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1. Author Correction: Comprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants

Author: Hayes, Tikvah K., Aquilanti, Elisa, Persky, Nicole S., Yang, Xiaoping, Kim, Erica E., Brenan, Lisa, Goodale, Amy B., Alan, Douglas, Sharpe, Ted, Shue, Robert E., Westlake, Lindsay, Golomb, Lior, Silverman, Brianna R., Morris, Myshal D., Fisher, Ty Running, Beyene, Eden, Li, Yvonne Y., Cherniack, Andrew D., Piccioni, Federica, Hicks, J. Kevin, Chi, Andrew S., Cahill, Daniel P., Dietrich, Jorg, Batchelor, Tracy T., Root, David E., Johannessen, Cory M., and Meyerson, Matthew
Published: 2024
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2. Comprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants

Author: Hayes, Tikvah K., Aquilanti, Elisa, Persky, Nicole S., Yang, Xiaoping, Kim, Erica E., Brenan, Lisa, Goodale, Amy B., Alan, Douglas, Sharpe, Ted, Shue, Robert E., Westlake, Lindsay, Golomb, Lior, Silverman, Brianna R., Morris, Myshal D., Fisher, Ty Running, Beyene, Eden, Li, Yvonne Y., Cherniack, Andrew D., Piccioni, Federica, Hicks, J. Kevin, Chi, Andrew S., Cahill, Daniel P., Dietrich, Jorg, Batchelor, Tracy T., Root, David E., Johannessen, Cory M., and Meyerson, Matthew
Published: 2024
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3. A structural variation reference for medical and population genetics

Author: Collins, Ryan L, Brand, Harrison, Karczewski, Konrad J, Zhao, Xuefang, Alföldi, Jessica, Francioli, Laurent C, Khera, Amit V, Lowther, Chelsea, Gauthier, Laura D, Wang, Harold, Watts, Nicholas A, Solomonson, Matthew, O’Donnell-Luria, Anne, Baumann, Alexander, Munshi, Ruchi, Walker, Mark, Whelan, Christopher W, Huang, Yongqing, Brookings, Ted, Sharpe, Ted, Stone, Matthew R, Valkanas, Elise, Fu, Jack, Tiao, Grace, Laricchia, Kristen M, Ruano-Rubio, Valentin, Stevens, Christine, Gupta, Namrata, Cusick, Caroline, Margolin, Lauren, Taylor, Kent D, Lin, Henry J, Rich, Stephen S, Post, Wendy S, Chen, Yii-Der Ida, Rotter, Jerome I, Nusbaum, Chad, Philippakis, Anthony, Lander, Eric, Gabriel, Stacey, Neale, Benjamin M, Kathiresan, Sekar, Daly, Mark J, Banks, Eric, MacArthur, Daniel G, and Talkowski, Michael E
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Biotechnology, Generic health relevance, Disease, Female, Genetic Testing, Genetic Variation, Genetics, Medical, Genetics, Population, Genome, Human, Genotyping Techniques, Humans, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Racial Groups, Reference Standards, Selection, Genetic, Whole Genome Sequencing, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, General Science & Technology
Abstract: Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.
Published: 2020

4. Assemblathon 2: evaluating de novo methods of genome assembly in three vertebrate species

Author: Bradnam, Keith R., Fass, Joseph N., Alexandrov, Anton, Baranay, Paul, Bechner, Michael, Birol, İnanç, Boisvert, Sébastien, Chapman, Jarrod A., Chapuis, Guillaume, Chikhi, Rayan, Chitsaz, Hamidreza, Chou, Wen-Chi, Corbeil, Jacques, Del Fabbro, Cristian, Docking, T. Roderick, Durbin, Richard, Earl, Dent, Emrich, Scott, Fedotov, Pavel, Fonseca, Nuno A., Ganapathy, Ganeshkumar, Gibbs, Richard A., Gnerre, Sante, Godzaridis, Élénie, Goldstein, Steve, Haimel, Matthias, Hall, Giles, Haussler, David, Hiatt, Joseph B., Ho, Isaac Y., Howard, Jason, Hunt, Martin, Jackman, Shaun D., Jaffe, David B, Jarvis, Erich, Jiang, Huaiyang, Kazakov, Sergey, Kersey, Paul J., Kitzman, Jacob O., Knight, James R., Koren, Sergey, Lam, Tak-Wah, Lavenier, Dominique, Laviolette, François, Li, Yingrui, Li, Zhenyu, Liu, Binghang, Liu, Yue, Luo, Ruibang, MacCallum, Iain, MacManes, Matthew D, Maillet, Nicolas, Melnikov, Sergey, Vieira, Bruno Miguel, Naquin, Delphine, Ning, Zemin, Otto, Thomas D., Paten, Benedict, Paulo, Octávio S., Phillippy, Adam M., Pina-Martins, Francisco, Place, Michael, Przybylski, Dariusz, Qin, Xiang, Qu, Carson, Ribeiro, Filipe J, Richards, Stephen, Rokhsar, Daniel S., Ruby, J. Graham, Scalabrin, Simone, Schatz, Michael C., Schwartz, David C., Sergushichev, Alexey, Sharpe, Ted, Shaw, Timothy I., Shendure, Jay, Shi, Yujian, Simpson, Jared T., Song, Henry, Tsarev, Fedor, Vezzi, Francesco, Vicedomini, Riccardo, Wang, Jun, Worley, Kim C., Yin, Shuangye, Yiu, Siu-Ming, Yuan, Jianying, Zhang, Guojie, Zhang, Hao, Zhou, Shiguo, and Korf, Ian F.
Subjects: Quantitative Biology - Genomics
Abstract: Background - The process of generating raw genome sequence data continues to become cheaper, faster, and more accurate. However, assembly of such data into high-quality, finished genome sequences remains challenging. Many genome assembly tools are available, but they differ greatly in terms of their performance (speed, scalability, hardware requirements, acceptance of newer read technologies) and in their final output (composition of assembled sequence). More importantly, it remains largely unclear how to best assess the quality of assembled genome sequences. The Assemblathon competitions are intended to assess current state-of-the-art methods in genome assembly. Results - In Assemblathon 2, we provided a variety of sequence data to be assembled for three vertebrate species (a bird, a fish, and snake). This resulted in a total of 43 submitted assemblies from 21 participating teams. We evaluated these assemblies using a combination of optical map data, Fosmid sequences, and several statistical methods. From over 100 different metrics, we chose ten key measures by which to assess the overall quality of the assemblies. Conclusions - Many current genome assemblers produced useful assemblies, containing a significant representation of their genes, regulatory sequences, and overall genome structure. However, the high degree of variability between the entries suggests that there is still much room for improvement in the field of genome assembly and that approaches which work well in assembling the genome of one species may not necessarily work well for another., Comment: Additional files available at http://korflab.ucdavis.edu/Datasets/Assemblathon/Assemblathon2/Additional_files/ Major changes 1. Accessions for the 3 read data sets have now been included 2. New file: spreadsheet containing details of all Study, Sample, Run, & Experiment identifiers 3. Made miscellaneous changes to address reviewers comments. DOIs added to GigaDB datasets
Published: 2013
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5. The genomic substrate for adaptive radiation in African cichlid fish.

Author: Brawand, David, Wagner, Catherine E, Li, Yang I, Malinsky, Milan, Keller, Irene, Fan, Shaohua, Simakov, Oleg, Ng, Alvin Y, Lim, Zhi Wei, Bezault, Etienne, Turner-Maier, Jason, Johnson, Jeremy, Alcazar, Rosa, Noh, Hyun Ji, Russell, Pamela, Aken, Bronwen, Alföldi, Jessica, Amemiya, Chris, Azzouzi, Naoual, Baroiller, Jean-François, Barloy-Hubler, Frederique, Berlin, Aaron, Bloomquist, Ryan, Carleton, Karen L, Conte, Matthew A, D'Cotta, Helena, Eshel, Orly, Gaffney, Leslie, Galibert, Francis, Gante, Hugo F, Gnerre, Sante, Greuter, Lucie, Guyon, Richard, Haddad, Natalie S, Haerty, Wilfried, Harris, Rayna M, Hofmann, Hans A, Hourlier, Thibaut, Hulata, Gideon, Jaffe, David B, Lara, Marcia, Lee, Alison P, MacCallum, Iain, Mwaiko, Salome, Nikaido, Masato, Nishihara, Hidenori, Ozouf-Costaz, Catherine, Penman, David J, Przybylski, Dariusz, Rakotomanga, Michaelle, Renn, Suzy CP, Ribeiro, Filipe J, Ron, Micha, Salzburger, Walter, Sanchez-Pulido, Luis, Santos, M Emilia, Searle, Steve, Sharpe, Ted, Swofford, Ross, Tan, Frederick J, Williams, Louise, Young, Sarah, Yin, Shuangye, Okada, Norihiro, Kocher, Thomas D, Miska, Eric A, Lander, Eric S, Venkatesh, Byrappa, Fernald, Russell D, Meyer, Axel, Ponting, Chris P, Streelman, J Todd, Lindblad-Toh, Kerstin, Seehausen, Ole, and Di Palma, Federica
Subjects: Animals, Cichlids, MicroRNAs, DNA Transposable Elements, Genomics, Evolution, Molecular, Phylogeny, Gene Expression Regulation, Gene Duplication, Polymorphism, Genetic, Genome, Africa, Eastern, Genetic Speciation, Lakes, Africa, Eastern, Evolution, Molecular, Polymorphism, Genetic, General Science & Technology
Abstract: Cichlid fishes are famous for large, diverse and replicated adaptive radiations in the Great Lakes of East Africa. To understand the molecular mechanisms underlying cichlid phenotypic diversity, we sequenced the genomes and transcriptomes of five lineages of African cichlids: the Nile tilapia (Oreochromis niloticus), an ancestral lineage with low diversity; and four members of the East African lineage: Neolamprologus brichardi/pulcher (older radiation, Lake Tanganyika), Metriaclima zebra (recent radiation, Lake Malawi), Pundamilia nyererei (very recent radiation, Lake Victoria), and Astatotilapia burtoni (riverine species around Lake Tanganyika). We found an excess of gene duplications in the East African lineage compared to tilapia and other teleosts, an abundance of non-coding element divergence, accelerated coding sequence evolution, expression divergence associated with transposable element insertions, and regulation by novel microRNAs. In addition, we analysed sequence data from sixty individuals representing six closely related species from Lake Victoria, and show genome-wide diversifying selection on coding and regulatory variants, some of which were recruited from ancient polymorphisms. We conclude that a number of molecular mechanisms shaped East African cichlid genomes, and that amassing of standing variation during periods of relaxed purifying selection may have been important in facilitating subsequent evolutionary diversification.
Published: 2014

