hwang, J-E, Jang, H-J, Weinstein, JN, Lu, Y, Sohn, BH, Mills, G, Seth, S, Protopopov, A, Bristow, CA, Mahadeshwar, HS, Tang, J, Song, X, Cho, J, Defrietas, T, Frazer, S, Gehlenborg, N, Heiman, DI, Lawrence, MS, Lin, P, Noble, MS, Doug, V, Zhang, H, Polak, P, Chin, L, Bernard, B, Iype, L, Reynolds, SM, Abeshouse, A, Armenia, J, Kundra, R, Ladanyi, M, Kjong-Van, L, Gao, J, Sander, C, Chakravarty, D, Radenbaugh, A, Hegde, A, Penny, R, Crain, D, Gardner, J, Curley, E, Mallery, D, Morris, S, Paulauskis, J, Shelton, T, Shelton, C, Frick, J, Gastier-Foster, JM, Gerken, M, Leraas, KM, Ramirez, NC, Wise, L, Zmuda, E, Tarvin, K, Saller, C, Park, YS, Button, M, Carvalho, AL, Reis, RM, Matsushita, MM, Lucchesi, F, de Oliveira, AT, Le, X, Paklina, O, Setdikova, G, Lee, J-H, Bennett, J, Iacocca, M, Huelsenbeck-Dill, L, Potapova, CO, Voronina, O, Liu, O, Fulidou, V, Cates, C, Sharp, A, Behera, M, Force, S, Khuri, F, Owonikoko, T, Pickens, A, Ramalingam, S, Sica, G, Dinjens, W, van Nistelrooij, A, Wijnhoven, B, Sandusky, G, Stepa, S, Juhl, IH, Zornig, C, Kwon, SY, Kelsen, D, Kim, GHK, Bartlett, J, Parfitt, J, Chetty, R, Darling, G, Knox, J, Wong, R, El-Zimaity, H, Liu, G, Boussioutas, A, Park, DY, Kemp, R, Carlotti, CG, da Cunha Tirapelli, DP, Saggioro, FP, Sankarankutty, AK, Noushmehr, H, dos Santos, JS, Trevisan, FA, Eschbacher, J, Dubina, M, Mozgovoy, E, Carey, F, Chalmers, S, Forgie, I, Godwin, A, Reilly, C, Madan, R, Naima, Z, Ferrer-Torres, D, Rathmell, WK, Dhir, R, Luketich, J, Ajani, JA, Janjigian, Y, Tang, L, Cheong, J-H, Chudamani, S, Liu, J, Lolla, L, Naresh, R, Pihl, T, Sun, Q, Wan, Y, Wu, Y, Demchok, JA, Ferguson, ML, Shaw, KRM, sheth, M, Tarnuzzer, R, Wang, Z, Hutter, CM, Sofia, HJ, Kim, J, Bowlby, R, Mungall, AJ, Robertson, AG, Odze, RD, Cherniack, AD, Shih, J, Pedamallu, CS, Cibulskis, C, Dunford, A, Meier, SR, Raphael, BJ, Wu, H-T, Wong, AM, Willis, JE, Bass, AJ, Derks, S, Garman, K, McCall, SJ, Wiznerowicz, M, Pantazi, A, Parfenov, M, Thorsson, V, Shmulevich, I, Dhankani, V, Miller, M, Sakai, R, Wang, K, Schultz, N, Shen, R, Arora, A, Weinhold, N, Sanchez-Vega, F, Kelsen, DP, Zhang, J, Felau, I, Demchok, J, Rabkin, CS, Camargo, MC, Zenklusen, JC, Bowen, J, Leraas, K, Lichtenberg, TM, Curtis, C, Seoane, JA, Ojesina, AI, Beer, DG, Gulley, ML, Pennathur, A, Luketich, JD, Zhou, Z, Weisenberger, DJ, Akbani, R, Lee, J-S, Liu, W, Mills, GB, Zhang, W, Reid, BJ, Hinoue, T, Laird, PW, Shen, H, Piazuelo, MB, Schneider, BG, McLellan, M, Taylor-Weiner, A, Lawrence, M, Cibulskis, K, Stewart, C, Getz, G, Lander, E, Gabriel, SB, Ding, L, McLellan, MD, Miller, CA, Appelbaum, EL, Cordes, MG, Fronick, CC, Fulton, LA, Mardis, ER, Wilson, RK, Schmidt, HK, Fulton, RS, Ally, A, Balasundaram, M, Carlsen, R, Chuah, E, Dhalla, N, Holt, RA, Jones, SJM, Kasaian, K, Brooks, D, Li, HI, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, KL, Schein, JE, Sipahimalani, P, Tam, A, Thiessen, N, Wong, T, Beroukhim, R, Bullman, S, Murray, BA, Saksena, G, Schumacher, SE, Gabriel, S, Meyerson, M, Hadjipanayis, A, Kucherlapati, R, Ren, X, Park, PJ, Lee, S, Kucherlapati, M, Yang, L, Baylin, SB, Hoadley, KA, Bootwalla, MS, Lai, PH, Van den Berg, DJ, Berrios, M, Holbrook, A, Hwang, J-E, Jang, H-J, Weinstein, JN, Lu, Y, Sohn, BH, Mills, G, Seth, S, Protopopov, A, Bristow, CA, Mahadeshwar, HS, Tang, J, Song, X, Cho, J, Defrietas, T, Frazer, S, Gehlenborg, N, Heiman, DI, Lawrence, MS, Lin, P, Noble, MS, Doug, V, Zhang, H, Polak, P, Chin, L, Bernard, B, Iype, L, Reynolds, SM, Abeshouse, A, Armenia, J, Kundra, R, Ladanyi, M, Kjong-Van, L, Gao, J, Sander, C, Chakravarty, D, Radenbaugh, A, Hegde, A, Penny, R, Crain, D, Gardner, J, Curley, E, Mallery, D, Morris, S, Paulauskis, J, Shelton, T, Shelton, C, Frick, J, Gastier-Foster, JM, Gerken, M, Leraas, KM, Ramirez, NC, Wise, L, Zmuda, E, Tarvin, K, Saller, C, Park, YS, Button, M, Carvalho, AL, Reis, RM, Matsushita, MM, Lucchesi, F, de Oliveira, AT, Le, X, Paklina, O, Setdikova, G, Lee, J-H, Bennett, J, Iacocca, M, Huelsenbeck-Dill, L, Potapova, CO, Voronina, O, Liu, O, Fulidou, V, Cates, C, Sharp, A, Behera, M, Force, S, Khuri, F, Owonikoko, T, Pickens, A, Ramalingam, S, Sica, G, Dinjens, W, van Nistelrooij, A, Wijnhoven, B, Sandusky, G, Stepa, S, Juhl, IH, Zornig, C, Kwon, SY, Kelsen, D, Kim, GHK, Bartlett, J, Parfitt, J, Chetty, R, Darling, G, Knox, J, Wong, R, El-Zimaity, H, Liu, G, Boussioutas, A, Park, DY, Kemp, R, Carlotti, CG, da Cunha Tirapelli, DP, Saggioro, FP, Sankarankutty, AK, Noushmehr, H, dos Santos, JS, Trevisan, FA, Eschbacher, J, Dubina, M, Mozgovoy, E, Carey, F, Chalmers, S, Forgie, I, Godwin, A, Reilly, C, Madan, R, Naima, Z, Ferrer-Torres, D, Rathmell, WK, Dhir, R, Luketich, J, Ajani, JA, Janjigian, Y, Tang, L, Cheong, J-H, Chudamani, S, Liu, J, Lolla, L, Naresh, R, Pihl, T, Sun, Q, Wan, Y, Wu, Y, Demchok, JA, Ferguson, ML, Shaw, KRM, sheth, M, Tarnuzzer, R, Wang, Z, Hutter, CM, and Sofia, HJ

Abstract

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.

Published
2017

7. Whole genome analysis of a schistosomiasis-transmitting freshwater snail

Author

Adema, CM, Hillier, LW, Jones, CS, Loker, ES, Knight, M, Minx, P, Oliveira, G, Raghavan, N, Shedlock, A, do Amaral, LR, Arican-Goktas, HD, Assis, JG, Baba, EH, Baron, OL, Bayne, CJ, Bickham-Wright, U, Biggar, KK, Blouin, M, Bonning, BC, Botka, C, Bridger, JM, Buckley, KM, Buddenborg, SK, Caldeira, RL, Carleton, J, Carvalho, OS, Castillo, MG, Chalmers, IW, Christensens, M, Clifton, S, Cosseau, C, Coustau, C, Cripps, RM, Cuesta-Astroz, Y, Cummins, SF, Di Stephano, L, Dinguirard, N, Duval, D, Emrich, S, Feschotte, C, Feyereisen, R, FitzGerald, P, Fronick, C, Fulton, L, Galinier, R, Gava, SG, Geusz, M, Geyer, KK, Giraldo-Calderon, GI, Gomes, MDS, Gordy, MA, Gourbal, B, Grunau, C, Hanington, PC, Hoffmann, KF, Hughes, D, Humphries, J, Jackson, DJ, Jannotti-Passos, LK, Jeremias, WDJ, Jobling, S, Kamel, B, Kapusta, A, Kaur, S, Koene, JM, Kohn, AB, Lawson, D, Lawton, SP, Liang, D, Limpanont, Y, Liu, S, Lockyer, AE, Lovato, TL, Ludolf, F, Magrini, V, McManus, DP, Medina, M, Misra, M, Mitta, G, Mkoji, GM, Montague, MJ, Montelongo, C, Moroz, LL, Munoz-Torres, MC, Niazi, U, Noble, LR, Oliveira, FS, Pais, FS, Papenfuss, AT, Peace, R, Pena, JJ, Pila, EA, Quelais, T, Raney, BJ, Rast, JP, Rollinson, D, Rosse, IC, Rotgans, B, Routledge, EJ, Ryan, KM, Scholte, LLS, Storey, KB, Swain, M, Tennessen, JA, Tomlinson, C, Trujillo, DL, Volpi, EV, Walker, AJ, Wang, T, Wannaporn, I, Warren, WC, Wu, X-J, Yoshino, TP, Yusuf, M, Zhang, S-M, Zhao, M, Wilson, RK, Adema, CM, Hillier, LW, Jones, CS, Loker, ES, Knight, M, Minx, P, Oliveira, G, Raghavan, N, Shedlock, A, do Amaral, LR, Arican-Goktas, HD, Assis, JG, Baba, EH, Baron, OL, Bayne, CJ, Bickham-Wright, U, Biggar, KK, Blouin, M, Bonning, BC, Botka, C, Bridger, JM, Buckley, KM, Buddenborg, SK, Caldeira, RL, Carleton, J, Carvalho, OS, Castillo, MG, Chalmers, IW, Christensens, M, Clifton, S, Cosseau, C, Coustau, C, Cripps, RM, Cuesta-Astroz, Y, Cummins, SF, Di Stephano, L, Dinguirard, N, Duval, D, Emrich, S, Feschotte, C, Feyereisen, R, FitzGerald, P, Fronick, C, Fulton, L, Galinier, R, Gava, SG, Geusz, M, Geyer, KK, Giraldo-Calderon, GI, Gomes, MDS, Gordy, MA, Gourbal, B, Grunau, C, Hanington, PC, Hoffmann, KF, Hughes, D, Humphries, J, Jackson, DJ, Jannotti-Passos, LK, Jeremias, WDJ, Jobling, S, Kamel, B, Kapusta, A, Kaur, S, Koene, JM, Kohn, AB, Lawson, D, Lawton, SP, Liang, D, Limpanont, Y, Liu, S, Lockyer, AE, Lovato, TL, Ludolf, F, Magrini, V, McManus, DP, Medina, M, Misra, M, Mitta, G, Mkoji, GM, Montague, MJ, Montelongo, C, Moroz, LL, Munoz-Torres, MC, Niazi, U, Noble, LR, Oliveira, FS, Pais, FS, Papenfuss, AT, Peace, R, Pena, JJ, Pila, EA, Quelais, T, Raney, BJ, Rast, JP, Rollinson, D, Rosse, IC, Rotgans, B, Routledge, EJ, Ryan, KM, Scholte, LLS, Storey, KB, Swain, M, Tennessen, JA, Tomlinson, C, Trujillo, DL, Volpi, EV, Walker, AJ, Wang, T, Wannaporn, I, Warren, WC, Wu, X-J, Yoshino, TP, Yusuf, M, Zhang, S-M, Zhao, M, and Wilson, RK

Abstract

Biomphalaria snails are instrumental in transmission of the human blood fluke Schistosoma mansoni. With the World Health Organization's goal to eliminate schistosomiasis as a global health problem by 2025, there is now renewed emphasis on snail control. Here, we characterize the genome of Biomphalaria glabrata, a lophotrochozoan protostome, and provide timely and important information on snail biology. We describe aspects of phero-perception, stress responses, immune function and regulation of gene expression that support the persistence of B. glabrata in the field and may define this species as a suitable snail host for S. mansoni. We identify several potential targets for developing novel control measures aimed at reducing snail-mediated transmission of schistosomiasis.