6. Assemblathon 2: evaluating de novo methods of genome assembly in three vertebrate species

Author: Bradnam, Keith R, Fass, Joseph N, Alexandrov, Anton, Baranay, Paul, Bechner, Michael, Birol, Inanç, Boisvert, Sébastien, Chapman, Jarrod A, Chapuis, Guillaume, Chikhi, Rayan, Chitsaz, Hamidreza, Chou, Wen-Chi, Corbeil, Jacques, Del Fabbro, Cristian, Docking, T, Durbin, Richard, Earl, Dent, Emrich, Scott, Fedotov, Pavel, Fonseca, Nuno A, Ganapathy, Ganeshkumar, Gibbs, Richard A, Gnerre, Sante, Godzaridis, Élénie, Goldstein, Steve, Haimel, Matthias, Hall, Giles, Haussler, David, Hiatt, Joseph B, Ho, Isaac Y, Howard, Jason, Hunt, Martin, Jackman, Shaun D, Jaffe, David B, Jarvis, Erich D, Jiang, Huaiyang, Kazakov, Sergey, Kersey, Paul J, Kitzman, Jacob O, Knight, James R, Koren, Sergey, Lam, Tak-Wah, Lavenier, Dominique, Laviolette, François, Li, Yingrui, Li, Zhenyu, Liu, Binghang, Liu, Yue, Luo, Ruibang, MacCallum, Iain, MacManes, Matthew D, Maillet, Nicolas, Melnikov, Sergey, Naquin, Delphine, Ning, Zemin, Otto, Thomas D, Paten, Benedict, Paulo, Octávio S, Phillippy, Adam M, Pina-Martins, Francisco, Place, Michael, Przybylski, Dariusz, Qin, Xiang, Qu, Carson, Ribeiro, Filipe J, Richards, Stephen, Rokhsar, Daniel S, Ruby, J, Scalabrin, Simone, Schatz, Michael C, Schwartz, David C, Sergushichev, Alexey, Sharpe, Ted, Shaw, Timothy I, Shendure, Jay, Shi, Yujian, Simpson, Jared T, Song, Henry, Tsarev, Fedor, Vezzi, Francesco, Vicedomini, Riccardo, Vieira, Bruno M, Wang, Jun, Worley, Kim C, Yin, Shuangye, Yiu, Siu-Ming, Yuan, Jianying, Zhang, Guojie, Zhang, Hao, Zhou, Shiguo, and Korf, Ian F
Abstract: Abstract Background The process of generating raw genome sequence data continues to become cheaper, faster, and more accurate. However, assembly of such data into high-quality, finished genome sequences remains challenging. Many genome assembly tools are available, but they differ greatly in terms of their performance (speed, scalability, hardware requirements, acceptance of newer read technologies) and in their final output (composition of assembled sequence). More importantly, it remains largely unclear how to best assess the quality of assembled genome sequences. The Assemblathon competitions are intended to assess current state-of-the-art methods in genome assembly. Results In Assemblathon 2, we provided a variety of sequence data to be assembled for three vertebrate species (a bird, a fish, and snake). This resulted in a total of 43 submitted assemblies from 21 participating teams. We evaluated these assemblies using a combination of optical map data, Fosmid sequences, and several statistical methods. From over 100 different metrics, we chose ten key measures by which to assess the overall quality of the assemblies. Conclusions Many current genome assemblers produced useful assemblies, containing a significant representation of their genes and overall genome structure. However, the high degree of variability between the entries suggests that there is still much room for improvement in the field of genome assembly and that approaches which work well in assembling the genome of one species may not necessarily work well for another.
Published: 2013

7. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy

Author: Barretina, Jordi, Taylor, Barry S, Banerji, Shantanu, Ramos, Alexis H, Lagos-Quintana, Mariana, DeCarolis, Penelope L, Shah, Kinjal, Socci, Nicholas D, Weir, Barbara A, Ho, Alan, Chiang, Derek Y, Reva, Boris, Mermel, Craig H, Getz, Gad, Antipin, Yevgenyi, Beroukhim, Rameen, Major, John E, Hatton, Charles, Nicoletti, Richard, Hanna, Megan, Sharpe, Ted, Fennell, Tim J, Cibulskis, Kristian, Onofrio, Robert C, Saito, Tsuyoshi, Shukla, Neerav, Lau, Christopher, Nelander, Sven, Silver, Serena J, Sougnez, Carrie, Viale, Agnes, Winckler, Wendy, Maki, Robert G, Garraway, Levi A, Lash, Alex, Greulich, Heidi, Root, David E, Sellers, William R, Schwartz, Gary K, Antonescu, Cristina R, Lander, Eric S, Varmus, Harold E, Ladanyi, Marc, Sander, Chris, Meyerson, Matthew, and Singer, Samuel
Subjects: Pediatric, Biotechnology, Cancer, Human Genome, Genetics, Adult, Aged, Female, Genes, Tumor Suppressor, Genome, Histiocytoma, Malignant Fibrous, Humans, Liposarcoma, Male, Middle Aged, Mutation, Sarcoma, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States, show remarkable histologic diversity, with more than 50 recognized subtypes. However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1. Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy.
Published: 2010

8. Mutational processes shape the landscape of TP53 mutations in human cancer

Author: Giacomelli, Andrew O., Yang, Xiaoping, Lintner, Robert E., McFarland, James M., Duby, Marc, Kim, Jaegil, Howard, Thomas P., Takeda, David Y., Ly, Seav Huong, Kim, Eejung, Gannon, Hugh S., Hurhula, Brian, Sharpe, Ted, Goodale, Amy, Fritchman, Briana, Steelman, Scott, Vazquez, Francisca, Tsherniak, Aviad, Aguirre, Andrew J., Doench, John G., Piccioni, Federica, Roberts, Charles W. M., Meyerson, Matthew, Getz, Gad, Johannessen, Cory M., Root, David E., and Hahn, William C.
Published: 2018
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9. High-quality draft assemblies of mammalian genomes from massively parallel sequence data

Author: Gnerre, Sante, MacCallum, Iain, Przybylski, Dariusz, Ribeiro, Filipe J., Burton, Joshua N., Walker, Bruce J., Sharpe, Ted, Hall, Giles, Shea, Terrance P., Sykes, Sean, Berlin, Aaron M., Aird, Daniel, Costello, Maura, Daza, Riza, Williams, Louise, Nicol, Robert, Gnirke, Andreas, Nusbaum, Chad, Lander, Eric S., and Jaffe, David B.
Published: 2011

10. Whole-genome resequencing reveals loci under selection during chicken domestication

Author: Rubin, Carl-Johan, Zody, Michael C., Eriksson, Jonas, Meadows, Jennifer R.S., Sherwood, Ellen, Webster, Matthew T., Jiang, Lin, Ingman, Max, Sharpe, Ted, Ka, Sojeong, Hallbook, Finn, Besnier, Francois, Carlborg, Orjan, Bed'hom, Bertrand, Tixier-Boichard, Michele, Jensen, Per, Siegel, Paul, Lindblad-Toh, Kerstin, and Andersson, Leif
Subjects: Physiological aspects, Models, Genetic aspects, Research, Thyrotropin -- Physiological aspects -- Genetic aspects -- Research -- Models, Single nucleotide polymorphisms -- Research -- Physiological aspects -- Models -- Genetic aspects, Chickens -- Models -- Genetic aspects -- Research -- Physiological aspects, Hormone receptors -- Physiological aspects -- Genetic aspects -- Research -- Models
Abstract: For most of their history, domestic chicken populations have been bred for two purposes, egg laying and meat production (5). The effective chicken population size must have been huge in [...], Domestic animals are excellent models for genetic studies of phenotypic evolution (1-3). They have evolved genetic adaptations to a new environment, the farm, and have been subjected to strong human-driven selection leading to remarkable phenotypic changes in morphology, physiology and behaviour. Identifying the genetic changes underlying these developments provides new insight into general mechanisms by which genetic variation shapes phenotypic diversity. Here we describe the use of massively parallel sequencing to identify selective sweeps of favourable alleles and candidate mutations that have had a prominent role in the domestication of chickens (Gallus gallus domesticus) and their subsequent specialization into broiler (meat-producing) and layer (egg-producing) chickens. We have generated 44.5-fold coverage of the chicken genome using pools of genomic DNA representing eight different populations of domestic chickens as well as red jungle fowl (Gallus gallus), the major wild ancestor (4). We report more than 7,000,000 single nucleotide polymorphisms, almost 1,300 deletions and a number of putative selective sweeps. One of the most striking selective sweeps found in all domestic chickens occurred at the locus for thyroid stimulating hormone receptor (TSHR), which has a pivotal role in metabolic regulation and photoperiod control of reproduction in vertebrates. Several of the selective sweeps detected in broilers overlapped genes associated with growth, appetite and metabolic regulation. We found little evidence that selection for loss-of-function mutations had a prominent role in chicken domestication, but we detected two deletions in coding sequences that we suggest are functionally important. This study has direct application to animal breeding and enhances the importance of the domestic chicken as a model organism for biomedical research.
Published: 2010
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11. Defining protein variant functions using high-complexity mutagenesis libraries and enhanced mutant detection software ASMv1.0

Author: Yang, Xiaoping, primary, Hong, Andrew L., additional, Sharpe, Ted, additional, Giacomelli, Andrew O., additional, Lintner, Robert E., additional, Alan, Douglas, additional, Green, Thomas, additional, Hayes, Tikvah K., additional, Piccioni, Federica, additional, Fritchman, Briana, additional, Kawabe, Hinako, additional, Sawyer, Edith, additional, Sprenkle, Luke, additional, Lee, Benjamin P., additional, Persky, Nicole S., additional, Brown, Adam, additional, Greulich, Heidi, additional, Aguirre, Andrew J., additional, Meyerson, Matthew, additional, Hahn, William C., additional, Johannessen, Cory M., additional, and Root, David E., additional
Published: 2021
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12. DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage

Author: Zody, Michael C., Garber, Manuel, Adams, David J., Sharpe, Ted, Harrow, Jennifer, Lupski, James R., Nicholson, Christine, Searle, Steven M., Wilming, Laurens, Young, Sarah K., Abouelleil, Amr, Allen, Nicole R., Bi, Weimin, Bloom, Toby, Borowsky, Mark L., Bugalter, Boris E., Butler, Jonathan, Chang, Jean L., Chen, Chao-Kung, Cook, April, Corum, Benjamin, Cuomo, Christina A., de Jong, Pieter J., DeCaprio, David, Dewar, Ken, FitzGerald, Michael, Gilbert, James, Gibson, Richard, Gnerre, Sante, Goldstein, Steven, Grafham, Darren V., Grocock, Russell, Hafez, Nabil, Hagopian, Daniel S., Hart, Elizabeth, Norman, Catherine Hosage, Humphray, Sean, Jaffe, David B., Jones, Matt, Kamal, Michael, Khodiyar, Varsha K., LaButti, Kurt, Laird, Gavin, Lehoczky, Jessica, Liu, Xiaohong, Lokyitsang, Tashi, Loveland, Jane, Lui, Annie, Macdonald, Pendexter, Major, John E., Matthews, Lucy, Mauceli, Evan, McCarroll, Steven A., Mihalev, Atanas H., Mudge, Jonathan, Nguyen, Cindy, Nicol, Robert, O'Leary, Sinéad B., Osoegawa, Kazutoyo, Schwartz, David C., Shaw-Smith, Charles, Stankiewicz, Pawel, Steward, Charles, Swarbreck, David, Venkataraman, Vijay, Whittaker, Charles A., Yang, Xiaoping, Zimmer, Andrew R., Bradley, Allan, Hubbard, Tim, Birren, Bruce W., Rogers, Jane, Lander, Eric S., and Nusbaum, Chad
Published: 2006
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13. Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences

Author: Mikkelsen, Tarjei S., Wakefield, Matthew J., Aken, Bronwen, Amemiya, Chris T., Chang, Jean L., Duke, Shannon, Garber, Manuel, Gentles, Andrew J., Goodstadt, Leo, Heger, Andreas, Jurka, Jerzy, Kamal, Michael, Mauceli, Evan, Searle, Stephen M. J., Sharpe, Ted, Baker, Michelle L., Batzer, Mark A., Benos, Panayiotis V., Belov, Katherine, Clamp, Michele, Cook, April, Cuff, James, Das, Radhika, Davidow, Lance, Deakin, Janine E., Fazzari, Melissa J., Glass, Jacob L., Grabherr, Manfred, Greally, John M., Gu, Wanjun, Hore, Timothy A., Huttley, Gavin A., Kleber, Michael, Jirtle, Randy L., Koina, Edda, Lee, Jeannie T., Mahony, Shaun, Marra, Marco A., Miller, Robert D., Nicholls, Robert D., Oda, Mayumi, Papenfuss, Anthony T., Parra, Zuly E., Pollock, David D., Ray, David A., Schein, Jacqueline E., Speed, Terence P., Thompson, Katherine, VandeBerg, John L., Wade, Claire M., Walker, Jerilyn A., Waters, Paul D., Webber, Caleb, Weidman, Jennifer R., Xie, Xiaohui, Zody, Michael C., Baldwin, Jennifer, Abdouelleil, Amr, Abdulkadir, Jamal, Abebe, Adal, Abera, Brikti, Abreu, Justin, Acer, St Christophe, Aftuck, Lynne, Alexander, Allen, An, Peter, Anderson, Erica, Anderson, Scott, Arachi, Harindra, Azer, Marc, Bachantsang, Pasang, Barry, Andrew, Bayul, Tashi, Berlin, Aaron, Bessette, Daniel, Bloom, Toby, Blye, Jason, Boguslavskiy, Leonid, Bonnet, Claude, Boukhgalter, Boris, Bourzgui, Imane, Brown, Adam, Cahill, Patrick, Channer, Sheridon, Cheshatsang, Yama, Chuda, Lisa, Citroen, Mieke, Collymore, Alville, Cooke, Patrick, Costello, Maura, D'Aco, Katie, Daza, Riza, De Haan, Georgius, DeGray, Stuart, DeMaso, Christina, Dhargay, Norbu, Dooley, Kimberly, Dooley, Erin, Doricent, Missole, Dorje, Passang, Dorjee, Kunsang, Dupes, Alan, Elong, Richard, Falk, Jill, Farina, Abderrahim, Faro, Susan, Ferguson, Diallo, Fisher, Sheila, Foley, Chelsea D., Franke, Alicia, Friedrich, Dennis, Gadbois, Loryn, Gearin, Gary, Gearin, Christina R., Giannoukos, Georgia, Goode, Tina, Graham, Joseph, Grandbois, Edward, Grewal, Sharleen, Gyaltsen, Kunsang, Hafez, Nabil, Hagos, Birhane, Hall, Jennifer, Henson, Charlotte, Hollinger, Andrew, Honan, Tracey, Huard, Monika D., Hughes, Leanne, Hurhula, Brian, Husby, M. Erii, Kamat, Asha, Kanga, Ben, Kashin, Seva, Khazanovich, Dmitry, Kisner, Peter, Lance, Krista, Lara, Marcia, Lee, William, Lennon, Niall, Letendre, Frances, LeVine, Rosie, Lipovsky, Alex, Liu, Xiaohong, Liu, Jinlei, Liu, Shangtao, Lokyitsang, Tashi, Lokyitsang, Yeshi, Lubonja, Rakela, Lui, Annie, MacDonald, Pen, Magnisalis, Vasilia, Maru, Kebede, Matthews, Charles, McCusker, William, McDonough, Susan, Mehta, Teena, Meldrim, James, Meneus, Louis, Mihai, Oana, Mihalev, Atanas, Mihova, Tanya, Mittelman, Rachel, Mlenga, Valentine, Montmayeur, Anna, Mulrain, Leonidas, Navidi, Adam, Naylor, Jerome, Negash, Tamrat, Nguyen, Thu, Nguyen, Nga, Nicol, Robert, Norbu, Choe, Norbu, Nyima, Novod, Nathaniel, O'Neill, Barry, Osman, Sahal, Markiewicz, Eva, Oyono, Otero L., Patti, Christopher, Phunkhang, Pema, Pierre, Fritz, Priest, Margaret, Raghuraman, Sujaa, Rege, Filip, Reyes, Rebecca, Rise, Cecil, Rogov, Peter, Ross, Keenan, Ryan, Elizabeth, Settipalli, Sampath, Shea, Terry, Sherpa, Ngawang, Shi, Lu, Shih, Diana, Sparrow, Todd, Spaulding, Jessica, Stalker, John, Stange-Thomann, Nicole, Stavropoulos, Sharon, Stone, Catherine, Strader, Christopher, Tesfaye, Senait, Thomson, Talene, Thoulutsang, Yama, Thoulutsang, Dawa, Topham, Kerri, Topping, Ira, Tsamla, Tsamla, Vassiliev, Helen, Vo, Andy, Wangchuk, Tsering, Wangdi, Tsering, Weiand, Michael, Wilkinson, Jane, Wilson, Adam, Yadav, Shailendra, Young, Geneva, Yu, Qing, Zembek, Lisa, Zhong, Danni, Zimmer, Andrew, Zwirko, Zac, Jaffe, David B., Alvarez, Pablo, Brockman, Will, Butler, Jonathan, Chin, CheeWhye, Gnerre, Sante, MacCallum, Iain, Graves, Jennifer A. Marshall, Ponting, Chris P., Breen, Matthew, Samollow, Paul B., Lander, Eric S., and Lindblad-Toh, Kerstin
Abstract: Author(s): Tarjei S. Mikkelsen (corresponding author) [1, 2]; Matthew J. Wakefield [3]; Bronwen Aken [4]; Chris T. Amemiya [5]; Jean L. Chang [1]; Shannon Duke [6]; Manuel Garber [1]; Andrew [...]
Published: 2007
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14. Analysis of the DNA sequence and duplication history of human chromosome 15