Published
2017

8. Initial sequencing and analysis of the human genome

Author

Lander, ES, Linton, LM, Birren, B, Nusbaum, C, Zody, MC, Baldwin, J, Devon, K, Dewar, K, Doyle, M, FitzHugh, W, Funke, R, Gage, D, Harris, K, Heaford, A, Howland, J, Kann, L, Lehoczky, J, LeVine, R, McEwan, P, McKernan, K, Meldrim, J, Mesirov, JP, Miranda, C, Morris, W, Naylor, J, Raymond, C, Rosetti, M, Santos, R, Sheridan, A, Sougnez, C, Stange-Thomann, N, Stojanovic, N, Subramanian, A, Wyman, D, Rogers, J, Sulston, J, Ainscough, R, Beck, S, Bentley, D, Burton, J, Clee, C, Carter, N, Coulson, A, Deadman, R, Deloukas, P, Dunham, A, Dunham, I, Durbin, R, French, L, Grafham, D, Gregory, S, Hubbard, T, Humphray, S, Hunt, A, Jones, M, Lloyd, C, McMurray, A, Matthews, L, Mercer, S, Milne, S, Mullikin, JC, Mungall, A, Plumb, R, Ross, M, Shownkeen, R, Sims, S, Waterston, RH, Wilson, RK, Hillier, LW, McPherson, JD, Marra, MA, Mardis, ER, Fulton, LA, Chinwalla, AT, Pepin, KH, Gish, WR, Chissoe, SL, Wendl, MC, Delehaunty, KD, Miner, TL, Delehaunty, A, Kramer, JB, Cook, LL, Fulton, RS, Johnson, DL, Minx, PJ, Clifton, SW, Hawkins, T, Branscomb, E, Predki, P, Richardson, P, Wenning, S, Slezak, T, Doggett, N, Cheng, JF, Olsen, A, Lucas, S, Elkin, C, Uberbacher, E, Frazier, M, Gibbs, RA, Muzny, DM, Scherer, SE, Bouck, JB, Sodergren, EJ, Worley, KC, Rives, CM, Gorrell, JH, Metzker, ML, Naylor, SL, Kucherlapati, RS, Nelson, DL, Weinstock, GM, Sakaki, Y, Fujiyama, A, Hattori, M, Yada, T, Toyoda, A, Itoh, T, Kawagoe, C, Watanabe, H, Totoki, Y, Taylor, T, Weissenbach, J, Heilig, R, Saurin, W, Artiguenave, F, Brottier, P, Bruls, T, Pelletier, E, Robert, C, Wincker, P, Smith, DR, Doucette-Stamm, L, Rubenfield, M, Weinstock, K, Lee, HM, Dubois, J, Rosenthal, A, Platzer, M, Nyakatura, G, Taudien, S, Rump, A, Yang, H, Yu, J, Wang, J, Huang, G, Gu, J, Hood, L, Rowen, L, Madan, A, Qin, S, Davis, RW, Federspiel, NA, Abola, AP, Proctor, MJ, Myers, RM, Schmutz, J, Dickson, M, Grimwood, J, Cox, DR, Olson, MV, Kaul, R, Shimizu, N, Kawasaki, K, Minoshima, S, Evans, GA, Athanasiou, M, Schultz, R, Roe, BA, Chen, F, Pan, H, Ramser, J, Lehrach, H, Reinhardt, R, McCombie, WR, de la Bastide, M, Dedhia, N, Blöcker, H, Hornischer, K, Nordsiek, G, Agarwala, R, Aravind, L, Bailey, JA, Bateman, A, Batzoglou, S, Birney, E, Bork, P, Brown, DG, Burge, CB, Cerutti, L, Chen, HC, Church, D, Clamp, M, Copley, RR, Doerks, T, Eddy, SR, Eichler, EE, Furey, TS, Galagan, J, Gilbert, JG, Harmon, C, Hayashizaki, Y, Haussler, D, Hermjakob, H, Hokamp, K, Jang, W, Johnson, LS, Jones, TA, Kasif, S, Kaspryzk, A, Kennedy, S, Kent, WJ, Kitts, P, Koonin, EV, Korf, I, Kulp, D, Lancet, D, Lowe, TM, McLysaght, A, Mikkelsen, T, Moran, JV, Mulder, N, Pollara, VJ, Ponting, CP, Schuler, G, Schultz, J, Slater, G, Smit, AF, Stupka, E, Szustakowski, J, Thierry-Mieg, D, Thierry-Mieg, J, Wagner, L, Wallis, J, Wheeler, R, Williams, A, Wolf, YI, Wolfe, KH, Yang, SP, Yeh, RF, Collins, F, Guyer, MS, Peterson, J, Felsenfeld, A, Wetterstrand, KA, Patrinos, A, Morgan, MJ, de Jong, P, Catanese, JJ, Osoegawa, K, Shizuya, H, Choi, S, Chen, YJ, and Szustakowki, J

Subjects
Genetics, Cancer genome sequencing, Chimpanzee genome project, Multidisciplinary, Cancer Genome Project, Gene density, DNA sequencing theory, Hybrid genome assembly, Computational biology, Biology, Genome, Personal genomics
Abstract

The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

Published
2016

9. A second generation human haplotype map of over 3.1 million SNPs

Author

Frazer, KA, Ballinger, DG, Cox, DR, Hinds, DA, Stuve, LL, Gibbs, RA, Belmont, JW, Boudreau, A, Hardenbol, P, Leal, SM, Pasternak, S, Wheeler, DA, Willis, TD, Yu, F, Yang, H, Zeng, C, Gao, Y, Hu, H, Hu, W, Li, C, Lin, W, Liu, S, Pan, H, Tang, X, Wang, J, Wang, W, Yu, J, Zhang, B, Zhang, Q, Zhao, H, Zhou, J, Gabriel, SB, Barry, R, Blumenstiel, B, Camargo, A, Defelice, M, Faggart, M, Goyette, M, Gupta, S, Moore, J, Nguyen, H, Onofrio, RC, Parkin, M, Roy, J, Stahl, E, Winchester, E, Ziaugra, L, Altshuler, D, Shen, Y, Yao, Z, Huang, W, Chu, X, He, Y, Jin, L, Liu, Y, Sun, W, Wang, H, Wang, Y, Xiong, X, Xu, L, Waye, MM, Tsui, SK, Xue, H, Wong, JT, Galver, LM, Fan, JB, Gunderson, K, Murray, SS, Oliphant, AR, Chee, MS, Montpetit, A, Chagnon, F, Ferretti, V, Leboeuf, M, Olivier, JF, Phillips, MS, Roumy, S, Sallée, C, Verner, A, Hudson, TJ, Kwok, PY, Cai, D, Koboldt, DC, Miller, RD, Pawlikowska, L, Taillon-Miller, P, Xiao, M, Tsui, LC, Mak, W, Song, YQ, Tam, PK, Nakamura, Y, Kawaguchi, T, Kitamoto, T, Morizono, T, Nagashima, A, Ohnishi, Y, Sekine, A, Tanaka, T, Tsunoda, T, Deloukas, P, Bird, CP, Delgado, M, Dermitzakis, ET, Gwilliam, R, Hunt, S, Morrison, J, Powell, D, Stranger, BE, Whittaker, P, Bentley, DR, Daly, MJ, de Bakker, PI, Barrett, J, Chretien, YR, Maller, J, McCarroll, S, Patterson, N, Pe'er, I, Price, A, Purcell, S, Richter, DJ, Sabeti, P, Saxena, R, Schaffner, SF, Sham, PC, Varilly, P, Stein, LD, Krishnan, L, Smith, AV, Tello-Ruiz, MK, Thorisson, GA, Chakravarti, A, Chen, PE, Cutler, DJ, Kashuk, CS, Lin, S, Abecasis, GR, Guan, W, Li, Y, Munro, HM, Qin, ZS, Thomas, DJ, McVean, G, Auton, A, Bottolo, L, Cardin, N, Eyheramendy, S, Freeman, C, Marchini, J, Myers, S, Spencer, C, Stephens, M, Donnelly, P, Cardon, LR, Clarke, G, Evans, DM, Morris, AP, Weir, BS, Mullikin, JC, Sherry, ST, Feolo, M, Skol, A, Zhang, H, Matsuda, I, Fukushima, Y, Macer, DR, Suda, E, Rotimi, CN, Adebamowo, CA, Ajayi, I, Aniagwu, T, Marshall, PA, Nkwodimmah, C, Royal, CD, Leppert, MF, Dixon, M, Peiffer, A, Qiu, R, Kent, A, Kato, K, Niikawa, N, Adewole, IF, Knoppers, BM, Foster, MW, Clayton, EW, Watkin, J, Muzny, D, Nazareth, L, Sodergren, E, Weinstock, GM, Yakub, I, Birren, BW, Wilson, RK, Fulton, LL, Rogers, J, Burton, J, Carter, NP, Clee, CM, Griffiths, M, Jones, MC, McLay, K, Plumb, RW, Ross, MT, Sims, SK, Willey, DL, Chen, Z, Han, H, Kang, L, Godbout, M, Wallenburg, JC, L'Archevêque, P, Bellemare, G, Saeki, K, An, D, Fu, H, Li, Q, Wang, Z, Wang, R, Holden, AL, Brooks, LD, McEwen, JE, Guyer, MS, Wang, VO, Peterson, JL, Shi, M, Spiegel, J, Sung, LM, Zacharia, LF, Collins, FS, Kennedy, K, Jamieson, R, and Stewart, J

Subjects
Male, Recombination, Genetic, Genetics, Linkage disequilibrium, education.field_of_study, Multidisciplinary, Homozygote, Racial Groups, Haplotype, Population, Single-nucleotide polymorphism, Tag SNP, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, Haplotypes, Humans, Female, Selection, Genetic, International HapMap Project, education, Imputation (genetics), Genetic association
Abstract

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r 2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r 2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations. ©2007 Nature Publishing Group., link_to_OA_fulltext

Published
2016

10. Dictyocaulus viviparus genome, variome and transcriptome elucidate lungworm biology and support future intervention

Author

McNulty, SN, Struebe, C, Rosa, BA, Martin, JC, Tyagi, R, Choi, Y-J, Wang, Q, Pepin, KH, Zhang, X, Ozersky, P, Wilson, RK, Sternberg, PW, Gasser, RB, Mitreva, M, McNulty, SN, Struebe, C, Rosa, BA, Martin, JC, Tyagi, R, Choi, Y-J, Wang, Q, Pepin, KH, Zhang, X, Ozersky, P, Wilson, RK, Sternberg, PW, Gasser, RB, and Mitreva, M

Abstract

The bovine lungworm, Dictyocaulus viviparus (order Strongylida), is an important parasite of livestock that causes substantial economic and production losses worldwide. Here we report the draft genome, variome, and developmental transcriptome of D. viviparus. The genome (161 Mb) is smaller than those of related bursate nematodes and encodes fewer proteins (14,171 total). In the first genome-wide assessment of genomic variation in any parasitic nematode, we found a high degree of sequence variability in proteins predicted to be involved host-parasite interactions. Next, we used extensive RNA sequence data to track gene transcription across the life cycle of D. viviparus, and identified genes that might be important in nematode development and parasitism. Finally, we predicted genes that could be vital in host-parasite interactions, genes that could serve as drug targets, and putative RNAi effectors with a view to developing functional genomic tools. This extensive, well-curated dataset should provide a basis for developing new anthelmintics, vaccines, and improved diagnostic tests and serve as a platform for future investigations of drug resistance and epidemiology of the bovine lungworm and related nematodes.

Published
2016

11. Human genomic regions with exceptionally high levels of population differentiation identified from 911 whole-genome sequences

Author

Colonna, V, Ayub, Q, Chen, Y, Pagani, L, Luisi, P, Pybus, M, Garrison, E, Xue, Y, Tyler-Smith, C, Abecasis, GR, Auton, A, Brooks, LD, Depristo, MA, Durbin, RM, Handsaker, RE, Kang, HM, Marth, GT, McVean, G, Altshuler, DM, Bentley, DR, Chakravarti, A, Clark, AG, Donnelly, P, Eichler, EE, Flicek, P, Gabriel, SB, Gibbs, RA, Green, ED, Hurles, ME, Knoppers, BM, Korbel, JO, Lander, ES, Lee, C, Lehrach, H, Mardis, ER, McVean, GA, Nickerson, DA, Schmidt, JP, Sherry, ST, Wang, J, Wilson, RK, Dinh, H, Kovar, C, Lee, S, Lewis, L, Muzny, D, Reid, J, Wang, M, Fang, X, Guo, X, Jian, M, Jiang, H, Jin, X, Li, G, Li, J, Li, Y, Li, Z, Liu, X, Lu, Y, Ma, X, Su, Z, Tai, S, Tang, M, Wang, B, Wang, G, Wu, H, Wu, R, Yin, Y, Zhang, W, Zhao, J, Zhao, M, Zheng, X, Zhou, Y, Gupta, N, Clarke, L, Leinonen, R, Smith, RE, Zheng-Bradley, X, Grocock, R, Humphray, S, James, T, Kingsbury, Z, Sudbrak, R, Albrecht, MW, Amstislavskiy, VS, Borodina, TA, Lienhard, M, Mertes, F, Sultan, M, Timmermann, B, Yaspo, ML, Fulton, L, Fulton, R, Weinstock, GM, Balasubramaniam, S, Burton, J, Danecek, P, Keane, TM, Kolb-Kokocinski, A, McCarthy, S, Molecular Dynamics, Biomimetics, Urban and Regional Studies Institute, Nanomedicine & Drug Targeting, Artificial Intelligence, Micromechanics, Molecular Cell Biology, Van Swinderen Institute for Particle Physics and G, Archaeology of Northwestern Europe, Polymer Chemistry and Bioengineering, Christianity and the History of Ideas, Scientific Visualization and Computer Graphics, Chemical Technology, Macromolecular Chemistry & New Polymeric Materials, Bernoulli Institute, Surfaces and Thin Films, Hemelrijk group, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Falcao Salles lab, Synthetic Organic Chemistry, Psychometrics and Statistics, Bio-inspired systems and circuits, Advanced Production Engineering, Drug Design, The 1000 Genomes Project Consortium, Faculteit Medische Wetenschappen/UMCG, Wellcome Trust, Consiglio Nazionale delle Ricerche, EMBO, and 1000 Genomes Project Consortium

Subjects
Historia y Arqueología, lactase persistence, POSITIVE SELECTION, BALANCING SELECTION, SOFT SWEEP, Biología, standing variation, Population, Biology, Balancing selection, Genome, Polymorphism, Single Nucleotide, Genètica de poblacions humanes, Ciencias Biológicas, purl.org/becyt/ford/1 [https], selective sweep, functional annotation cluster, Genética y Herencia, HUMANIDADES, Genetic drift, Gene Frequency, INDEL Mutation, Humans, Selection, Genetic, education, purl.org/becyt/ford/1.6 [https], Selection (genetic algorithm), education.field_of_study, purl.org/becyt/ford/6 [https], Genome, Human, Research, Genetic Drift, Levenshtein distance, Selecció natural, Sequence Analysis, DNA, Human genetics, Otras Historia y Arqueología, Evolutionary biology, Human genome, purl.org/becyt/ford/6.1 [https], Selective sweep, Genètica humana -- Variació, CIENCIAS NATURALES Y EXACTAS
Abstract

It contains associated material.-- The 1000 Genomes Project Consortium, [Background] Population differentiation has proved to be effective for identifying loci under geographically localized positive selection, and has the potential to identify loci subject to balancing selection. We have previously investigated the pattern of genetic differentiation among human populations at 36.8 million genomic variants to identify sites in the genome showing high frequency differences. Here, we extend this dataset to include additional variants, survey sites with low levels of differentiation, and evaluate the extent to which highly differentiated sites are likely to result from selective or other processes., [Results] We demonstrate that while sites with low differentiation represent sampling effects rather than balancing selection, sites showing extremely high population differentiation are enriched for positive selection events and that one half may be the result of classic selective sweeps. Among these, we rediscover known examples, where we actually identify the established functional SNP, and discover novel examples including the genes ABCA12, CALD1 and ZNF804, which we speculate may be linked to adaptations in skin, calcium metabolism and defense, respectively., [Conclusions] We identify known and many novel candidate regions for geographically restricted positive selection, and suggest several directions for further research. © 2014 Colonna et al., This work was supported by The Wellcome Trust (098051), an Italian National Research Council (CNR) short-term mobility fellowship from the 2013 program to VC, and an EMBO Short Term Fellowship ASTF 324–2010 to VC.