Author: Zody, Michael C., Garber, Manuel, Sharpe, Ted, Young, Sarah K., Rowen, Lee, O'Neill, Keith, Whittaker, Charles A., Kamal, Michael, Chang, Jean L., Cuomo, Christina A., Dewar, Ken, FitzGerald, Michael G., Kodira, Chinnappa D., Madan, Anup, Qin, Shizhen, Yang, Xiaoping, Abbasi, Nissa, Abouelleil, Amr, Arachchi, Harindra M., Baradarani, Lida, Birditt, Brian, Bloom, Scott, Bloom, Toby, Borowsky, Mark L., Burke, Jeremy, Butler, Jonathan, Cook, April, DeArellano, Kurt, DeCaprio, David, Dorris, III, Lester, Dors, Monica, Eichler, Evan E., Engels, Reinhard, Fahey, Jessica, Fleetwood, Peter, Friedman, Cynthia, Gearin, Gary, Hall, Jennifer L., Hensley, Grace, Johnson, Ericka, Jones, Charlien, Kamat, Asha, Kaur, Amardeep, Locke, Devin P., Madan, Anuradha, Munson, Glen, Jaffe, David B., Lui, Annie, Macdonald, Pendexter, Mauceli, Evan, Naylor, Jerome W., Nesbitt, Ryan, Nicol, Robert, O'Leary, Sinead B., Ratcliffe, Amber, Rounsley, Steven, She, Xinwei, Sneddon, Katherine M. B., Stewart, Sandra, Sougnez, Carrie, Stone, Sabrina M., Topham, Kerri, Vincent, Dascena, Wang, Shunguang, Zimmer, Andrew R., Birren, Bruce W., Hood, Leroy, Lander, Eric S., and Nusbaum, Chad
Abstract: Author(s): Michael C. Zody (corresponding author) [1]; Manuel Garber [1]; Ted Sharpe [1]; Sarah K. Young [1]; Lee Rowen [2]; Keith O'Neill [1]; Charles A. Whittaker [1, 6]; Michael Kamal [...]
Published: 2006
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15. The African coelacanth genome provides insights into tetrapod evolution

Author: Amemiya, Chris T., Alföldi, Jessica J, Lee, Alison P., Fan, Shaohua S, Philippe, Hervé H, MacCallum, Iain I, Braasch, Ingo I, Manousaki, Tereza T, Schneider, Igor I, Rohner, Nicolas N, Organ, Chris C, Chalopin, Domitille D, Smith, Jeramiah J., Robinson, Mark M, Dorrington, Rosemary A., Gerdol, Marco M, Aken, Bronwen B, Biscotti, Maria Assunta, Barucca, Marco M, Baurain, Denis D, Berlin, Aaron M., Blatch, Gregory L., Buonocore, Francesco F, Burmester, Thorsten T, Campbell, Michael S., Canapa, Adriana A, Cannon, John P., Christoffels, Alan A, De Moro, Gianluca G, Edkins, Adrienne L., Fan, Lin L, Fausto, Anna Maria, Feiner, Nathalie N, Forconi, Mariko M, Gamieldien, Junaid J, Gnerre, Sante S, Gnirke, Andreas A, Goldstone, Jared V., Haerty, Wilfried W, Hahn, Mark E., Hesse, Uljana U, Hoffmann, Steve S, Johnson, Jeremy J, Karchner, Sibel I., Kuraku, Shigehiro S, Lara, Marcia M, Levin, Joshua Z., Litman, Gary W., Mauceli, Evan E, Miyake, Tsutomu T, Mueller, Gail M., Nelson, David R., Nitsche, Anne A, Olmo, Ettore E, Ota, Tatsuya T, Pallavicini, Alberto A, Panji, Sumir S, Picone, Barbara B, Ponting, Chris P., Prohaska, Sonja J., Przybylski, Dariusz D, Saha, Nil Ratan, Ravi, Vydianathan V, Ribeiro, Filipe J., Sauka-Spengler, Tatjana T, Scapigliati, Giuseppe G, Searle, Stephen M. J., Sharpe, Ted T, Simakov, Oleg O, Stadler, Peter F., Stegeman, John J., Sumiyama, Kenta K, Tabbaa, Diana D, Tafer, Hakim H, Turner-Maier, Jason J, van Heusden, Peter P, White, Simon S, Williams, Louise L, Yandell, Mark M, Brinkmann, Henner H, Volff, Jean-Nicolas J, Tabin, Clifford J., Shubin, Neil N, Schartl, Manfred M, Jaffe, David B., Postlethwait, John H., Venkatesh, Byrappa B, Di Palma, Federica F, Lander, Eric S., Meyer, Axel A, and Lindblad-Toh, Kerstin K
Published: 2013
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16. Initial sequencing and comparative analysis of the mouse genome

Author: Chinwalla, Asif T., Cook, Lisa L., Delehaunty, Kimberly D., Fewell, Ginger A., Fulton, Lucinda A., Fulton, Robert S., Graves, Tina A., Hillier, LaDeana W., Mardis, Elaine R., McPherson, John D., Miner, Tracie L., Nash, William E., Nelson, Joanne O., Nhan, Michael N., Pepin, Kymberlie H., Pohl, Craig S., Ponce, Tracy C., Schultz, Brian, Thompson, Johanna, Trevaskis, Evanne, Waterston, Robert H., Wendl, Michael C., Wilson, Richard K., Yang, Shiaw-Pyng, An, Peter, Berry, Eric, Birren, Bruce, Bloom, Toby, Brown, Daniel G., Butler, Jonathan, Daly, Mark, David, Robert, Deri, Justin, Dodge, Sheila, Foley, Karen, Gage, Diane, Gnerre, Sante, Holzer, Timothy, Jaffe, David B., Kamal, Michael, Karlsson, Elinor K., Kells, Cristyn, Kirby, Andrew, Kulbokas, III, Edward J., Lander, Eric S., Landers, Tom, Leger, J. P., Levine, Rosie, Lindblad-Toh, Kerstin, Mauceli, Evan, Mayer, John H., McCarthy, Megan, Meldrim, Jim, Mesirov, Jill P., Nicol, Robert, Nusbaum, Chad, Seaman, Steven, Sharpe, Ted, Sheridan, Andrew, Singer, Jonathan B., Santos, Ralph, Spencer, Brian, Stange-Thomann, Nicole, Vinson, Jade P., Wade, Claire M., Wierzbowski, Jamey, Wyman, Dudley, Zody, Michael C., Birney, Ewan, Goldman, Nick, Kasprzyk, Arkadiusz, Mongin, Emmanuel, Rust, Alistair G., Slater, Guy, Stabenau, Arne, Ureta-Vidal, Abel, Whelan, Simon, Ainscough, Rachel, Attwood, John, Bailey, Jonathon, Barlow, Karen, Beck, Stephan, Burton, John, Clamp, Michele, Clee, Christopher, Coulson, Alan, Cuff, James, Curwen, Val, Cutts, Tim, Davies, Joy, Eyras, Eduardo, Grafham, Darren, Gregory, Simon, Hubbard, Tim, Hunt, Adrienne, Jones, Matthew, Joy, Ann, Leonard, Steven, Lloyd, Christine, Matthews, Lucy, McLaren, Stuart, McLay, Kirsten, Meredith, Beverley, Mullikin, James C., Ning, Zemin, Oliver, Karen, Overton-Larty, Emma, Plumb, Robert, Potter, Simon, Quail, Michael, Rogers, Jane, Scott, Carol, Searle, Steve, Shownkeen, Ratna, Sims, Sarah, Wall, Melanie, West, Anthony P., Willey, David, Williams, Sophie, Abril, Josep F., Guigo, Roderic, Parra, Genis, Agarwal, Pankaj, Agarwala, Richa, Church, Deanna M., Hlavina, Wratko, Maglott, Donna R., Sapojnikov, Victor, Alexandersson, Marina, Pachter, Lior, Antonarakis, Stylianos E., Dermitzakis, Emmanouil T., Reymond, Alexandre, Ucla, Catherine, Baertsch, Robert, Diekhans, Mark, Furey, Terrence S., Hinrichs, Angela, Hsu, Fan, Karolchik, Donna, Kent, W. James, Roskin, Krishna M., Schwartz, Matthias S., Sugnet, Charles, Weber, Ryan J., Bork, Peer, Letunic, Ivica, Suyama, Mikita, Torrents, David, Zdobnov, Evgeny M., Botcherby, Marc, Brown, Stephen D., Campbell, Robert D., Jackson, Ian, Bray, Nicolas, Couronne, Olivier, Dubchak, Inna, Poliakov, Alex, Rubin, Edward M., Brent, Michael R., Flicek, Paul, Keibler, Evan, Korf, Ian, Batalov, S., Bult, Carol, Frankel, Wayne N., Carninci, Piero, Hayashizaki, Yoshihide, Kawai, Jun, Okazaki, Yasushi, Cawley, Simon, Kulp, David, Wheeler, Raymond, Chiaromonte, Francesca, Collins, Francis S., Felsenfeld, Adam, Guyer, Mark, Peterson, Jane, Wetterstrand, Kris, Copley, Richard R., Mott, Richard, Dewey, Colin, Dickens, Nicholas J., Emes, Richard D., Goodstadt, Leo, Ponting, Chris P., Winter, Eitan, Dunn, Diane M., von Niederhausern, Andrew C., Weiss, Robert B., Eddy, Sean R., Johnson, L. Steven, Jones, Thomas A., Elnitski, Laura, Kolbe, Diana L., Eswara, Pallavi, Miller, Webb, O'Connor, Michael J., Schwartz, Scott, Muzny, Donna M., Glusman, Gustavo, Smit, Arian, Green, Eric D., Hardison, Ross C., Yang, Shan, Haussler, David, Hua, Axin, Roe, Bruce A., Kucherlapati, Raju S., Montgomery, Kate T., Li, Jia, Li, Ming, Lucas, Susan, Ma, Bin, McCombie, W. Richard, Morgan, Michael, Pevzner, Pavel, Tesler, Glenn, Schultz, Jorg, Smith, Douglas R., Tromp, John, and Worley, Kim C.
Abstract: Author(s): Mouse Genome Sequencing Consortium ; Genome Sequencing Center: ; Asif T. Chinwalla [1, 47]; Lisa L. Cook [1]; Kimberly D. Delehaunty [1]; Ginger A. Fewell [1]; Lucinda A. Fulton [...]
Published: 2002
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17. Genome sequence and analysis of the Irish potato famine pathogen Phytophthora infestans