Published
2014

12. The elephant shark genome provides unique insights into gnathostome evolution

Author

Venkatesh B, Lee AP, Ravi V, Maurya AK, Lian MM, Swann JB, Ohta Y, Flajnik MF, Sutoh Y, Kasahara M, Hoon S, Gangu V, Roy SW, Irimia M, Korzh V, Kondrychyn I, Lim ZW, Tay BH, Tohari S, Kong KW, Ho S, Lorente-Galdos B, Quilez J, Marques-Bonet T, Raney BJ, Ingham PW, Tay A, Hillier LW, Minx P, Boehm T, Wilson RK, Brenner S, and Warren WC.

Published
2014

13. The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

Author

Andersson, AK, Ma, J, Wang, J, Chen, X, Gedman, AL, Dang, J, Nakitandwe, J, Holmfeldt, L, Parker, M, Easton, J, Huether, R, Kriwacki, R, Rusch, M, Wu, G, Li, Y, Mulder, H, Raimondi, S, Pounds, S, Kang, G, Shi, L, Becksfort, J, Gupta, P, Payne-Turner, D, Vadodaria, B, Boggs, K, Yergeau, D, Manne, J, Song, G, Edmonson, M, Nagahawatte, P, Wei, L, Cheng, C, Pei, D, Sutton, R, Venn, NC, Chetcuti, A, Rush, A, Catchpoole, D, Heldrup, J, Fioretos, T, Lu, C, Ding, L, Pui, C-H, Shurtleff, S, Mullighan, CG, Mardis, ER, Wilson, RK, Gruber, TA, Zhang, J, Downing, JR, St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project, Andersson, AK, Ma, J, Wang, J, Chen, X, Gedman, AL, Dang, J, Nakitandwe, J, Holmfeldt, L, Parker, M, Easton, J, Huether, R, Kriwacki, R, Rusch, M, Wu, G, Li, Y, Mulder, H, Raimondi, S, Pounds, S, Kang, G, Shi, L, Becksfort, J, Gupta, P, Payne-Turner, D, Vadodaria, B, Boggs, K, Yergeau, D, Manne, J, Song, G, Edmonson, M, Nagahawatte, P, Wei, L, Cheng, C, Pei, D, Sutton, R, Venn, NC, Chetcuti, A, Rush, A, Catchpoole, D, Heldrup, J, Fioretos, T, Lu, C, Ding, L, Pui, C-H, Shurtleff, S, Mullighan, CG, Mardis, ER, Wilson, RK, Gruber, TA, Zhang, J, Downing, JR, and St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project

Abstract

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.

Published
2015

14. Integrated genomic characterization of endometrial carcinoma

Author

Getz, G, Gabriel, SB, Cibulskis, K, Lander, E, Sivachenko, A, Sougnez, C, Lawrence, M, Kandoth, C, Dooling, D, Fulton, R, Fulton, L, Kalicki-Veizer, J, McLellan, MD, O'Laughlin, M, Schmidt, H, Wilson, RK, Ye, K, Li, D, Ally, A, Balasundaram, M, Birol, I, Butterfield, YSN, Carlsen, R, Carter, C, Chu, A, Chuah, E, Chun, HJE, Dhalla, N, Guin, R, Hirst, C, Holt, RA, Jones, SJM, Lee, D, Li, HI, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Plettner, P, Schein, JE, Sipahimalani, P, Tam, A, Varhol, RJ, Gordon Robertson, A, Cherniack, AD, Pashtan, I, Saksena, G, Onofrio, RC, Schumacher, SE, Tabak, B, Carter, SL, Hernandez, B, Gentry, J, Salvesen, HB, Ardlie, K, Winckler, W, Beroukhim, R, Meyerson, M, Hadjipanayis, A, Lee, S, Mahadeshwar, HS, Park, P, Protopopov, A, Ren, X, Seth, S, Song, X, Tang, J, Xi, R, Yang, L, Dong, Z, Kucherlapati, R, Chin, L, Zhang, J, Todd Auman, J, Balu, S, Bodenheimer, T, Buda, E, Neil Hayes, D, Hoyle, AP, Jefferys, SR, Jones, CD, Meng, S, Mieczkowski, PA, Mose, LE, Parker, JS, and Perou, CM

Subjects
endocrine system diseases
Abstract

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array-and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours. © 2013 Macmillan Publishers Limited. All rights reserved.

Published
2013

15. Sequencing of the sea lamprey (Petromyzon marinus) genome provides insights into vertebrate evolution

Author

Smith, JJ, Kuraku, S, Holt, C, Sauka-Spengler, T, Jiang, N, Campbell, MS, Yandell, MD, Manousaki, T, Meyer, A, Bloom, OE, Morgan, JR, Buxbaum, JD, Sachidanandam, R, Sims, C, Garruss, AS, Cook, M, Krumlauf, R, Wiedemann, LM, Sower, SA, Decatur, WA, Hall, JA, Amemiya, CT, Saha, NR, Buckley, KM, Rast, JP, Das, S, Hirano, M, McCurley, N, Guo, P, Rohner, N, Tabin, CJ, Piccinelli, P, Elgar, G, Ruffier, M, Aken, BL, Searle, SMJ, Muffato, M, Pignatelli, M, Herrero, J, Jones, M, Brown, CT, Chung-Davidson, YW, Nanlohy, KG, Libants, SV, Yeh, CY, McCauley, DW, Langeland, JA, Pancer, Z, Fritzsch, B, De Jong, PJ, Zhu, B, Fulton, LL, Theising, B, Flicek, P, Bronner, ME, Warren, WC, Clifton, SW, Wilson, RK, and Li, W

Subjects
Lethenteron, Lineage (evolution), Vertebrate Biology, Genome, Article, Evolution, Molecular, 03 medical and health sciences, 0302 clinical medicine, Phylogenetics, ddc:570, biology.animal, Genetics, Animals, Petromyzon, 14. Life underwater, Phylogeny, Repetitive Sequences, Nucleic Acid, 030304 developmental biology, 0303 health sciences, biology, Lamprey, Chromosome Mapping, Vertebrate, Sequence Analysis, DNA, biology.organism_classification, Vertebrates, human activities, 030217 neurology & neurosurgery
Abstract

Lampreys are representatives of an ancient vertebrate lineage that diverged from our own ~500 million years ago. By virtue of this deeply shared ancestry, the sea lamprey (P. marinus) genome is uniquely poised to provide insight into the ancestry of vertebrate genomes and the underlying principles of vertebrate biology. Here, we present the first lamprey whole-genome sequence and assembly. We note challenges faced owing to its high content of repetitive elements and GC bases, as well as the absence of broad-scale sequence information from closely related species. Analyses of the assembly indicate that two whole-genome duplications likely occurred before the divergence of ancestral lamprey and gnathostome lineages. Moreover, the results help define key evolutionary events within vertebrate lineages, including the origin of myelin-associated proteins and the development of appendages. The lamprey genome provides an important resource for reconstructing vertebrate origins and the evolutionary events that have shaped the genomes of extant organisms.

Published
2013

16. An integrated map of genetic variation from 1,092 human genomes

Author

Altshuler, DM, Durbin, RM, Abecasis, GR, Bentley, DR, Chakravarti, A, Clark, AG, Donnelly, P, Eichler, EE, Flicek, P, Gabriel, SB, Gibbs, RA, Green, ED, Hurles, ME, Knoppers, BM, Korbel, JO, Lander, ES, Lee, C, Lehrach, H, Mardis, ER, Marth, GT, McVean, GA, Nickerson, DA, Schmidt, JP, Sherry, ST, Wang, J, Wilson, RK, Dinh, H, Kovar, C, Lee, S, Lewis, L, Muzny, D, Reid, J, Wang, M, Fang, X, Guo, X, Jian, M, Jiang, H, Jin, X, Li, G, Li, J, Li, Y, Li, Z, Liu, X, Lu, Y, Ma, X, Su, Z, Tai, S, Tang, M, Wang, B, Wang, G, Wu, H, Wu, R, Yin, Y, Zhang, W, Zhao, J, Zhao, M, Zheng, X, Zhou, Y, Gupta, N, Clarke, L, Leinonen, R, Smith, RE, Zheng-Bradley, X, Grocock, R, Humphray, S, James, T, Kingsbury, Z, Sudbrak, R, Albrecht, MW, Amstislavskiy, VS, Borodina, TA, Lienhard, M, Mertes, F, Sultan, M, Timmermann, B, Yaspo, M-L, Fulton, L, Fulton, R, Weinstock, GM, Balasubramaniam, S, Burton, J, Danecek, P, Keane, TM, Kolb-Kokocinski, A, McCarthy, S, Stalker, J, Quail, M, Davies, CJ, Gollub, J, Webster, T, Wong, B, Zhan, Y, Auton, A, Yu, F, Bainbridge, M, Challis, D, Evani, US, Lu, J, Nagaswamy, U, Sabo, A, Wang, Y, Yu, J, Coin, LJM, Fang, L, Li, Q, Lin, H, Liu, B, Luo, R, Qin, N, Shao, H, Xie, Y, Ye, C, Yu, C, Zhang, F, Zheng, H, Zhu, H, Garrison, EP, Kural, D, Lee, W-P, Leong, WF, Ward, AN, Wu, J, Zhang, M, Griffin, L, Hsieh, C-H, Mills, RE, Shi, X, Von Grotthuss, M, Zhang, C, Daly, MJ, DePristo, MA, Banks, E, Bhatia, G, Carneiro, MO, Del Angel, G, Genovese, G, Handsaker, RE, Hartl, C, McCarroll, SA, Nemesh, JC, Poplin, RE, Schaffner, SF, Shakir, K, Yoon, SC, Lihm, J, Makarov, V, Jin, H, Kim, W, Kim, KC, Rausch, T, Beal, K, Cunningham, F, Herrero, J, McLaren, WM, Ritchie, GRS, Gottipati, S, Keinan, A, Rodriguez-Flores, JL, Sabeti, PC, Grossman, SR, Tabrizi, S, Tariyal, R, Cooper, DN, Ball, EV, Stenson, PD, Barnes, B, Bauer, M, Cheetham, RK, Cox, T, Eberle, M, Kahn, S, Murray, L, Peden, J, Shaw, R, Ye, K, Batzer, MA, Konkel, MK, Walker, JA, MacArthur, DG, Lek, M, Herwig, R, Shriver, MD, Bustamante, CD, Byrnes, JK, De la Vega, FM, Gravel, S, Kenny, EE, Kidd, JM, Lacroute, P, Maples, BK, Moreno-Estrada, A, Zakharia, F, Halperin, E, Baran, Y, Craig, DW, Christoforides, A, Homer, N, Izatt, T, Kurdoglu, AA, Sinari, SA, Squire, K, Xiao, C, Sebat, J, Bafna, V, Burchard, EG, Hernandez, RD, Gignoux, CR, Haussler, D, Katzman, SJ, Kent, WJ, Howie, B, Ruiz-Linares, A, Dermitzakis, ET, Lappalainen, T, Devine, SE, Maroo, A, Tallon, LJ, Rosenfeld, JA, Michelson, LP, Kang, HM, 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, Trost, MK, Awadalla, P, Hodgkinson, A, Lunter, G, Marchini, JL, Myers, S, Churchhouse, C, Delaneau, O, Gupta-Hinch, A, Iqbal, Z, Mathieson, I, Rimmer, A, Xifara, DK, Oleksyk, TK, Fu, Y, Xiong, M, Jorde, L, Witherspoon, D, Xing, J, Browning, BL, Alkan, C, Hajirasouliha, I, Hormozdiari, F, Ko, A, Sudmant, PH, Chen, K, Chinwalla, A, Ding, L, Dooling, D, Koboldt, DC, McLellan, MD, Wallis, JW, Wendl, MC, Zhang, Q, Tyler-Smith, C, Albers, CA, Ayub, Q, Chen, Y, Coffey, AJ, Colonna, V, Huang, N, Jostins, L, Li, H, Scally, A, Walter, K, Xue, Y, Zhang, Y, Gerstein, MB, Abyzov, A, Balasubramanian, S, Chen, J, Clarke, D, Habegger, L, Harmanci, AO, Jin, M, Khurana, E, Mu, XJ, Sisu, C, Degenhardt, J, Stuetz, AM, Church, D, Michaelson, JJ, Ben, B, Lindsay, SJ, Ning, Z, Frankish, A, Harrow, J, Fowler, G, Hale, W, Kalra, D, Barker, J, Kelman, G, Kulesha, E, Radhakrishnan, R, Roa, A, Smirnov, D, Streeter, I, 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, Zhang, H, Barnes, KC, Beiswanger, C, Cai, H, Cao, H, Gharani, N, Henn, B, Jones, D, Kaye, JS, Kent, A, Kerasidou, A, Mathias, R, Ossorio, PN, Parker, M, Reich, D, Rotimi, CN, Royal, CD, Sandoval, K, Su, Y, Tian, Z, Tishkoff, S, Toji, LH, Via, M, Yang, H, Yang, L, Zhu, J, Bodmer, W, Bedoya, G, Ming, CZ, Yang, G, You, CJ, Peltonen, L, Garcia-Montero, A, Orfao, A, Dutil, J, Martinez-Cruzado, JC, Brooks, LD, Felsenfeld, AL, McEwen, JE, Clemm, NC, Duncanson, A, Dunn, M, Guyer, MS, Peterson, JL, 1000 Genomes Project Consortium, Dermitzakis, Emmanouil, Universitat de Barcelona, Massachusetts Institute of Technology. Department of Biology, Altshuler, David, and Lander, Eric S.