Author: Haas, Brian J., Kamoun, Sophien, Zody, Michael C., Jiang, Rays H. Y., Handsaker, Robert E., Cano, Liliana M., Grabherr, Manfred, Kodira, Chinnappa D., Raffaele, Sylvain, Torto-Alalibo, Trudy, Bozkurt, Tolga O., Ah-Fong, Audrey M. V., Alvarado, Lucia, Anderson, Vicky L., Armstrong, Miles R., Avrova, Anna, Baxter, Laura, Beynon, Jim, Boevink, Petra C., Bollmann, Stephanie R., Bos, Jorunn I. B., Bulone, Vincent, Cai, Guohong, Cakir, Cahid, Carrington, James C., Chawner, Megan, Conti, Lucio, Costanzo, Stefano, Ewan, Richard, Fahlgren, Noah, Fischbach, Michael A., Fugelstad, Johanna, Gilroy, Eleanor M., Gnerre, Sante, Green, Pamela J., Grenville-Briggs, Laura J., Griffith, John, Grünwald, Niklaus J., Horn, Karolyn, Horner, Neil R., Hu, Chia-Hui, Huitema, Edgar, Jeong, Dong-Hoon, Jones, Alexandra M. E., Jones, Jonathan D. G., Jones, Richard W., Karlsson, Elinor K., Kunjeti, Sridhara G., Lamour, Kurt, Liu, Zhenyu, Ma, LiJun, MacLean, Daniel, Chibucos, Marcus C., McDonald, Hayes, McWalters, Jessica, Meijer, Harold J. G., Morgan, William, Morris, Paul F., Munro, Carol A., O’Neill, Keith, Ospina-Giraldo, Manuel, Pinzón, Andrés, Pritchard, Leighton, Ramsahoye, Bernard, Ren, Qinghu, Restrepo, Silvia, Roy, Sourav, Sadanandom, Ari, Savidor, Alon, Schornack, Sebastian, Schwartz, David C., Schumann, Ulrike D., Schwessinger, Ben, Seyer, Lauren, Sharpe, Ted, Silvar, Cristina, Song, Jing, Studholme, David J., Sykes, Sean, Thines, Marco, van de Vondervoort, Peter J. I., Phuntumart, Vipaporn, Wawra, Stephan, Weide, Rob, Win, Joe, Young, Carolyn, Zhou, Shiguo, Fry, William, Meyers, Blake C., van West, Pieter, Ristaino, Jean, Govers, Francine, Birch, Paul R. J., Whisson, Stephen C., Judelson, Howard S., and Nusbaum, Chad
Published: 2009
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18. Managing Data from High-Throughput Genomic Processing

Author: Bloom, Toby, primary and Sharpe, Ted, additional
Published: 2004
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19. An open resource of structural variation for medical and population genetics

Author: Collins, Ryan L., Brand, Harrison, Karczewski, Konrad J., Zhao, Xuefang, Alföldi, Jessica, Francioli, Laurent C., Khera, Amit V., Lowther, Chelsea, Gauthier, Laura D., Wang, Harold, Watts, Nicholas A., Solomonson, Matthew, O’Donnell-Luria, Anne, Baumann, Alexander, Munshi, Ruchi, Walker, Mark, Whelan, Christopher, Huang, Yongqing, Brookings, Ted, Sharpe, Ted, Stone, Matthew R., Valkanas, Elise, Fu, Jack, Tiao, Grace, Laricchia, Kristen M., Ruano-Rubio, Valentin, Stevens, Christine, Gupta, Namrata, Margolin, Lauren, Taylor, Kent D., Lin, Henry J., Rich, Stephen S., Post, Wendy, Chen, Yii-Der Ida, Rotter, Jerome I., Nusbaum, Chad, Philippakis, Anthony, Lander, Eric, Gabriel, Stacey, Neale, Benjamin M., Kathiresan, Sekar, Daly, Mark J., Banks, Eric, MacArthur, Daniel G., and Talkowski, Michael E.
Subjects: Structural variation, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Resource (biology), business.industry, Environmental resource management, Population genetics, Biology, business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: SUMMARYStructural variants (SVs) rearrange large segments of the genome and can have profound consequences for evolution and human diseases. As national biobanks, disease association studies, and clinical genetic testing grow increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral for interpreting genetic variation. To date, no large-scale reference maps of SVs exist from high-coverage sequencing comparable to those available for point mutations in protein-coding genes. Here, we constructed a reference atlas of SVs across 14,891 genomes from diverse global populations (54% non-European) as a component of gnomAD. We discovered a rich landscape of 433,371 distinct SVs, including 5,295 multi-breakpoint complex SVs across 11 mutational subclasses, and examples of localized chromosome shattering, as in chromothripsis. The average individual harbored 7,439 SVs, which accounted for 25-29% of all rare protein-truncating events per genome. We found strong correlations between constraint against damaging point mutations and rare SVs that both disrupt and duplicate protein-coding sequence, suggesting intolerance to reciprocal dosage alterations for a subset of tightly regulated genes. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than any effect on noncoding SVs. Finally, we benchmarked carrier rates for medically relevant SVs, finding very large (≥1Mb) rare SVs in 3.8% of genomes (~1:26 individuals) and clinically reportable incidental SVs in 0.18% of genomes (~1:556 individuals). These data have been integrated directly into the gnomAD browser (https://gnomad.broadinstitute.org) and will have broad utility for population genetics, disease association, and diagnostic screening.
Published: 2019
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20. Why Human Color Vision Cannot Reliably Detect Cerebrospinal Fluid Xanthochromia

Author: Petzold, Axel, Keir, Geoffrey, and Sharpe, Ted L.
Published: 2005
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21. GATK PathSeq: a customizable computational tool for the discovery and identification of microbial sequences in libraries from eukaryotic hosts

Author: Walker, Mark A, primary, Pedamallu, Chandra Sekhar, additional, Ojesina, Akinyemi I, additional, Bullman, Susan, additional, Sharpe, Ted, additional, Whelan, Christopher W, additional, and Meyerson, Matthew, additional
Published: 2018
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22. SvABA: genome-wide detection of structural variants and indels by local assembly

Author: Wala, Jeremiah A., primary, Bandopadhayay, Pratiti, additional, Greenwald, Noah F., additional, O'Rourke, Ryan, additional, Sharpe, Ted, additional, Stewart, Chip, additional, Schumacher, Steve, additional, Li, Yilong, additional, Weischenfeldt, Joachim, additional, Yao, Xiaotong, additional, Nusbaum, Chad, additional, Campbell, Peter, additional, Getz, Gad, additional, Meyerson, Matthew, additional, Zhang, Cheng-Zhong, additional, Imielinski, Marcin, additional, and Beroukhim, Rameen, additional
Published: 2018
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23. SvABA:genome-wide detection of structural variants and indels by local assembly

Author: Wala, Jeremiah A, Bandopadhayay, Pratiti, Greenwald, Noah F, O'Rourke, Ryan, Sharpe, Ted, Stewart, Chip, Schumacher, Steve, Li, Yilong, Weischenfeldt, Joachim, Yao, Xiaotong, Nusbaum, Chad, Campbell, Peter, Getz, Gad, Meyerson, Matthew, Zhang, Cheng-Zhong, Imielinski, Marcin, Beroukhim, Rameen, Wala, Jeremiah A, Bandopadhayay, Pratiti, Greenwald, Noah F, O'Rourke, Ryan, Sharpe, Ted, Stewart, Chip, Schumacher, Steve, Li, Yilong, Weischenfeldt, Joachim, Yao, Xiaotong, Nusbaum, Chad, Campbell, Peter, Getz, Gad, Meyerson, Matthew, Zhang, Cheng-Zhong, Imielinski, Marcin, and Beroukhim, Rameen
Abstract: Structural variants (SVs), including small insertion and deletion variants (indels), are challenging to detect through standard alignment-based variant calling methods. Sequence assembly offers a powerful approach to identifying SVs, but is difficult to apply at scale genome-wide for SV detection due to its computational complexity and the difficulty of extracting SVs from assembly contigs. We describe SvABA, an efficient and accurate method for detecting SVs from short-read sequencing data using genome-wide local assembly with low memory and computing requirements. We evaluated SvABA's performance on the NA12878 human genome and in simulated and real cancer genomes. SvABA demonstrates superior sensitivity and specificity across a large spectrum of SVs and substantially improves detection performance for variants in the 20-300 bp range, compared with existing methods. SvABA also identifies complex somatic rearrangements with chains of short (<1000 bp) templated-sequence insertions copied from distant genomic regions. We applied SvABA to 344 cancer genomes from 11 cancer types and found that short templated-sequence insertions occur in ∼4% of all somatic rearrangements. Finally, we demonstrate that SvABA can identify sites of viral integration and cancer driver alterations containing medium-sized (50-300 bp) SVs.
Published: 2018

24. Prospective functional classification of all possible missense variants in PPARG

Author: Majithia, Amit R, Tsuda, Ben, Agostini, Maura, Gnanapradeepan, Keerthana, Rice, Robert, Peloso, Gina, Patel, Kashyap A, Zhang, Xiaolan, Broekema, Marjoleine F, Patterson, Nick, Duby, Marc, Sharpe, Ted, Kalkhoven, Eric, Rosen, Evan D, Barroso, Inês, Ellard, Sian, UK Monogenic Diabetes Consortium, Kathiresan, Sekar, Myocardial Infarction Genetics Consortium, O'Rahilly, Stephen, UK Congenital Lipodystrophy Consortium, Chatterjee, Krishna, Florez, Jose C, Mikkelsen, Tarjei, Savage, David B, Altshuler, David, Barroso, Ines [0000-0001-5800-4520], O'Rahilly, Stephen [0000-0003-2199-4449], Chatterjee, Krishna [0000-0002-2654-8854], Savage, David [0000-0002-7857-7032], and Apollo - University of Cambridge Repository
Subjects: Male, PPAR gamma, Amino Acid Substitution, Diabetes Mellitus, Type 2, Lipodystrophy, Case-Control Studies, Macrophages, Mutation, Missense, Myocardial Infarction, Humans, Female, Prospective Studies
Abstract: Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty. For example, mutations in PPARG cause Mendelian lipodystrophy and increase risk of type 2 diabetes (T2D). Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single-amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning. When applied to 55 new missense variants identified in population-based and clinical sequencing, the classifier annotated 6 variants as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.
Published: 2016

25. SvABA: Genome-wide detection of structural variants and indels by local assembly

Author: Wala, Jeremiah, primary, Bandopadhayay, Pratiti, additional, Greenwald, Noah, additional, O’Rourke, Ryan, additional, Sharpe, Ted, additional, Stewart, Chip, additional, Schumacher, Steve, additional, Li, Yilong, additional, Weischenfeldt, Joachim, additional, Yao, Xiaotong, additional, Nusbaum, Chad, additional, Campbell, Peter, additional, Meyerson, Matthew, additional, Zhang, Cheng-Zhong, additional, Imielinski, Marcin, additional, and Beroukhim, Rameen, additional
Published: 2017
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26. Comprehensive variation discovery in single human genomes

Author: Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., Weisenfeld, Neil I, Yin, Shuangye, Sharpe, Ted, Lau, Bayo, Hegarty, Ryan, Holmes, Laurie, Sogoloff, Brian, Tabbaa, Diana, Williams, Louise, Russ, Carsten, Nusbaum, Chad, MacCallum, Iain, Jaffe, David B., Lander, Eric Steven, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., Weisenfeld, Neil I, Yin, Shuangye, Sharpe, Ted, Lau, Bayo, Hegarty, Ryan, Holmes, Laurie, Sogoloff, Brian, Tabbaa, Diana, Williams, Louise, Russ, Carsten, Nusbaum, Chad, MacCallum, Iain, Jaffe, David B., and Lander, Eric Steven
Abstract: Complete knowledge of the genetic variation in individual human genomes is a crucial foundation for understanding the etiology of disease. Genetic variation is typically characterized by sequencing individual genomes and comparing reads to a reference. Existing methods do an excellent job of detecting variants in approximately 90% of the human genome; however, calling variants in the remaining 10% of the genome (largely low-complexity sequence and segmental duplications) is challenging. To improve variant calling, we developed a new algorithm, DISCOVAR, and examined its performance on improved, low-cost sequence data. Using a newly created reference set of variants from the finished sequence of 103 randomly chosen fosmids, we find that some standard variant call sets miss up to 25% of variants. We show that the combination of new methods and improved data increases sensitivity by several fold, with the greatest impact in challenging regions of the human genome., National Human Genome Research Institute (U.S.) (Grant R01HG003474), National Human Genome Research Institute (U.S.) (Grant U54HG003067), National Institute of Allergy and Infectious Diseases (U.S.) (Contract HHSN272200900018C)
Published: 2015

27. Comprehensive variation discovery in single human genomes

Author: Weisenfeld, Neil I, primary, Yin, Shuangye, additional, Sharpe, Ted, additional, Lau, Bayo, additional, Hegarty, Ryan, additional, Holmes, Laurie, additional, Sogoloff, Brian, additional, Tabbaa, Diana, additional, Williams, Louise, additional, Russ, Carsten, additional, Nusbaum, Chad, additional, Lander, Eric S, additional, MacCallum, Iain, additional, and Jaffe, David B, additional
Published: 2014
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28. Mutational processes shape the landscape of TP53mutations in human cancer

Author: Giacomelli, Andrew O., Yang, Xiaoping, Lintner, Robert E., McFarland, James M., Duby, Marc, Kim, Jaegil, Howard, Thomas P., Takeda, David Y., Ly, Seav Huong, Kim, Eejung, Gannon, Hugh S., Hurhula, Brian, Sharpe, Ted, Goodale, Amy, Fritchman, Briana, Steelman, Scott, Vazquez, Francisca, Tsherniak, Aviad, Aguirre, Andrew J., Doench, John G., Piccioni, Federica, Roberts, Charles W. M., Meyerson, Matthew, Getz, Gad, Johannessen, Cory M., Root, David E., and Hahn, William C.
Abstract: Unlike most tumor suppressor genes, the most common genetic alterations in tumor protein p53 (TP53) are missense mutations1,2. Mutant p53 protein is often abundantly expressed in cancers and specific allelic variants exhibit dominant-negative or gain-of-function activities in experimental models3–8. To gain a systematic view of p53 function, we interrogated loss-of-function screens conducted in hundreds of human cancer cell lines and performed TP53 saturation mutagenesis screens in an isogenic pair of TP53 wild-type and null cell lines. We found that loss or dominant-negative inhibition of wild-type p53 function reliably enhanced cellular fitness. By integrating these data with the Catalog of Somatic Mutations in Cancer (COSMIC) mutational signatures database9,10, we developed a statistical model that describes the TP53 mutational spectrum as a function of the baseline probability of acquiring each mutation and the fitness advantage conferred by attenuation of p53 activity. Collectively, these observations show that widely-acting and tissue-specific mutational processes combine with phenotypic selection to dictate the frequencies of recurrent TP53 mutations.
Published: 2018
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29. Novel origins of copy number variation in the dog genome