Subjects
Natural selection, LOCI, Genome-wide association study, Evolutionary biology, Continental Population Groups/genetics, Human genetic variation, VARIANTS, Genoma humà, Binding Sites/genetics, 0302 clinical medicine, RARE, Sequence Deletion/genetics, WIDE ASSOCIATION, ddc:576.5, Copy-number variation, MUTATION, Exome sequencing, transcription factor, Conserved Sequence, Human evolution, Sequence Deletion, Genetics, RISK, 0303 health sciences, Multidisciplinary, Continental Population Groups, 1000 Genomes Project Consortium, Genetic analysis, Genomics, Polymorphism, Single Nucleotide/genetics, Research Highlight, 3. Good health, Algorithm, Multidisciplinary Sciences, Genetic Variation/genetics, Map, Science & Technology - Other Topics, Conserved Sequence/genetics, Integrated approach, General Science & Technology, Genetics, Medical, Haplotypes/genetics, Biology, Polymorphism, Single Nucleotide, Evolution, Molecular, 03 medical and health sciences, Genetic variation, Humans, Transcription Factors/metabolism, POPULATION-STRUCTURE, 1000 Genomes Project, Polymorphism, Nucleotide Motifs, Alleles, 030304 developmental biology, COPY NUMBER VARIATION, Science & Technology, Binding Sites, Human genome, Genome, Human, Racial Groups, Genetic Variation, Genetics, Population, Haplotypes, Genome, Human/genetics, untranslated RNA, 030217 neurology & neurosurgery, Transcription Factors, Genome-Wide Association Study
Abstract

By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations., National Institutes of Health (U.S.) (Grant RC2HL102925), National Institutes of Health (U.S.) (Grant U54HG3067)

Published
2012

17. Integrated genomic analyses of ovarian carcinoma

Author

Bell, D, Berchuck, A, Birrer, M, Chien, J, Cramer, DW, Dao, F, Dhir, R, DiSaia, P, Gabra, H, Glenn, P, Godwin, AK, Triche, T, Berman, BP, Van den Berg, DJ, Buckley, J, Baylin, SB, Zhang, J, Spellman, PT, Purdom, E, Iacocca, M, Shelton, T, Voet, D, Neuvial, P, Bengtsson, H, Jakkula, LR, Durinck, S, Han, J, Dorton, S, Marr, H, Zhang, H, Choi, YG, Wang, V, Wilkinson, J, Nguyen, H, Wang, NJ, Imielinski, M, Ngai, J, Conboy, JG, Parvin, B, Feiler, HS, Speed, TP, Gray, JW, Wu, CJ, Bloom, T, Levine, DA, Li, L, Socci, ND, Liang, Y, Taylor, BS, Kalloger, S, Schultz, N, Borsu, L, Lash, AE, Brennan, C, Ardlie, K, Viale, A, Shukla, S, Grimm, D, Sander, C, Ladanyi, M, Hoadley, KA, Meng, S, Du, Y, Karlan, BY, Shi, Y, Fennell, T, Cibulskis, K, Lawrence, MS, Meyerson, M, Hatfield, M, Mills, GB, Sivachenko, A, Jing, R, Park, RW, Liu, Y, Park, PJ, Ramos, AH, Noble, M, Chin, L, Carter, H, Kim, D, Morris, S, Winckler, W, Karchin, R, Morrison, C, Baldwin, J, Korkola, JE, Yena, P, Heiser, LM, Getz, G, Cho, RJ, Hu, Z, Gabriel, S, Mutch, D, Cerami, E, Rhodes, P, Olshen, A, Verhaak, RGW, Lander, ES, Reva, B, Antipin, Y, Shen, R, Olvera, N, Mankoo, P, Sheridan, R, Ciriello, G, Sherman, M, Chang, WK, Bernanke, JA, Hayes, DN, Carter, SL, Haussler, D, Orsulic, S, Benz, CC, Paulauskis, J, Stuart, JM, Zhang, N, Benz, SC, Sanborn, JZ, Vaske, CJ, Mermel, CH, Zhu, J, Szeto, C, Scott, GK, Yau, C, Rabeno, B, Ding, L, Park, K, Balu, S, Perou, CM, Saksena, G, Wilkerson, MD, Millis, S, Kahn, A, Turman, YJ, Fulton, RS, Onofrio, RC, Greene, JM, Sfeir, R, Jensen, MA, Chen, J, Whitmore, J, Alonso, S, Jordan, J, Chu, A, Rader, JS, Koboldt, DC, Zang, D, Gross, J, Barker, A, Compton, C, Eley, G, Ferguson, M, Fielding, P, Gerhard, DS, Myles, R, McLellan, MD, Schaefer, C, Helms, EB, Shaw, KRM, Sikic, BI, Vaught, J, Vockley, JB, Good, PJ, Guyer, MS, Ozenberger, B, Wylie, T, Peterson, J, Thomson, E, Smith-McCune, K, Sood, AK, Bowtell, D, Hubbard, D, Penny, R, Testa, JR, Chang, K, Walker, J, Dinh, HH, Drummond, JA, Fowler, G, Zhou, X, Gunaratne, P, Hawes, AC, Kovar, CL, Lewis, LR, Gupta, S, Morgan, MB, O'Laughlin, M, Newsham, IF, Santibanez, J, Reid, JG, Trevino, LR, Wu, J, Wu, Y-Q, Wang, M, Muzny, DM, Wheeler, DA, Gibbs, RA, Crenshaw, A, Sivachenko, AY, Topal, MD, Sougnez, C, Dooling, DJ, Fulton, L, Akbani, R, Abbott, R, Dees, ND, Zhang, Q, Kandoth, C, Wendl, M, Schierding, W, Shen, D, Harris, CC, Baggerly, KA, Schmidt, H, Wilson, RK, Kalicki, J, Delehaunty, KD, Fronick, CC, Demeter, R, Cook, L, Wallis, JW, Lin, L, Magrini, VJ, Yung, WK, Hodges, JS, Protopopov, A, Eldred, JM, Smith, SM, Pohl, CS, Vandin, F, Raphael, BJ, Weinstock, GM, Mardis, R, Kim, TM, Hartmann, L, Perna, I, Xiao, Y, Ren, G, Sathiamoorthy, N, Petrelli, N, Lee, E, Kucherlapati, R, Absher, DM, Huang, M, Waite, L, Sherlock, G, Brooks, JD, Li, JZ, Weinstein, JN, Xu, J, Myers, RM, Laird, PW, Cope, L, Herman, JG, Shen, H, Huntsman, DG, Weisenberger, DJ, Noushmehr, H, Pan, F, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Meyerson, Matthew L.

Subjects
endocrine system diseases, Serous carcinoma, Messenger, Gene Dosage, Cancer Genome Atlas Research Network, GYNECOLOGIC-ONCOLOGY-GROUP, GRADE SEROUS CARCINOMA, 0302 clinical medicine, Ovarian carcinoma, Aged, Carcinoma, DNA Methylation, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, MicroRNAs, Middle Aged, Mutation, Ovarian Neoplasms, RNA, Messenger, Genomics, Multidisciplinary, Genetics, HYBRID SELECTION, 0303 health sciences, female genital diseases and pregnancy complications, 3. Good health, Multidisciplinary Sciences, Serous fluid, BRCA MUTATION CARRIERS, 030220 oncology & carcinogenesis, DNA methylation, PARP inhibitor, Science & Technology - Other Topics, General Science & Technology, Biology, Article, 03 medical and health sciences, CLEAR-CELL CARCINOMA, MD Multidisciplinary, microRNA, HIGH-THROUGHPUT ANNOTATION, medicine, DRIVER MUTATIONS, Gene, 030304 developmental biology, Neoplastic, Science & Technology, MUTANT-CELLS, SOMATIC MUTATIONS, medicine.disease, CANCER STATISTICS, Gene Expression Regulation, Cancer research, RNA, Ovarian cancer
Abstract

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology., National Institutes of Health (U.S.) (Grant U54HG003067), National Institutes of Health (U.S.) (Grant U54HG003273), National Institutes of Health (U.S.) (Grant U54HG003079), National Institutes of Health (U.S.) (Grant U24CA126543), National Institutes of Health (U.S.) (Grant U24CA126544), National Institutes of Health (U.S.) (Grant U24CA126546), National Institutes of Health (U.S.) (Grant U24CA126551), National Institutes of Health (U.S.) (Grant U24CA126554), National Institutes of Health (U.S.) (Grant U24CA126561), National Institutes of Health (U.S.) (Grant U24CA126563), National Institutes of Health (U.S.) (Grant U24CA143882), National Institutes of Health (U.S.) (Grant U24CA143731), National Institutes of Health (U.S.) (Grant U24CA143835), National Institutes of Health (U.S.) (Grant U24CA143845), National Institutes of Health (U.S.) (Grant U24CA143858), National Institutes of Health (U.S.) (Grant U24CA144025), National Institutes of Health (U.S.) (Grant U24CA143866), National Institutes of Health (U.S.) (Grant U24CA143867), National Institutes of Health (U.S.) (Grant U24CA143848), National Institutes of Health (U.S.) (Grant U24CA143843), National Institutes of Health (U.S.) (Grant R21CA135877)

Published
2010

18. Genome of the human hookworm Necator americanus

Author

Tang, YT, Gao, X, Rosa, BA, Abubucker, S, Hallsworth-Pepin, K, Martin, J, Tyagi, R, Heizer, E, Zhang, X, Bhonagiri-Palsikar, V, Minx, P, Warren, WC, Wang, Q, Zhan, B, Hotez, PJ, Sternberg, PW, Dougall, A, Gaze, ST, Mulvenna, J, Sotillo, J, Ranganathan, S, Rabelo, EM, Wilson, RK, Felgner, PL, Bethony, J, Hawdon, JM, Gasser, RB, Loukas, A, Mitreva, M, Tang, YT, Gao, X, Rosa, BA, Abubucker, S, Hallsworth-Pepin, K, Martin, J, Tyagi, R, Heizer, E, Zhang, X, Bhonagiri-Palsikar, V, Minx, P, Warren, WC, Wang, Q, Zhan, B, Hotez, PJ, Sternberg, PW, Dougall, A, Gaze, ST, Mulvenna, J, Sotillo, J, Ranganathan, S, Rabelo, EM, Wilson, RK, Felgner, PL, Bethony, J, Hawdon, JM, Gasser, RB, Loukas, A, and Mitreva, M

Abstract

The hookworm Necator americanus is the predominant soil-transmitted human parasite. Adult worms feed on blood in the small intestine, causing iron-deficiency anemia, malnutrition, growth and development stunting in children, and severe morbidity and mortality during pregnancy in women. We report sequencing and assembly of the N. americanus genome (244 Mb, 19,151 genes). Characterization of this first hookworm genome sequence identified genes orchestrating the hookworm's invasion of the human host, genes involved in blood feeding and development, and genes encoding proteins that represent new potential drug targets against hookworms. N. americanus has undergone a considerable and unique expansion of immunomodulator proteins, some of which we highlight as potential treatments against inflammatory diseases. We also used a protein microarray to demonstrate a postgenomic application of the hookworm genome sequence. This genome provides an invaluable resource to boost ongoing efforts toward fundamental and applied postgenomic research, including the development of new methods to control hookworm and human immunological diseases.

Published
2014

19. Genome of the house fly, Musca domestica L., a global vector of diseases with adaptations to a septic environment

Author

Scott, JG, Warren, WC, Beukeboom, LW, Bopp, D, Clark, AG, Giers, SD, Hediger, M, Jones, A, Kasai, S, Leichter, CA, Li, M, Meisel, RP, Minx, P, Murphy, TD, Nelson, DR, Reid, WR, Rinkevich, FD, Robertson, HM, Sackton, TB, Sattelle, DB, Thibaud-Nissen, F, Tomlinson, C, van de Zande, L, Walden, KK, Wilson, RK, Liu, N, Scott, JG, Warren, WC, Beukeboom, LW, Bopp, D, Clark, AG, Giers, SD, Hediger, M, Jones, A, Kasai, S, Leichter, CA, Li, M, Meisel, RP, Minx, P, Murphy, TD, Nelson, DR, Reid, WR, Rinkevich, FD, Robertson, HM, Sackton, TB, Sattelle, DB, Thibaud-Nissen, F, Tomlinson, C, van de Zande, L, Walden, KK, Wilson, RK, and Liu, N

Abstract

BACKGROUND: Adult house flies, Musca domestica L., are mechanical vectors of more than 100 devastating diseases that have severe consequences for human and animal health. House fly larvae play a vital role as decomposers of animal wastes, and thus live in intimate association with many animal pathogens. RESULTS: We have sequenced and analyzed the genome of the house fly using DNA from female flies. The sequenced genome is 691 Mb. Compared with Drosophila melanogaster, the genome contains a rich resource of shared and novel protein coding genes, a significantly higher amount of repetitive elements, and substantial increases in copy number and diversity of both the recognition and effector components of the immune system, consistent with life in a pathogen-rich environment. There are 146 P450 genes, plus 11 pseudogenes, in M. domestica, representing a significant increase relative to D. melanogaster and suggesting the presence of enhanced detoxification in house flies. Relative to D. melanogaster, M. domestica has also evolved an expanded repertoire of chemoreceptors and odorant binding proteins, many associated with gustation. CONCLUSIONS: This represents the first genome sequence of an insect that lives in intimate association with abundant animal pathogens. The house fly genome provides a rich resource for enabling work on innovative methods of insect control, for understanding the mechanisms of insecticide resistance, genetic adaptation to high pathogen loads, and for exploring the basic biology of this important pest. The genome of this species will also serve as a close out-group to Drosophila in comparative genomic studies.