Author: Berglund, Jonas, Nevalainen, Elisa M, Molin, Anna-Maja, Perloski, Michele, André, Catherine, Zody, Michael C, Sharpe, Ted, Hitte, Christophe, Lindblad-Toh, Kerstin, Lohi, Hannes, Webster, Matthew T, Berglund, Jonas, Nevalainen, Elisa M, Molin, Anna-Maja, Perloski, Michele, André, Catherine, Zody, Michael C, Sharpe, Ted, Hitte, Christophe, Lindblad-Toh, Kerstin, Lohi, Hannes, and Webster, Matthew T
Abstract: BACKGROUND: Copy number variants (CNVs) account for substantial variation between genomes and are a major source of normal and pathogenic phenotypic differences. The dog is an ideal model to investigate mutational mechanisms that generate CNVs as its genome lacks a functional ortholog of the PRDM9 gene implicated in recombination and CNV formation in humans. Here we comprehensively assay CNVs using high-density array comparative genomic hybridization in 50 dogs from 17 dog breeds and 3 gray wolves. RESULTS: We use a stringent new method to identify a total of 430 high-confidence CNV loci, which range in size from 9 kb to 1.6 Mb and span 26.4 Mb, or 1.08%, of the assayed dog genome, overlapping 413 annotated genes. Of CNVs observed in each breed, 98% are also observed in multiple breeds. CNVs predicted to disrupt gene function are significantly less common than expected by chance. We identify a significant overrepresentation of peaks of GC content, previously shown to be enriched in dog recombination hotspots, in the vicinity of CNV breakpoints. CONCLUSIONS: A number of the CNVs identified by this study are candidates for generating breed-specific phenotypes. Purifying selection seems to be a major factor shaping structural variation in the dog genome, suggesting that many CNVs are deleterious. Localized peaks of GC content appear to be novel sites of CNV formation in the dog genome by non-allelic homologous recombination, potentially activated by the loss of PRDM9. These sequence features may have driven genome instability and chromosomal rearrangements throughout canid evolution., Additional author: The LUPA Consortium (www.eurolupa.org)
Published: 2012
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30. High-quality draft assemblies of mammalian genomes from massively parallel sequence data

Author: Massachusetts Institute of Technology. Department of Biology, Lander, Eric S, Lander, Eric S., Gnerre, Sante, MacCallum, Iain, Przybylski, Dariusz, Ribeiro, Felipe J., Burton, Joshua, Walker, Bruce J., Sharpe, Ted, Hall, Giles, Shea, Terrance P., Sykes, Sean, Berlin, Aaron M., Aird, Daniel, Costello, Maura, Daza, Riza, Williams, Louise, Nicol, Robert, Gnirke, Andreas, Nusbaum, Chad, Jaffe, David B., Lander, Eric Steven, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S, Lander, Eric S., Gnerre, Sante, MacCallum, Iain, Przybylski, Dariusz, Ribeiro, Felipe J., Burton, Joshua, Walker, Bruce J., Sharpe, Ted, Hall, Giles, Shea, Terrance P., Sykes, Sean, Berlin, Aaron M., Aird, Daniel, Costello, Maura, Daza, Riza, Williams, Louise, Nicol, Robert, Gnirke, Andreas, Nusbaum, Chad, Jaffe, David B., and Lander, Eric Steven
Abstract: Massively parallel DNA sequencing technologies are revolutionizing genomics by making it possible to generate billions of relatively short (~100-base) sequence reads at very low cost. Whereas such data can be readily used for a wide range of biomedical applications, it has proven difficult to use them to generate high-quality de novo genome assemblies of large, repeat-rich vertebrate genomes. To date, the genome assemblies generated from such data have fallen far short of those obtained with the older (but much more expensive) capillary-based sequencing approach. Here, we report the development of an algorithm for genome assembly, ALLPATHS-LG, and its application to massively parallel DNA sequence data from the human and mouse genomes, generated on the Illumina platform. The resulting draft genome assemblies have good accuracy, short-range contiguity, long-range connectivity, and coverage of the genome. In particular, the base accuracy is high (≥99.95%) and the scaffold sizes (N50 size = 11.5 Mb for human and 7.2 Mb for mouse) approach those obtained with capillary-based sequencing. The combination of improved sequencing technology and improved computational methods should now make it possible to increase dramatically the de novo sequencing of large genomes. The ALLPATHS-LG program is available at http://www.broadinstitute.org/science/programs/genome-biology/crd., National Institutes of Health (U.S.), National Human Genome Research Institute (U.S.) (Grant U54HG003067), National Human Genome Research Institute (U.S.) (Grant R01HG003474), National Institute of Allergy and Infectious Diseases (U.S.) (Contract HHSN2722009000018C)
Published: 2011

31. Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences

Author: Mikkelsen, Tarjei S, Wakefield, Matthew J, Aken, Bronwen, Amemiya, Chris T, Chang, Jean L, Duke, Shannon, Garber, Manuel, Gentles, Andrew J, Goodstadt, Leo, Heger, Andreas, Jurka, Jerzy, Kamal, Michael, Mauceli, Evan, Searle, Stephen M J, Sharpe, Ted, Baker, Michelle L, Batzer, Mark A, Benos, Panayiotis V, Belov, Katherine, Clamp, Michele, Cook, April, Cuff, James, Das, Radhika, Davidow, Lance, Deakin, Janine E, Fazzari, Melissa J, Glass, Jacob L, Grabherr, Manfred, Greally, John M, Gu, Wanjun, Hore, Timothy A, Huttley, Gavin A, Kleber, Michael, Jirtle, Randy L, Koina, Edda, Lee, Jeannie T, Mahony, Shaun, Marra, Marco A, Miller, Robert D, Nicholls, Robert D, Oda, Mayumi, Papenfuss, Anthony T, Parra, Zuly E, Pollock, David D, Ray, David A, Schein, Jacqueline E, Speed, Terence P, Thompson, Katherine, VandeBerg, John L, Wade, Claire M, Walker, Jerilyn A, Waters, Paul D, Webber, Caleb, Weidman, Jennifer R, Xie, Xiaohui, Zody, Michael C, Graves, Jennifer A Marshall, Ponting, Chris P, Breen, Matthew, Samollow, Paul B, Lander, Eric S, Lindblad-Toh, Kerstin, Mikkelsen, Tarjei S, Wakefield, Matthew J, Aken, Bronwen, Amemiya, Chris T, Chang, Jean L, Duke, Shannon, Garber, Manuel, Gentles, Andrew J, Goodstadt, Leo, Heger, Andreas, Jurka, Jerzy, Kamal, Michael, Mauceli, Evan, Searle, Stephen M J, Sharpe, Ted, Baker, Michelle L, Batzer, Mark A, Benos, Panayiotis V, Belov, Katherine, Clamp, Michele, Cook, April, Cuff, James, Das, Radhika, Davidow, Lance, Deakin, Janine E, Fazzari, Melissa J, Glass, Jacob L, Grabherr, Manfred, Greally, John M, Gu, Wanjun, Hore, Timothy A, Huttley, Gavin A, Kleber, Michael, Jirtle, Randy L, Koina, Edda, Lee, Jeannie T, Mahony, Shaun, Marra, Marco A, Miller, Robert D, Nicholls, Robert D, Oda, Mayumi, Papenfuss, Anthony T, Parra, Zuly E, Pollock, David D, Ray, David A, Schein, Jacqueline E, Speed, Terence P, Thompson, Katherine, VandeBerg, John L, Wade, Claire M, Walker, Jerilyn A, Waters, Paul D, Webber, Caleb, Weidman, Jennifer R, Xie, Xiaohui, Zody, Michael C, Graves, Jennifer A Marshall, Ponting, Chris P, Breen, Matthew, Samollow, Paul B, Lander, Eric S, and Lindblad-Toh, Kerstin
Abstract: We report a high-quality draft of the genome sequence of the grey, short-tailed opossum (Monodelphis domestica). As the first metatherian ('marsupial') species to be sequenced, the opossum provides a unique perspective on the organization and evolution of mammalian genomes. Distinctive features of the opossum chromosomes provide support for recent theories about genome evolution and function, including a strong influence of biased gene conversion on nucleotide sequence composition, and a relationship between chromosomal characteristics and X chromosome inactivation. Comparison of opossum and eutherian genomes also reveals a sharp difference in evolutionary innovation between protein-coding and non-coding functional elements. True innovation in protein-coding genes seems to be relatively rare, with lineage-specific differences being largely due to diversification and rapid turnover in gene families involved in environmental interactions. In contrast, about 20% of eutherian conserved non-coding elements (CNEs) are recent inventions that postdate the divergence of Eutheria and Metatheria. A substantial proportion of these eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation.
Published: 2007
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32. Analysis of the DNA sequence and duplication history of human chromosome 15