Published
2014

20. Genome analysis of the platypus reveals unique signatures of evolution (Nature (2008) 453, (175-183))

Author

Warren, WC, Hillier, LW, Marshall Graves, JA, Birney, E, Ponting, CP, Grützner, F, Belov, K, Miller, W, Clarke, L, Chinwalla, AT, Yang, S-P, Heger, A, Locke, DP, Miethke, P, Waters, PD, Veyrunes, F, Fulton, L, Fulton, B, Graves, T, Wallis, J, Puente, XS, López-Otín, C, Ordó̃ez, GR, Eichler, EE, Chen, L, Cheng, Z, Deakin, JE, Alsop, A, Thompson, K, Kirby, P, Papenfuss, AT, Wakefield, MJ, Olender, T, Lancet, D, Huttley, GA, Smit, AFA, Pask, A, Temple-Smith, P, Batzer, MA, Walker, JA, Konkel, MK, Harris, RS, Whittington, CM, Wong, ESW, Gemmell, NJ, Buschiazzo, E, Vargas Jentzsch, IM, Merkel, A, Schmitz, J, Zemann, A, Churakov, G, Kriegs, JO, Brosius, J, Murchison, EP, Sachidanandam, R, Smith, C, Hannon, GJ, Tsend-Ayush, E, McMillan, D, Attenborough, R, Rens, W, Ferguson-Smith, M, Lefèvre, CM, Sharp, JA, Nicholas, KR, Ray, DA, Kube, M, Reinhardt, R, Pringle, TH, Taylor, J, Jones, RC, Nixon, B, Dacheux, J-L, Niwa, H, Sekita, Y, Huang, X, Stark, A, Kheradpour, P, Kellis, M, Flicek, P, Chen, Y, Webber, C, Hardison, R, Nelson, J, Hallsworth-Pepin, K, Delehaunty, K, Markovic, C, Minx, P, Feng, Y, Kremitzki, C, Mitreva, M, Glasscock, J, Wylie, T, Wohldmann, P, Thiru, P, Nhan, MN, Pohl, CS, Smith, SM, Hou, S, Nefedov, M, De Jong, PJ, Renfree, MB, Mardis, ER, and Wilson, RK

Published
2008

21. Influence of Smoking on Radiographic Profusion and Pleural Changes in Asbestos- Exposed Subjects

Author

Wilson Rk, Bradley Bl, and George L. Delclos

Subjects
Male, medicine.medical_specialty, business.industry, Radiography, Smoking, Public Health, Environmental and Occupational Health, Odds ratio, Middle Aged, medicine.disease_cause, Asbestos, Confidence interval, Surgery, Natural history, Cross-Sectional Studies, Internal medicine, Asbestosis, medicine, Humans, Pleura, Female, business, Aged
Abstract

The influence of smoking on pleural and parenchymal radiographic changes, particularly in asbestos-exposed cohorts, has been debated. We studied this issue in 440 asbestos-exposed subjects referred for evaluation between 1981 and 1985. Information was obtained on age, exposure, and smoking. Chest radiographs were independently read by three "B" readers under blind conditions and it was determined that 80.5% of the subjects had a history of smoking. The odds ratio for smoking and parenchymal opacities greater than or equal to 1/0 was 1.98 (95% confidence interval, 1.2 to 3.3); this association was not affected by adjustment for asbestos exposure and/or age. A dose-response pattern emerged between increasing pack-years and parenchymal opacities greater than or equal to 1/0; the effect between asbestos exposure and smoking appeared to be additive. No associations were found between smoking and pleural abnormalities. The findings in this investigation are consistent with prior studies showing an influence of smoking on radiographic parenchymal, but not pleural, changes, at least in asbestos-exposed groups. The anatomical equivalent of these radiographic changes and their impact, if any, on the natural history of asbestos-associated disease remains unclear.

Published
1990

22. Genome-wide detection and characterization of positive selection in human populations

Author

Sabeti, PC, Varilly, P, Fry, B, Lohmueller, J, Hostetter, E, Cotsapas, C, Xie, X, Byrne, EH, McCarroll, SA, Gaudet, R, Schaffner, SF, Lander, ES, Frazer, KA, Ballinger, DG, Cox, DR, Hinds, DA, Stuve, LL, Gibbs, RA, Belmont, JW, Boudreau, A, Hardenbol, P, Leal, SM, Pasternak, S, Wheeler, DA, Willis, TD, Yu, F, Yang, H, Zeng, C, Gao, Y, Hu, H, Hu, W, Li, C, Lin, W, Liu, S, Pan, H, Tang, X, Wang, J, Wang, W, Yu, J, Zhang, B, Zhang, Q, Zhao, H, Zhou, J, Gabriel, SB, Barry, R, Blumenstiel, B, Camargo, A, Defelice, M, Faggart, M, Goyette, M, Gupta, S, Moore, J, Nguyen, H, Onofrio, RC, Parkin, M, Roy, J, Stahl, E, Winchester, E, Ziaugra, L, Altshuler, D, Shen, Y, Yao, Z, Huang, W, Chu, X, He, Y, Jin, L, Liu, Y, Sun, W, Wang, H, Wang, Y, Xiong, X, Xu, L, Waye, MM, Tsui, SK, Xue, H, Wong, JT, Galver, LM, Fan, JB, Gunderson, K, Murray, SS, Oliphant, AR, Chee, MS, Montpetit, A, Chagnon, F, Ferretti, V, Leboeuf, M, Olivier, JF, Phillips, MS, Roumy, S, Sallée, C, Verner, A, Hudson, TJ, Kwok, PY, Cai, D, Koboldt, DC, Miller, RD, Pawlikowska, L, Taillon-Miller, P, Xiao, M, Tsui, LC, Mak, W, Song, YQ, Tam, PK, Nakamura, Y, Kawaguchi, T, Kitamoto, T, Morizono, T, Nagashima, A, Ohnishi, Y, Sekine, A, Tanaka, T, Tsunoda, T, Deloukas, P, Bird, CP, Delgado, M, Dermitzakis, ET, Gwilliam, R, Hunt, S, Morrison, J, Powell, D, Stranger, BE, Whittaker, P, Bentley, DR, Daly, MJ, de Bakker, PI, Barrett, J, Chretien, YR, Maller, J, McCarroll, S, Patterson, N, Pe'er, I, Price, A, Purcell, S, Richter, DJ, Sabeti, P, Saxena, R, Sham, PC, Stein, LD, Krishnan, L, Smith, AV, Tello-Ruiz, MK, Thorisson, GA, Chakravarti, A, Chen, PE, Cutler, DJ, Kashuk, CS, Lin, S, Abecasis, GR, Guan, W, Li, Y, Munro, HM, Qin, ZS, Thomas, DJ, McVean, G, Auton, A, Bottolo, L, Cardin, N, Eyheramendy, S, Freeman, C, Marchini, J, Myers, S, Spencer, C, Stephens, M, Donnelly, P, Cardon, LR, Clarke, G, Evans, DM, Morris, AP, Weir, BS, Johnson, TA, Mullikin, JC, Sherry, ST, Feolo, M, Skol, A, Zhang, H, Matsuda, I, Fukushima, Y, Macer, DR, Suda, E, Rotimi, CN, Adebamowo, CA, Ajayi, I, Aniagwu, T, Marshall, PA, Nkwodimmah, C, Royal, CD, Leppert, MF, Dixon, M, Peiffer, A, Qiu, R, Kent, A, Kato, K, Niikawa, N, Adewole, IF, Knoppers, BM, Foster, MW, Clayton, EW, Watkin, J, Muzny, D, Nazareth, L, Sodergren, E, Weinstock, GM, Yakub, I, Birren, BW, Wilson, RK, Fulton, LL, Rogers, J, Burton, J, Carter, NP, Clee, CM, Griffiths, M, Jones, MC, McLay, K, Plumb, RW, Ross, MT, Sims, SK, Willey, DL, Chen, Z, Han, H, Kang, L, Godbout, M, Wallenburg, JC, L'Archevêque, P, Bellemare, G, Saeki, K, An, D, Fu, H, Li, Q, Wang, Z, Wang, R, Holden, AL, Brooks, LD, McEwen, JE, Guyer, MS, Wang, VO, Peterson, JL, Shi, M, Spiegel, J, Sung, LM, Zacharia, LF, Collins, FS, Kennedy, K, Jamieson, R, and Stewart, J

Subjects
Models, Molecular, Population, Single-nucleotide polymorphism, Human genetic variation, Biology, Polymorphism, Single Nucleotide, Article, Antiporters, Gene Frequency, Humans, International HapMap Project, Selection, Genetic, education, Selection (genetic algorithm), Genetics, education.field_of_study, Multidisciplinary, Natural selection, Geography, Edar Receptor, Genome, Human, Haplotype, Regional Index: Eurasia, Protein Structure, Tertiary, Europe, Genetics, Population, Haplotypes, Human genome
Abstract

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia. ©2007 Nature Publishing Group., link_to_OA_fulltext

Published
2007

24. Identification of a rare coding variant in complement 3 associated with age-related macular degeneration

Author

Zhan, X, Larson, DE, Wang, C, Koboldt, DC, Sergeev, YV, Fulton, RS, Fulton, LL, Fronick, CC, Branham, KE, Bragg-Gresham, J, Jun, G, Hu, Y, Kang, HM, Liu, D, Othman, M, Brooks, M, Ratnapriya, R, Boleda, A, Grassmann, F, von Strachwitz, C, Olson, LM, Buitendijk, GHS, Hofman, A, van Duijn, CM, Cipriani, V, Moore, AT, Shahid, H, Jiang, Y, Conley, YP, Morgan, DJ, Kim, IK, Johnson, MP, Cantsilieris, S, Richardson, AJ, Guymer, RH, Luo, H, Ouyang, H, Licht, C, Pluthero, FG, Zhang, MM, Zhang, K, Baird, PN, Blangero, J, Klein, ML, Farrer, LA, DeAngelis, MM, Weeks, DE, Gorin, MB, Yates, JRW, Klaver, CCW, Pericak-Vance, MA, Haines, JL, Weber, BHF, Wilson, RK, Heckenlively, JR, Chew, EY, Stambolian, D, Mardis, ER, Swaroop, A, Abecasis, GR, Zhan, X, Larson, DE, Wang, C, Koboldt, DC, Sergeev, YV, Fulton, RS, Fulton, LL, Fronick, CC, Branham, KE, Bragg-Gresham, J, Jun, G, Hu, Y, Kang, HM, Liu, D, Othman, M, Brooks, M, Ratnapriya, R, Boleda, A, Grassmann, F, von Strachwitz, C, Olson, LM, Buitendijk, GHS, Hofman, A, van Duijn, CM, Cipriani, V, Moore, AT, Shahid, H, Jiang, Y, Conley, YP, Morgan, DJ, Kim, IK, Johnson, MP, Cantsilieris, S, Richardson, AJ, Guymer, RH, Luo, H, Ouyang, H, Licht, C, Pluthero, FG, Zhang, MM, Zhang, K, Baird, PN, Blangero, J, Klein, ML, Farrer, LA, DeAngelis, MM, Weeks, DE, Gorin, MB, Yates, JRW, Klaver, CCW, Pericak-Vance, MA, Haines, JL, Weber, BHF, Wilson, RK, Heckenlively, JR, Chew, EY, Stambolian, D, Mardis, ER, Swaroop, A, and Abecasis, GR

Abstract

Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p.Arg1210Cys encoded in the CFH gene (case frequency (fcase) = 0.51%; control frequency (fcontrol) = 0.02%; odds ratio (OR) = 23.11) and newly identified p.Lys155Gln encoded in the C3 gene (fcase = 1.06%; fcontrol = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.

Published
2013

25. An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia

Author

Gruber, T, Larson Gedman, A, Zhang, J, Koss, C, Marada, S, Ta, H, Chen, S, Su, X, Ogden, S, Dang, J, Wu, G, Gupta, V, Andersson, A, Pounds, S, Sh, L, Easton, J, Barbato, M, Mulder, H, Manne, J, Wang, J, Rusch, M, Ranade, S, Ganti, R, Parker, M, Ma, J, Radtke, I, Ding, L, Cazzaniga, G, Biondi, A, Kornblau, S, Ravandi, F, Kantarjian, H, Nimer, S, Döhner, K, Döhner, H, Ley, T, Ballerini, P, Shurtleff, S, Tomizawa, D, Adachi, S, Hayashi, Y, Tawa, A, Shih, L, Liang, D, Rubnitz, J, Pui, C, Mardis, E, Wilson, R, Downing, J, Gruber, TA, Koss, CS, Ta, HQ, Chen, SC, Ogden, SK, Andersson, AK, Barbato, MI, Mulder, HL, Kornblau, SM, Nimer, SD, Ley, TJ, Shih, LY, Liang, DC, Rubnitz, JE, Pui, CH, Mardis, ER, Wilson, RK, Downing, JR, BIONDI, ANDREA, Gruber, T, Larson Gedman, A, Zhang, J, Koss, C, Marada, S, Ta, H, Chen, S, Su, X, Ogden, S, Dang, J, Wu, G, Gupta, V, Andersson, A, Pounds, S, Sh, L, Easton, J, Barbato, M, Mulder, H, Manne, J, Wang, J, Rusch, M, Ranade, S, Ganti, R, Parker, M, Ma, J, Radtke, I, Ding, L, Cazzaniga, G, Biondi, A, Kornblau, S, Ravandi, F, Kantarjian, H, Nimer, S, Döhner, K, Döhner, H, Ley, T, Ballerini, P, Shurtleff, S, Tomizawa, D, Adachi, S, Hayashi, Y, Tawa, A, Shih, L, Liang, D, Rubnitz, J, Pui, C, Mardis, E, Wilson, R, Downing, J, Gruber, TA, Koss, CS, Ta, HQ, Chen, SC, Ogden, SK, Andersson, AK, Barbato, MI, Mulder, HL, Kornblau, SM, Nimer, SD, Ley, TJ, Shih, LY, Liang, DC, Rubnitz, JE, Pui, CH, Mardis, ER, Wilson, RK, Downing, JR, and BIONDI, ANDREA

Abstract

To define the mutation spectrum in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL samples. Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis

Published
2012

26. International network of cancer genome projects

Author

Hudson, TJ, Anderson, W, Aretz, A, Barker, AD, Bell, C, Bernabe, RR, Bhan, MK, Calvo, F, Eerola, I, Gerhard, DS, Guttmacher, A, Guyer, M, Hemsley, FM, Jennings, JL, Kerr, D, Klatt, P, Kolar, P, Kusuda, J, Lane, DP, Laplace, F, Lu, Y, Nettekoven, G, Ozenberger, B, Peterson, J, Rao, TS, Remacle, J, Schafer, AJ, Shibata, T, Stratton, MR, Vockley, JG, Watanabe, K, Yang, H, Yuen, MMF, Knoppers, M, Bobrow, M, Cambon-Thomsen, A, Dressler, LG, Dyke, SOM, Joly, Y, Kato, K, Kennedy, KL, Nicolas, P, Parker, MJ, Rial-Sebbag, E, Romeo-Casabona, CM, Shaw, KM, Wallace, S, Wiesner, GL, Zeps, N, Lichter, P, Biankin, AV, Chabannon, C, Chin, L, Clement, B, de Alava, E, Degos, F, Ferguson, ML, Geary, P, Hayes, DN, Johns, AL, Nakagawa, H, Penny, R, Piris, MA, Sarin, R, Scarpa, A, van de Vijver, M, Futreal, PA, Aburatani, H, Bayes, M, Bowtell, DDL, Campbell, PJ, Estivill, X, Grimmond, SM, Gut, I, Hirst, M, Lopez-Otin, C, Majumder, P, Marra, M, Ning, Z, Puente, XS, Ruan, Y, Stunnenberg, HG, Swerdlow, H, Velculescu, VE, Wilson, RK, Xue, HH, Yang, L, Spellman, PT, Bader, GD, Boutros, PC, Flicek, P, Getz, G, Guigo, R, Guo, G, Haussler, D, Heath, S, Hubbard, TJ, Jiang, T, Jones, SM, Li, Q, Lopez-Bigas, N, Luo, R, Pearson, JV, Quesada, V, Raphael, BJ, Sander, C, Speed, TP, Stuart, JM, Teague, JW, Totoki, Y, Tsunoda, T, Valencia, A, Wheeler, DA, Wu, H, Zhao, S, Zhou, G, Stein, LD, Lathrop, M, Ouellette, BFF, Thomas, G, Yoshida, T, Axton, M, Gunter, C, McPherson, JD, Miller, LJ, Kasprzyk, A, Zhang, J, Haider, SA, Wang, J, Yung, CK, Cross, A, Liang, Y, Gnaneshan, S, Guberman, J, Hsu, J, Chalmers, DRC, Hasel, KW, Kaan, TSH, Knoppers, BM, Lowrance, WW, Masui, T, Rodriguez, LL, Vergely, C, Cloonan, N, Defazio, A, Eshleman, JR, Etemadmoghadam, D, Gardiner, BA, Kench, JG, Sutherland, RL, Tempero, MA, Waddell, NJ, Wilson, PJ, Gallinger, S, Tsao, M-S, Shaw, PA, Petersen, GM, Mukhopadhyay, D, DePinho, RA, Thayer, S, Muthuswamy, L, Shazand, K, Beck, T, Sam, M, Timms, L, Ballin, V, Ji, J, Zhang, X, Chen, F, Hu, X, Yang, Q, Tian, G, Zhang, L, Xing, X, Li, X, Zhu, Z, Yu, Y, Yu, J, Tost, J, Brennan, P, Holcatova, I, Zaridze, D, Brazma, A, Egevad, L, Prokhortchouk, E, Banks, RE, Uhlen, M, Viksna, J, Ponten, F, Skryabin, K, Birney, E, Borg, A, Borresen-Dale, A-L, Caldas, C, Foekens, JA, Martin, S, Reis-Filho, JS, Richardson, AL, Sotiriou, C, van't Veer, L, Birnbaum, D, Blanche, H, Boucher, P, Boyault, S, Masson-Jacquemier, JD, Pauporte, I, Pivot, X, Vincent-Salomon, A, Tabone, E, Theillet, C, Treilleux, I, Bioulac-Sage, P, Decaens, T, Franco, D, Gut, M, Samuel, D, Zucman-Rossi, J, Eils, R, Brors, B, Korbel, JO, Korshunov, A, Landgraf, P, Lehrach, H, Pfister, S, Radlwimmer, B, Reifenberger, G, Taylor, MD, von Kalle, C, Majumder, PP, Pederzoli, P, Lawlor, RT, Delledonne, M, Bardelli, A, Gress, T, Klimstra, D, Zamboni, G, Nakamura, Y, Miyano, S, Fujimoto, A, Campo, E, de Sanjose, S, Montserrat, E, Gonzalez-Diaz, M, Jares, P, Himmelbaue, H, Bea, S, Aparicio, S, Easton, DF, Collins, FS, Compton, CC, Lander, ES, Burke, W, Green, AR, Hamilton, SR, Kallioniemi, OP, Ley, TJ, Liu, ET, Wainwright, BJ, Hudson, TJ, Anderson, W, Aretz, A, Barker, AD, Bell, C, Bernabe, RR, Bhan, MK, Calvo, F, Eerola, I, Gerhard, DS, Guttmacher, A, Guyer, M, Hemsley, FM, Jennings, JL, Kerr, D, Klatt, P, Kolar, P, Kusuda, J, Lane, DP, Laplace, F, Lu, Y, Nettekoven, G, Ozenberger, B, Peterson, J, Rao, TS, Remacle, J, Schafer, AJ, Shibata, T, Stratton, MR, Vockley, JG, Watanabe, K, Yang, H, Yuen, MMF, Knoppers, M, Bobrow, M, Cambon-Thomsen, A, Dressler, LG, Dyke, SOM, Joly, Y, Kato, K, Kennedy, KL, Nicolas, P, Parker, MJ, Rial-Sebbag, E, Romeo-Casabona, CM, Shaw, KM, Wallace, S, Wiesner, GL, Zeps, N, Lichter, P, Biankin, AV, Chabannon, C, Chin, L, Clement, B, de Alava, E, Degos, F, Ferguson, ML, Geary, P, Hayes, DN, Johns, AL, Nakagawa, H, Penny, R, Piris, MA, Sarin, R, Scarpa, A, van de Vijver, M, Futreal, PA, Aburatani, H, Bayes, M, Bowtell, DDL, Campbell, PJ, Estivill, X, Grimmond, SM, Gut, I, Hirst, M, Lopez-Otin, C, Majumder, P, Marra, M, Ning, Z, Puente, XS, Ruan, Y, Stunnenberg, HG, Swerdlow, H, Velculescu, VE, Wilson, RK, Xue, HH, Yang, L, Spellman, PT, Bader, GD, Boutros, PC, Flicek, P, Getz, G, Guigo, R, Guo, G, Haussler, D, Heath, S, Hubbard, TJ, Jiang, T, Jones, SM, Li, Q, Lopez-Bigas, N, Luo, R, Pearson, JV, Quesada, V, Raphael, BJ, Sander, C, Speed, TP, Stuart, JM, Teague, JW, Totoki, Y, Tsunoda, T, Valencia, A, Wheeler, DA, Wu, H, Zhao, S, Zhou, G, Stein, LD, Lathrop, M, Ouellette, BFF, Thomas, G, Yoshida, T, Axton, M, Gunter, C, McPherson, JD, Miller, LJ, Kasprzyk, A, Zhang, J, Haider, SA, Wang, J, Yung, CK, Cross, A, Liang, Y, Gnaneshan, S, Guberman, J, Hsu, J, Chalmers, DRC, Hasel, KW, Kaan, TSH, Knoppers, BM, Lowrance, WW, Masui, T, Rodriguez, LL, Vergely, C, Cloonan, N, Defazio, A, Eshleman, JR, Etemadmoghadam, D, Gardiner, BA, Kench, JG, Sutherland, RL, Tempero, MA, Waddell, NJ, Wilson, PJ, Gallinger, S, Tsao, M-S, Shaw, PA, Petersen, GM, Mukhopadhyay, D, DePinho, RA, Thayer, S, Muthuswamy, L, Shazand, K, Beck, T, Sam, M, Timms, L, Ballin, V, Ji, J, Zhang, X, Chen, F, Hu, X, Yang, Q, Tian, G, Zhang, L, Xing, X, Li, X, Zhu, Z, Yu, Y, Yu, J, Tost, J, Brennan, P, Holcatova, I, Zaridze, D, Brazma, A, Egevad, L, Prokhortchouk, E, Banks, RE, Uhlen, M, Viksna, J, Ponten, F, Skryabin, K, Birney, E, Borg, A, Borresen-Dale, A-L, Caldas, C, Foekens, JA, Martin, S, Reis-Filho, JS, Richardson, AL, Sotiriou, C, van't Veer, L, Birnbaum, D, Blanche, H, Boucher, P, Boyault, S, Masson-Jacquemier, JD, Pauporte, I, Pivot, X, Vincent-Salomon, A, Tabone, E, Theillet, C, Treilleux, I, Bioulac-Sage, P, Decaens, T, Franco, D, Gut, M, Samuel, D, Zucman-Rossi, J, Eils, R, Brors, B, Korbel, JO, Korshunov, A, Landgraf, P, Lehrach, H, Pfister, S, Radlwimmer, B, Reifenberger, G, Taylor, MD, von Kalle, C, Majumder, PP, Pederzoli, P, Lawlor, RT, Delledonne, M, Bardelli, A, Gress, T, Klimstra, D, Zamboni, G, Nakamura, Y, Miyano, S, Fujimoto, A, Campo, E, de Sanjose, S, Montserrat, E, Gonzalez-Diaz, M, Jares, P, Himmelbaue, H, Bea, S, Aparicio, S, Easton, DF, Collins, FS, Compton, CC, Lander, ES, Burke, W, Green, AR, Hamilton, SR, Kallioniemi, OP, Ley, TJ, Liu, ET, and Wainwright, BJ

Abstract

The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

Published
2010

27. Novel venom gene discovery in the platypus

Author

Whittington, CM, Papenfuss, AT, Locke, DP, Mardis, ER, Wilson, RK, Abubucker, S, Mitreva, M, Wong, ESW, Hsu, AL, Kuchel, PW, Belov, K, Warren, WC, Whittington, CM, Papenfuss, AT, Locke, DP, Mardis, ER, Wilson, RK, Abubucker, S, Mitreva, M, Wong, ESW, Hsu, AL, Kuchel, PW, Belov, K, and Warren, WC

Abstract

BACKGROUND: To date, few peptides in the complex mixture of platypus venom have been identified and sequenced, in part due to the limited amounts of platypus venom available to study. We have constructed and sequenced a cDNA library from an active platypus venom gland to identify the remaining components. RESULTS: We identified 83 novel putative platypus venom genes from 13 toxin families, which are homologous to known toxins from a wide range of vertebrates (fish, reptiles, insectivores) and invertebrates (spiders, sea anemones, starfish). A number of these are expressed in tissues other than the venom gland, and at least three of these families (those with homology to toxins from distant invertebrates) may play non-toxin roles. Thus, further functional testing is required to confirm venom activity. However, the presence of similar putative toxins in such widely divergent species provides further evidence for the hypothesis that there are certain protein families that are selected preferentially during evolution to become venom peptides. We have also used homology with known proteins to speculate on the contributions of each venom component to the symptoms of platypus envenomation. CONCLUSIONS: This study represents a step towards fully characterizing the first mammal venom transcriptome. We have found similarities between putative platypus toxins and those of a number of unrelated species, providing insight into the evolution of mammalian venom.

Published
2010

29. Genomic structure of a cytoplasmic dynein heavy chain gene from the nematode Caenorhabditis elegans

Author

Waterston Rh, Lye Rj, and Wilson Rk

Subjects
Genetic Linkage, RNA Splicing, Dynein, Molecular Sequence Data, Biology, Homology (biology), Exon, Structural Biology, Microtubule, Consensus Sequence, Consensus sequence, Animals, Cloning, Molecular, Caenorhabditis elegans, Gene, Chromosomes, Artificial, Yeast, Genes, Helminth, Genetics, Base Sequence, Sequence Homology, Amino Acid, Chromosome Mapping, Dyneins, Cell Biology, Exons, Sequence Analysis, DNA, Blotting, Northern, Introns, genomic DNA, Blotting, Southern, Dynactin
Abstract

We report the cloning and sequencing of genomic DNA encoding a cytoplasmic dynein heavy chain from the nematode Caenorhabditis elegans. In a contiguous stretch of 35,103 bp of DNA from the left arm of linkage group I, we have found a gene that is predicted to encode a protein of 4,568 amino acids. This gene is composed of 15 exons and 14 relatively short introns, and it has significant homology of the other dynein heavy chains in the databases. The deduced molecular mass of the derived polypeptide is 512,624 Da. As with other dynein heavy chains that have been sequenced to date, it contains four GXXGXGK(S/T) motifs that form part of the consensus sequence for nucleotide triphosphate-binding domains. Comparison of axonemal and cytoplasmic dynein heavy chains shows that regions of homology among all dyneins are clustered in the carboxyl terminal two-thirds of the polypeptide, whereas the amino terminal one-third of the heavy chains may contain domains that specify functions that differ between axonemal and cytoplasmic forms of the dynein heavy chain. © 1995 Wiley-Liss, Inc.

Published
1995

30. The International HapMap Project

Author

Gibbs, RA, Belmont, JW, Hardenbol, P., Willis, TD, Yu, FL, Yang, HM, Ch'ang, LY, Huang, W., Liu, B., Shen, Y., Tam, PKH, Foster, MW, Jasperse, M., Knoppers, BM, Kwok, PY, Licinio, J., Long, JC, Marshall, PA, Ossorio, PN, Wang, VO, Rotimi, CN, Tsui, LC, Royal, CDM, Spallone, P., Terry, SF, Lander, ES, Lai, EH, Nickerson, DA, Abecasis, GR, Altshuler, D., Bentley, DR, Boehnke, M., Waye, MMY, Cardon, LR, Daly, MJ, Deloukas, P., Douglas, JA, Gabriel, SB, Hudson, RR, Hudson, TJ, Kruglyak, L., Nakamura, Y., Wong, JTF, Nussbaum, RL, Schaffner, SF, Sherry, ST, Stein, LD, Tanaka, T., Zeng, CQ, Zhang, QR, Chee, MS, Galver, LM, Kruglyak, S., Murray, SS, Oliphant, AR, Montpetit, A., Chagnon, F., Ferretti, V., Leboeuf, M., Phillips, MS, Verner, A., Duan, SH, Lind, DL, Miller, RD, Rice, JP, Saccone, NL, Taillon-Miller, P., Xiao, M., Sekine, A., Sorimachi, K., Tanaka, Y., Tsunoda, T., Yoshino, E., Hunt, S., Powell, D., Qiu, RZ, Ken, A., Dunston, GM, Kato, K., Niikawa, N., Clayton, EW, Watkin, J., Sodergren, E., Weinstock, GM, Wilson, RK, Fulton, LL, Rogers, J., Birren, BW, Han, H., Wang, HG, Godbout, M., Wallenburg, JC, L'Archeveque, P., Bellemare, G., Todani, K., Fujita, T., Tanaka, S., Holden, AL, Collins, FS, Brooks, LD, McEwen, JE, Guyer, MS, Jordan, E., Peterson, JL, Spiegel, J., Sung, LM, Zacharia, LF, Kennedy, K., Dunn, MG, Seabrook, R., Shillito, M., Skene, B., Stewart, JG, Valle, DL, Jorde, LB, Chakravarti, A., Cho, MK, Duster, T., Gibbs, RA, Belmont, JW, Hardenbol, P., Willis, TD, Yu, FL, Yang, HM, Ch'ang, LY, Huang, W., Liu, B., Shen, Y., Tam, PKH, Foster, MW, Jasperse, M., Knoppers, BM, Kwok, PY, Licinio, J., Long, JC, Marshall, PA, Ossorio, PN, Wang, VO, Rotimi, CN, Tsui, LC, Royal, CDM, Spallone, P., Terry, SF, Lander, ES, Lai, EH, Nickerson, DA, Abecasis, GR, Altshuler, D., Bentley, DR, Boehnke, M., Waye, MMY, Cardon, LR, Daly, MJ, Deloukas, P., Douglas, JA, Gabriel, SB, Hudson, RR, Hudson, TJ, Kruglyak, L., Nakamura, Y., Wong, JTF, Nussbaum, RL, Schaffner, SF, Sherry, ST, Stein, LD, Tanaka, T., Zeng, CQ, Zhang, QR, Chee, MS, Galver, LM, Kruglyak, S., Murray, SS, Oliphant, AR, Montpetit, A., Chagnon, F., Ferretti, V., Leboeuf, M., Phillips, MS, Verner, A., Duan, SH, Lind, DL, Miller, RD, Rice, JP, Saccone, NL, Taillon-Miller, P., Xiao, M., Sekine, A., Sorimachi, K., Tanaka, Y., Tsunoda, T., Yoshino, E., Hunt, S., Powell, D., Qiu, RZ, Ken, A., Dunston, GM, Kato, K., Niikawa, N., Clayton, EW, Watkin, J., Sodergren, E., Weinstock, GM, Wilson, RK, Fulton, LL, Rogers, J., Birren, BW, Han, H., Wang, HG, Godbout, M., Wallenburg, JC, L'Archeveque, P., Bellemare, G., Todani, K., Fujita, T., Tanaka, S., Holden, AL, Collins, FS, Brooks, LD, McEwen, JE, Guyer, MS, Jordan, E., Peterson, JL, Spiegel, J., Sung, LM, Zacharia, LF, Kennedy, K., Dunn, MG, Seabrook, R., Shillito, M., Skene, B., Stewart, JG, Valle, DL, Jorde, LB, Chakravarti, A., Cho, MK, and Duster, T.

Published
2003

31. Identification of a novel type IV pilus gene cluster required for gastrointestinal colonization of Citrobacter rodentium

Author

Mundy, R, Pickard, D, Wilson, RK, Simmons, CP, Dougan, G, Frankel, G, Mundy, R, Pickard, D, Wilson, RK, Simmons, CP, Dougan, G, and Frankel, G

Abstract

Citrobacter rodentium is used as an in vivo model system for clinically significant enteric pathogens such as enterohaemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC). These pathogens all colonize the lumen side of the host gastrointestinal tract via attaching and effacing (A/E) lesion formation. In order to identify genes required for the colonization of A/E-forming pathogens, a library of signature-tagged transposon mutants of C. rodentium was constructed and screened in mice. Of the 576 mutants tested, 14 were attenuated in their ability to colonize the descending colon. Of these, eight mapped to the locus of enterocyte effacement (LEE), which is required for the formation of A/E lesions, underlying the importance of this mechanism for pathogenesis. Another mutant, P5H2, was found to have a transposon insertion in an open reading frame that has strong similarity to type IV pilus nucleotide-binding proteins. The region flanking the transposon insertion was sequenced, identifying a cluster of 12 genes that encode the first described pilus of C. rodentium (named colonization factor Citrobacter, CFC). The proteins encoded by cfc genes have identity to proteins of the type IV COF pilus of enterotoxigenic E. coli (ETEC), the toxin co-regulated pilus of Vibrio cholerae and the bundle-forming pilus of EPEC. A non-polar mutation in cfcI, complementation of this strain with wild-type cfcI and complementation of strain P5H2 with wild-type cfcH confirmed that these genes are required for colonization of the gastrointestinal tract by C. rodentium. Thus, CFC provides a convenient model to study type IV pilus-mediated pathogen-host interactions under physiological conditions in the natural colonic environment.

Published
2003

32. Fatal Hepatic Sarcocystosis in Two Polar Bears (Ursus maritimus)

Author

B. C. Barr, Burek Huntington Ka, Andrea E. Packham, Wilson Rk, Dubney Jp, Garner Hm, and Antoinette E. Marsh

Subjects
Pathology, medicine.medical_specialty, biology, Rhoptry, Residual body, Sarcocystosis, biology.organism_classification, Apicomplexa, parasitic diseases, medicine, Sarcocystis, Ultrastructure, Parasite hosting, Parasitology, Conoid, Ecology, Evolution, Behavior and Systematics
Abstract

Fatal hepatic sarcocystosis was diagnosed in 2 polar bears from a zoo in Anchorage, Alaska. Gross lesions were icterus and systemic petechiae. Marked microscopic lesions were detected only in the liver and included severe random necrotizing hepatitis with hemorrhage. Only asexual stages of an apicomplexan parasite were detected within hepatocytes, and rare extracellular zoites were seen in foci of necrosis. The parasite divided by endopolygeny, and occasionally merozoites formed rosettes around a central residual body. Ultrastructural features of the merozoites included a conoid and low numbers of micronemes at the apical pole, centrally located nuclei, and absence of rhoptries. The parasites failed to react with anti-Neospora sp., anti-Toxoplasma gondii, or anti-Sarcocystis neurona sera. The microscopic and ultrastructural morphology of the parasite are most compatible with an apicomplexan protozoan of the genus Sarcocystis. The life cycle of this parasite in bears is not known.

Published
1997

33. The first European chiropractors.

Author

Wilson FJH and Wilson RK

Abstract

At the beginning of the twenty-first century, secondary histories available in chiropractic literature did not provide definitive answers to the questions: who were the first Europeans to study chiropractic, and, who were the first chiropractors to practise in Europe? This paper sheds new light on the answers to these questions. Based on the findings of archival research undertaken in the United States during 2004, the authors conclude that four chiropractors: Godfrey Heathcote (England), Marie Nesseth (Norway), C. Rasmussen (Norway), and Elizabeth Van Raders (France), were probably the first Europeans to study chiropractic, in 1906. In the absence of evidence suggesting that any of these individuals established a chiropractic practice in Europe, and evidence to suggest that at least two of them might have practised chiropractic in the United States, it is postulated that another individual, Arthur Eteson, an Englishman, was the first to establish a chiropractic practice in Europe, in about 1908. [ABSTRACT FROM AUTHOR]

Published
2007

34. Evidence that congenital hydrocephalus is a precursor to idiopathic normal pressure hydrocephalus in only a subset of patients.

Author

Wilson RK, Williams MA, Wilson, Robin K, and Williams, Michael A

Abstract

Objective: To identify the proportion of patients in a large idiopathic normal pressure hydrocephalus (INPH) cohort with large head circumference (HC) who presumably have congenital hydrocephalus that has not become clinically apparent until late in life.Methods: HC was measured in 158 patients diagnosed with communicating INPH and assigned to HC centile range adjusted for height and sex. The proportion of patients with INPH and HC above the 97th, 90th or 50th centiles was compared with the proportion expected in a normal population.Results: The proportion of patients with HC >90th centile was significantly larger than would be expected in a normal distribution (19.6% vs 10%, p = 0.0001), as was the proportion of patients with HC >97th centile (8.9% vs 3%, p = 0.0001). The relative association between INPH and HC >97th centile was nearly tripled (relative association 2.95; CI 1.36 to 6.41), but the relative association between INPH and HC >50th centile was not significantly higher than predicted (relative association 1.13; CI 0.95 to 1.34).Conclusion: A significantly larger proportion of elderly adults with INPH have a HC greater than the 90th or 97th centile than predicted by population norms, supporting the concept that compensated congenital hydrocephalus that does not become symptomatic until late in life is one aetiology of INPH, but is not responsible for all INPH. The mechanism that leads to the development of INPH in most patients remains elusive. [ABSTRACT FROM AUTHOR]

Published
2007

37. Evaluation of Transbronchial Biopsy of the Lung

Author

Paul M. Stevens, Greenberg Sd, Wilson Rk, and Robert E. Fechner

Subjects
Lung Diseases, Pathology, medicine.medical_specialty, Lung Neoplasms, Biopsy, Bronchoscopy, medicine, Carcinoma, Fiber Optic Technology, Humans, Lung, medicine.diagnostic_test, business.industry, Cancer, General Medicine, medicine.disease, Fully developed, medicine.anatomical_structure, Pneumocystis carinii, Evaluation Studies as Topic, Radiology, business, Transbronchial biopsy
Abstract

Transbronchial biopsy of the lung through the fiberoptic bronchoscope is becoming a widely utilized clinical diagnostic technic. The authors reviewed the histologic features of 109 consecutive cases. The primary problem is the small size of the pulmonary tissue samples obtained, which is further compounded by an apparent mechanical inability to enter the biopsy forceps into dense nodules of neoplastic tissue. The diagnosis of carcinoma can best be made by examining the periphery of the cancer for microscopic extension into adjacent pulmonary parenchyma; however, multiple levels of the tissue block are needed to find such foci. A second problem reflects the use of transbronchial biopsy in the early clinical evolution of various infectious diseases in which pulmonary tissue may contain organisms without a fully developed inflammatory response, which would ordinarily provide the clue to the infective agent. The latter problem appears in cases of infections by Pneumocystis carinii. Close cooperation between the clinician and the pathologist is particularly important in all of these clinical situations.

Published
1977

38. Two cases of appendicitis in New Guinea natives

Author

Wilson Rk

Subjects
medicine.medical_specialty, New Guinea, business.industry, General surgery, New guinea, General Medicine, medicine.disease, Appendicitis, Surgery, Population Groups, Acute Disease, Medicine, Humans, business
Published
1956

42. Somatic mutations affect key pathways in lung adenocarcinoma

Author

Aldi T. Kraja, Brian H. Dunford-Shore, Tittu Mathew, Otis Hall, Barbara A. Weir, Timothy Fennell, William Pao, Jack A. Roth, Alicia Hawes, Heidi Greulich, Steven E. Scherer, Xiaoqi Shi, Giovanni Tonon, Manuel L. Gonzalez-Garay, Yuzhu Tang, Mark B. Orringer, Qunyuan Zhang, Bruce E. Johnson, Li Ding, David G. Beer, Amit Dutt, Margaret R. Spitz, Carrie A. Haipek, Michael A. Province, Yiming Zhu, Liuda Ziaugra, Lucian R. Chirieac, Ken Chen, Rachel Abbott, William D. Travis, George M. Weinstock, Harold E. Varmus, Lucinda Fulton, Daniel C. Koboldt, Kristian Cibulskis, Carrie Sougnez, Christopher S. Sawyer, Richard A. Gibbs, Bradley A. Ozenberger, Thomas J. Giordano, Heather Schmidt, Ling Lin, Jennifer Baldwin, Elaine R. Mardis, Rick Meyer, Tracie L. Miner, David E. Larson, Ignacio I. Wistuba, Jiqiang Yao, Margaret Morgan, Andrew C. Chang, Akihiko Yoshizawa, Shalini N. Jhangiani, Xiaojun Zhao, David A. Wheeler, Stephen R. Broderick, Jody S. Robinson, Kerstin Clerc, Eric S. Lander, Richard K. Wilson, Ginger A. Fewell, Hua Shen, David J. Dooling, Robert S. Fulton, Aleksandar Milosavljevic, John R. Osborne, Gad Getz, Donna M. Muzny, Yanru Ren, Wendy Winckler, Roman K. Thomas, Mark A. Watson, Peter J. Good, Sacha N. Sander, Megan Hanna, Michael D. McLellan, Ginger A. Metcalf, Brian Ng, Michael C. Wendl, Lora Lewis, Seth D. Crosby, Michael C. Zody, Matthew Meyerson, Robert C. Onofrio, Michael S. Lawrence, Marc Ladanyi, Aniko Sabo, Craig Pohl, Stacey Gabriel, Tammi L. Vickery, Ding, L, Getz, G, Wheeler, Da, Mardis, Ea, Mclellan, Md, Cibulskis, K, Sougnez, C, Greulich, H, Muzny, Dm, Morgan, Mb, Fulton, L, Fulton, R, Zhang, Q, Wendl, Mc, Lawrence, M, Larson, De, Chen, K, Dooling, Dj, Sabo, A, Hawes, Ac, Shen, H, Jhangiani, Sh, Lewis, Lr, Hall, O, Zhu, Y, Mathew, T, Ren, Y, Yao, J, Scherer, Se, Clerc, K, Metcalf, Ga, Ng, B, Milosavljevic, A, Gonzalez-Garay, Ml, Osborne, Jr, Meyer, R, Shi, X, Tang, Y, Koboldt, Dc, Lin, L, Abbott, R, Miner, Tl, Pohl, C, Fewell, G, Haipek, C, Schmidt, H, Dunford-Shore, Bh, Kraja, A, Crosby, Sd, Sawyer, C, Vickery, T, Sander, S, Robinson, J, Winckler, W, Baldwin, J, Chirieac, Lr, Dutt, A, Fennell, T, Hanna, M, Johnson, Be, Onofrio, Rc, Thomas, Rk, Tonon, G, Weir, Ba, Zhao, X, Ziaugra, L, Zody, Mc, Giordano, T, Orringer, Mb, Roth, Ja, Spitz, Mr, Wistuba, Ii, Ozenberger, B, Good, Pj, Chang, Ac, Beer, Dg, Watson, Ma, Ladanyi, M, Broderick, S, Yoshizawa, A, Travis, Wd, Pao, W, Province, Ma, Weinstock, Gm, Varmus, He, Gabriel, Sb, Lander, E, Gibbs, Ra, Meyerson, M, and Wilson, Rk.

Subjects
Male, Genetics, Mutation, Lung Neoplasms, Multidisciplinary, Tumor suppressor gene, DNA repair, Gene Dosage, Adenocarcinoma, Bronchiolo-Alveolar, Biology, medicine.disease, medicine.disease_cause, Article, Gene Expression Regulation, Neoplastic, Germline mutation, Proto-Oncogenes, medicine, Humans, Adenocarcinoma, Female, Genes, Tumor Suppressor, Carcinogenesis, Lung cancer, Gene
Abstract

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.

Published
2008

43. Identification and quantitative estimates of groundwater transfers to formerly charophyte dominated marl lakes with radon-222.

Author

Wilson RK, Arnscheidt J, McElarney Y, and Stewart N

Abstract

Interaction with groundwater determines many processes in marl lakes. Net transfer of inorganic carbon helps define their chemical characteristics and determines their unique benthic flora. Nutrient enrichment weakens the biogeochemical buffering mechanisms which help maintain a clear-water state and many small, shallow marl lakes are prone to siltation. Despite hydrological processes being recognised as important for the complex interactions between plants, nutrient availability and physical sediment properties which shape marl lake ecology, groundwater discharge to many of these lakes has never been quantified. The aim of this study was to locate and quantify groundwater transfers to degraded marl lakes in a Special Area of Conservation on the island of Ireland. A RAD7 radon detector identified and measured elevated concentrations of 222 Rn in three lakes for quantifying their groundwater influx with a 222 Rn mass-balance equation. Conservative estimates of mean daily groundwater discharge to Kilroosky Lough, Drumacrittin Lough, and Dummy's Lough were 143 m 3 , 502 m 3 , and 269 m 3 respectively. With extrapolation to the entire hydrological year, annual groundwater recharge contributed approximately 47 %, 155 %, and 50 % of the respective lake volumes. The areas within the lakes which were found to have the highest groundwater influence also closely matched the locations where substantial charophyte communities persist suggesting that the two are linked. These findings underline the importance of groundwater transfers for the water budget in small marl lakes and will inform management efforts to mitigate their eutrophication., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2024
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44. Germline susceptibility from broad genomic profiling of pediatric brain cancers.

Author

Mardis ER, Potter SL, Schieffer KM, Varga EA, Mathew MT, Costello HM, Wheeler G, Kelly BJ, Miller KE, Garfinkle EAR, Wilson RK, and Cottrell CE

Abstract

Background: Identifying germline predisposition in CNS malignancies is of increasing clinical importance, as it contributes to diagnosis and prognosis, and determines aspects of treatment. The inclusion of germline testing has historically been limited due to challenges surrounding access to genetic counseling, complexity in acquiring a germline comparator specimen, concerns about the impact of findings, or cost considerations. These limitations were further defined by the breadth and scope of clinical testing to precisely identify complex variants as well as concerns regarding the clinical interpretation of variants including those of uncertain significance., Methods: In the course of conducting an IRB-approved protocol that performed genomic, transcriptomic and methylation-based characterization of pediatric CNS malignancies, we cataloged germline predisposition to cancer based on paired exome capture sequencing, coupled with computational analyses to identify variants in known cancer predisposition genes and interpret them relative to established clinical guidelines., Results: In certain cases, these findings refined diagnosis or prognosis or provided important information for treatment planning., Conclusions: We outline our aggregate findings on cancer predisposition within this cohort which identified 16% of individuals (27 of 168) harboring a variant predicting cancer susceptibility and contextualize the impact of these results in terms of treatment-related aspects of precision oncology., Competing Interests: None., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Published
2024
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45. Full-length isoform concatenation sequencing to resolve cancer transcriptome complexity.

Author

Wijeratne S, Gonzalez MEH, Roach K, Miller KE, Schieffer KM, Fitch JR, Leonard J, White P, Kelly BJ, Cottrell CE, Mardis ER, Wilson RK, and Miller AR

Subjects
Humans, Child, Gene Expression Profiling methods, Protein Isoforms genetics, Protein Isoforms metabolism, RNA Splicing, Sequence Analysis, RNA, High-Throughput Nucleotide Sequencing methods, Transcriptome, Glioma
Abstract

Background: Cancers exhibit complex transcriptomes with aberrant splicing that induces isoform-level differential expression compared to non-diseased tissues. Transcriptomic profiling using short-read sequencing has utility in providing a cost-effective approach for evaluating isoform expression, although short-read assembly displays limitations in the accurate inference of full-length transcripts. Long-read RNA sequencing (Iso-Seq), using the Pacific Biosciences (PacBio) platform, can overcome such limitations by providing full-length isoform sequence resolution which requires no read assembly and represents native expressed transcripts. A constraint of the Iso-Seq protocol is due to fewer reads output per instrument run, which, as an example, can consequently affect the detection of lowly expressed transcripts. To address these deficiencies, we developed a concatenation workflow, PacBio Full-Length Isoform Concatemer Sequencing (PB_FLIC-Seq), designed to increase the number of unique, sequenced PacBio long-reads thereby improving overall detection of unique isoforms. In addition, we anticipate that the increase in read depth will help improve the detection of moderate to low-level expressed isoforms., Results: In sequencing a commercial reference (Spike-In RNA Variants; SIRV) with known isoform complexity we demonstrated a 3.4-fold increase in read output per run and improved SIRV recall when using the PB_FLIC-Seq method compared to the same samples processed with the Iso-Seq protocol. We applied this protocol to a translational cancer case, also demonstrating the utility of the PB_FLIC-Seq method for identifying differential full-length isoform expression in a pediatric diffuse midline glioma compared to its adjacent non-malignant tissue. Our data analysis revealed increased expression of extracellular matrix (ECM) genes within the tumor sample, including an isoform of the Secreted Protein Acidic and Cysteine Rich (SPARC) gene that was expressed 11,676-fold higher than in the adjacent non-malignant tissue. Finally, by using the PB_FLIC-Seq method, we detected several cancer-specific novel isoforms., Conclusion: This work describes a concatenation-based methodology for increasing the number of sequenced full-length isoform reads on the PacBio platform, yielding improved discovery of expressed isoforms. We applied this workflow to profile the transcriptome of a pediatric diffuse midline glioma and adjacent non-malignant tissue. Our findings of cancer-specific novel isoform expression further highlight the importance of long-read sequencing for characterization of complex tumor transcriptomes., (© 2024. The Author(s).)

Published
2024
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46. Biallelic variants in HTRA2 cause 3-methylglutaconic aciduria mitochondrial disorder: case report and literature review.

Author

Gurusamy U, Ramadesikan S, Marhabaie M, Colwell CM, Hunter JM, Leung ML, Mardis ER, White P, Manickam M, Wilson RK, and Koboldt DC

Abstract

Background: Leigh syndrome is a rare, genetic, and severe mitochondrial disorder characterized by neuromuscular issues (ataxia, seizure, hypotonia, developmental delay, dystonia) and ocular abnormalities (nystagmus, atrophy, strabismus, ptosis). It is caused by pathogenic variants in either mitochondrial or nuclear DNA genes, with an estimated incidence rate of 1 per 40,000 live births. Case presentation: Herein, we present an infant male with nystagmus, hypotonia, and developmental delay who carried a clinical diagnosis of Leigh-like syndrome. Cerebral magnetic resonance imaging changes further supported the clinical evidence of an underlying mitochondrial disorder, but extensive diagnostic testing was negative. Trio exome sequencing under a research protocol uncovered compound-heterozygous missense variants in the HTRA2 gene (MIM: #606441): NM_013247.5:c.1037A>T:(p.Glu346Val) (maternal) and NM_013247.5:c.1172T>A:(p.Val391Glu) (paternal). Both variants are absent from public databases, making them extremely rare in the population. The maternal variant is adjacent to an exon-intron boundary and predicted to disrupt splicing, while the paternal variant alters a highly conserved amino acid and is predicted to be damaging by nearly all in silico tools. Biallelic variants in HTRA2 cause 3-methylglutaconic aciduria, type VIII (MGCA8), an extremely rare autosomal recessive disorder with fewer than ten families reported to date. Variant interpretation is challenging given the paucity of known disease-causing variants, and indeed we assess both paternal and maternal variants as Variants of Uncertain Significance under current American College of Medical Genetics guidelines. However, based on the inheritance pattern, suggestive evidence of pathogenicity, and significant clinical correlation with other reported MGCA8 patients, the clinical care team considers this a diagnostic result. Conclusion: Our findings ended the diagnostic odyssey for this family and provide further insights into the genetic and clinical spectrum of this critically under-studied disorder., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gurusamy, Ramadesikan, Marhabaie, Colwell, Hunter, Leung, Mardis, White, Manickam, Wilson and Koboldt.)

Published
2024
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47. Robotic colorectal surgery in the emergent diverticulitis setting: is it safe? A review of large national database.

Author

Curfman KR, Jones IF, Conner JR, Neighorn CC, Wilson RK, and Rashidi L

Subjects
Humans, Anastomotic Leak, Reproducibility of Results, Robotic Surgical Procedures adverse effects, Colorectal Surgery, Diverticulitis surgery
Abstract

Background: As robotic colorectal surgery continues to advance in conjunction with improved recovery protocols, we began implementing robotic surgery (RS) as an option for emergent diverticulitis surgery. Our hospital system utilizes the Da Vinci Xi system, and staff are required to undergo training, making emergent colorectal surgery a feasible option. However, it is essential to determine the safety with reproducibility of our experiences., Methods: A de-identified retrospective review was performed of Intuitive's national database which obtained data from 262 facilities from January 2018 through December 2021. This identified over 22,000 emergent colorectal surgeries. Of those, over 2500 were performed for diverticulitis in which 126 were RS, 446 laparoscopic surgery (LS), and 1952 open surgery (OS). Clinical outcome metrics including conversion rates, anastomotic leaks, intensive care unit (ICU) admissions, length of stay, mortality, and readmissions were obtained. The cohort was defined by patients who were seen in the emergency department (ED) with diverticulitis and proceeded to have a sigmoid colectomy within 24 h of ED arrival., Results: RS was associated with increased operating time (RS 262, LS 207, OS 182 min), but data has shown many benefits of emergent RS compared to OS. We identified significant decreases in ICU admission rates (OS 19.0%, RS 9.5%, p = 0.01) and anastomotic leak rates (OS 4.4%, RS 0.8%, p = 0.04), with borderline improvement in overall length of stay (OS 9.9, RS 8.9 days, p = 0.05). When compared with LS, RS showed many comparable results. However, RS witnessed a statistically significant improvement in anastomotic leak rates (LS 4.5%, RS 0.8%, p = 0.04). Importantly, there was a striking difference in conversion rates to OS. LS converted over 28.7% of cases to OS, whereas RS only converted 7.9%, p = 0.000005., Conclusion: Given these findings, RS is another MIS tool that could be a safe and feasible option for the acute management of emergent diverticulitis., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Published
2023
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48. Cerebral organoids containing an AUTS2 missense variant model microcephaly.

Author

Fair SR, Schwind W, Julian DL, Biel A, Guo G, Rutherford R, Ramadesikan S, Westfall J, Miller KE, Kararoudi MN, Hickey SE, Mosher TM, McBride KL, Neinast R, Fitch J, Lee DA, White P, Wilson RK, Bedrosian TA, Koboldt DC, and Hester ME

Subjects
Humans, Organoids metabolism, Cytoskeletal Proteins, Transcription Factors metabolism, Microcephaly genetics, Microcephaly metabolism, Intellectual Disability genetics, Autistic Disorder, Neural Stem Cells
Abstract

Variants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain malformations. Here, we use a human cerebral organoid model to investigate the pathophysiology of a heterozygous de novo missense AUTS2 variant identified in a patient with multiple neurological impairments including primary microcephaly and profound intellectual disability. Proband cerebral organoids exhibit reduced growth, deficits in neural progenitor cell (NPC) proliferation and disrupted NPC polarity within ventricular zone-like regions compared to control cerebral organoids. We used CRISPR-Cas9-mediated gene editing to correct this variant and demonstrate rescue of impaired organoid growth and NPC proliferative deficits. Single-cell RNA sequencing revealed a marked reduction of G1/S transition gene expression and alterations in WNT-β-catenin signalling within proband NPCs, uncovering a novel role for AUTS2 in NPCs during human cortical development. Collectively, these results underscore the value of cerebral organoids to investigate molecular mechanisms underlying AUTS2 syndrome., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Published
2023
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49. Infantile metastatic ependymoma with a novel molecular profile and favorable outcome to intensive chemotherapy without irradiation: Case-based review.

Author

De Faria FW, Schieffer KM, Pierson CR, Boue DR, LaHaye S, Miller KE, Amayiri N, Koboldt DC, Lichtenberg T, Leraas K, Brennan P, Kelly B, White P, Magrini V, Wilson RK, Mardis ER, Cottrell CE, Rusin J, Finlay JL, and Osorio DS

Subjects
Child, Male, Humans, Child, Preschool, Infant, Adolescent, Neoplasm Recurrence, Local, Ependymoma drug therapy, Ependymoma genetics, Ependymoma radiotherapy, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Brain Neoplasms diagnosis, Hematopoietic Stem Cell Transplantation
Abstract

Ependymal tumors are the third most common brain tumor under 14 years old. Even though metastatic disease is a rare event, it affects mostly young children and carries an adverse prognosis. The factors associated with dissemination and the best treatment approach have not yet been established and there is limited published data on how to manage metastatic disease, especially in patients under 3 years of age. We provide a review of the literature on clinical characteristics and radiation-sparing treatments for metastatic ependymoma in children under 3 years of age treated. The majority (73%) of the identified cases were above 12 months old and had the PF as the primary site at diagnosis. Chemotherapy-based approaches, in different regimens, were used with radiation reserved for progression or relapse. The prognosis varied among the studies, with an average of 50%-58% overall survival. This study also describes the case of a 7-month-old boy with metastatic posterior fossa (PF) ependymoma, for whom we identified a novel SPECC1L-RAF1 gene fusion using a patient-centric comprehensive molecular profiling protocol. The patient was successfully treated with intensive induction chemotherapy followed by high-dose chemotherapy and autologous hematopoietic progenitor cell rescue (AuHSCR). Currently, the patient is in continuous remission 5 years after his diagnosis, without radiation therapy. The understanding of the available therapeutic approaches may assist physicians in their management of such patients. This report also opens the perspective of newly identified molecular alterations in metastatic ependymomas that might drive more chemo-sensitive tumors., (© 2022 Wiley Periodicals LLC.)

Published
2023
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50. Novel Presentation of Hemiplegic Migraine in a Patient With Cockayne Syndrome.

Author

Carroll J, Pabst L, Koboldt DC, Franklin SJ, Choi S, Wilson RK, and Lo W

Subjects
Male, Humans, Hemiplegia genetics, Siblings, Phenotype, Migraine with Aura diagnosis, Cockayne Syndrome genetics
Abstract

Background: Cockayne syndrome is a rare DNA repair disorder marked by premature aging, poor growth, and intellectual disability. Neurological complications such as seizures, movement disorder, and stroke have been reported. Hemiplegic migraine has not been reported in association with Cockayne syndrome., Methods: We report a male with Cockayne syndrome due to biallelic heterozygous pathogenic variants in ERCC6 who presented repeatedly with transient focal neurological deficits and headache, which were consistent with hemiplegic migraine. Two siblings also had Cockayne syndrome and presented with similar symptoms., Results: Our patient was originally diagnosed based on clinical suspicion and then confirmed by targeted exome analysis of genes associated with Cockayne syndrome. The family's research exome sequencing data were reanalyzed to identify variants in genes known to cause familial hemiplegic migraine. No variants in the genes known to cause familial hemiplegic migraine were identified., Conclusion: This is a novel association of familial hemiplegic migraine in three full siblings with Cockayne syndrome. Hemiplegic migraine has not previously been described as part of the Cockayne syndrome presentation. A separate genetic cause of familial hemiplegic migraines was not identified in an exome-based analysis of genes known to cause this condition. This report may represent an expansion of the Cockayne syndrome phenotype., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Published
2023
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