Author: Zody, Michael, Garber, Manuel, Sharpe, Ted, Young, Sarah, Rowen, Lee, O'Neill, Keith, Whittaker, Charles, Kamal, Michael, Chang, Jean, Cuomo, Christina, Dewar, Ken, FitzGerald, Michael, Kodira, Chinnappa, Madan, Anup, Qin, Shizhen, Yang, Xiaoping, Abbasi, Nissa, Abouelleil, Amr, Arachchi, Harindra, Baradarani, Lida, Birditt, Brian, Bloom, Scott, Bloom, Toby, Borowsky, Mark, Burke, Jeremy, Butler, Jonathan, Cook, April, DeArellano, Kurt, DeCaprio, David, Dorris, Lester, Dors, Monica, Eichler, Evan, Engels, Reinhard, Fahey, Jessica, Fleetwood, Peter, Friedman, Cynthia, Gearin, Gary, Hall, Jennifer, Hensley, Grace, Johnson, Ericka, Jones, Charlien, Kamat, Asha, Kaur, Amardeep, Locke, Devin, Madan, Anuradha, Munson, Glen, Jaffe, David, Lui, Annie, Macdonald, Pendexter, Mauceli, Evan, Naylor, Jerome, Nesbitt, Ryan, Nicol, Robert, O'Leary, Sinéad, Ratcliffe, Amber, Rounsley, Steven, She, Xinwei, Sneddon, Katherine, Stewart, Sandra, Sougnez, Carrie, Stone, Sabrina, Topham, Kerri, Vincent, Dascena, Wang, Shunguang, Zimmer, Andrew, Birren, Bruce, Hood, Leroy, Lander, ic, Nusbaum, Chad, Zody, Michael, Garber, Manuel, Sharpe, Ted, Young, Sarah, Rowen, Lee, O'Neill, Keith, Whittaker, Charles, Kamal, Michael, Chang, Jean, Cuomo, Christina, Dewar, Ken, FitzGerald, Michael, Kodira, Chinnappa, Madan, Anup, Qin, Shizhen, Yang, Xiaoping, Abbasi, Nissa, Abouelleil, Amr, Arachchi, Harindra, Baradarani, Lida, Birditt, Brian, Bloom, Scott, Bloom, Toby, Borowsky, Mark, Burke, Jeremy, Butler, Jonathan, Cook, April, DeArellano, Kurt, DeCaprio, David, Dorris, Lester, Dors, Monica, Eichler, Evan, Engels, Reinhard, Fahey, Jessica, Fleetwood, Peter, Friedman, Cynthia, Gearin, Gary, Hall, Jennifer, Hensley, Grace, Johnson, Ericka, Jones, Charlien, Kamat, Asha, Kaur, Amardeep, Locke, Devin, Madan, Anuradha, Munson, Glen, Jaffe, David, Lui, Annie, Macdonald, Pendexter, Mauceli, Evan, Naylor, Jerome, Nesbitt, Ryan, Nicol, Robert, O'Leary, Sinéad, Ratcliffe, Amber, Rounsley, Steven, She, Xinwei, Sneddon, Katherine, Stewart, Sandra, Sougnez, Carrie, Stone, Sabrina, Topham, Kerri, Vincent, Dascena, Wang, Shunguang, Zimmer, Andrew, Birren, Bruce, Hood, Leroy, Lander, ic, and Nusbaum, Chad
Abstract: Here we present a finished sequence of human chromosome 15, together with a high-quality gene catalogue. As chromosome 15 is one of seven human chromosomes with a high rate of segmental duplication, we have carried out a detailed analysis of the duplication structure of the chromosome. Segmental duplication in chromosome 15 are largely clustered in two regions, on proximal and distal 15q; the proximal region is notable because recombination among the segmental duplications can result in deletions causing Prader-Willi and Angelman syndromes. Sequence analysis shows that the proximal and distal regions of 15q share extensive ancient similarity. Using a simple approach, we have been able to reconstruct many of the events by which the current duplication structure arose. We find that most of the intrachromosomal duplications seem to share a common ancestry. Finally, we demonstrate that some remaining gaps in the genome sequence are probably due to structural polymorphisms between haplotypes; this may explain a significant fraction of the gaps remaining in the human genome.
Published: 2006
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33. DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage

Author: Zody, Michael, Garber, Manuel, Adams, David, Sharpe, Ted, Harrow, Jennifer, Lupski, James, Nicholson, Christine, Searle, Steven, Wilming, Laurens, Young, Sarah, Abouelleil, Amr, Allen, Nicole, Bi, Weimin, Bloom, Toby, Borowsky, Mark, Bugalter, Boris, Butler, Jonathan, Chang, Jean, Chen, Chao-Kung, Cook, April, Corum, Benjamin, Cuomo, Christina, de Jong, Pieter, DeCaprio, David, Dewar, Ken, FitzGerald, Michael, Gilbert, James, Gibson, Richard, Gnerre, Sante, Goldstein, Steven, Grafham, Darren, Grocock, Russell, Hafez, Nabil, Hagopian, Daniel, Hart, Elizabeth, Hosage Norman, Catherine, Humphray, Sean, Jaffe, David, Jones, Matt, Kamal, Michael, Khodiyan, Varsha, LaButti, Kurt, Laird, Gavin, Lehoczky, Jessica, Liu, Xiaohong, Lokyitsang, Tashi, Loveland, Jane, Lui, Annie, Macdonald, Pendexter, Major, John, Matthews, Lucy, Mauceli, Evan, McCarroll, Steven, Mihalev, Atanas, Mudge, Jonathan, Nguyen, Cindy, Nicol, Robert, O'Leary, Sinéad, Osoegawa, Kazutoyo, Schwartz, David, Shaw-Smith, Charles, Stankiewicz, Pawel, Steward, Charles, Swarbreck, David, Venkataraman, Vijay, Whittaker, Charles, Yang, Xiaoping, Zimmer, Andrew, Bradley, Allan, Hubbard, Tim, Birren, Bruce, Rogers, Jane, Lander, Eric, Nusbaum, Chad, Zody, Michael, Garber, Manuel, Adams, David, Sharpe, Ted, Harrow, Jennifer, Lupski, James, Nicholson, Christine, Searle, Steven, Wilming, Laurens, Young, Sarah, Abouelleil, Amr, Allen, Nicole, Bi, Weimin, Bloom, Toby, Borowsky, Mark, Bugalter, Boris, Butler, Jonathan, Chang, Jean, Chen, Chao-Kung, Cook, April, Corum, Benjamin, Cuomo, Christina, de Jong, Pieter, DeCaprio, David, Dewar, Ken, FitzGerald, Michael, Gilbert, James, Gibson, Richard, Gnerre, Sante, Goldstein, Steven, Grafham, Darren, Grocock, Russell, Hafez, Nabil, Hagopian, Daniel, Hart, Elizabeth, Hosage Norman, Catherine, Humphray, Sean, Jaffe, David, Jones, Matt, Kamal, Michael, Khodiyan, Varsha, LaButti, Kurt, Laird, Gavin, Lehoczky, Jessica, Liu, Xiaohong, Lokyitsang, Tashi, Loveland, Jane, Lui, Annie, Macdonald, Pendexter, Major, John, Matthews, Lucy, Mauceli, Evan, McCarroll, Steven, Mihalev, Atanas, Mudge, Jonathan, Nguyen, Cindy, Nicol, Robert, O'Leary, Sinéad, Osoegawa, Kazutoyo, Schwartz, David, Shaw-Smith, Charles, Stankiewicz, Pawel, Steward, Charles, Swarbreck, David, Venkataraman, Vijay, Whittaker, Charles, Yang, Xiaoping, Zimmer, Andrew, Bradley, Allan, Hubbard, Tim, Birren, Bruce, Rogers, Jane, Lander, Eric, and Nusbaum, Chad
Abstract: Chromosome 17 is unusual among the human chromosomes in many respects. It is the largest human autosome with orthology to only a single mouse chromosome, mapping entirely to the distal half of mouse chromosome 11. Chromosome 17 is rich in protein-coding genes, having the second highest gene density in the genome. It is also enriched in segmental duplications, ranking third in density among the autosomes. Here we report a finished sequence for human chromosome 17, as well as a structural comparison with the finished sequence for mouse chromosome 11, the first finished mouse chromosome. Comparison of the orthologous regions reveals striking differences. In contrast to the typical pattern seen in mammalian evolution, the human sequence has undergone extensive intrachromosomal rearrangement, whereas the mouse sequence has been remarkably stable. Moreover, although the human sequence has a high density of segmental duplication, the mouse sequence has a very low density. Notably, these segmental duplications correspond closely to the sites of structural rearrangement, demonstrating a link between duplication and rearrangement. Examination of the main classes of duplicated segments provides insight into the dynamics underlying expansion of chromosome-specific, low-copy repeats in the human genome.
Published: 2006
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34. Finished bacterial genomes from shotgun sequence data

Author: Ribeiro, Filipe J., primary, Przybylski, Dariusz, additional, Yin, Shuangye, additional, Sharpe, Ted, additional, Gnerre, Sante, additional, Abouelleil, Amr, additional, Berlin, Aaron M., additional, Montmayeur, Anna, additional, Shea, Terrance P., additional, Walker, Bruce J., additional, Young, Sarah K., additional, Russ, Carsten, additional, Nusbaum, Chad, additional, MacCallum, Iain, additional, and Jaffe, David B., additional
Published: 2012
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35. Assemblathon 1: A competitive assessment of de novo short read assembly methods

Author: Earl, Dent, primary, Bradnam, Keith, additional, St. John, John, additional, Darling, Aaron, additional, Lin, Dawei, additional, Fass, Joseph, additional, Yu, Hung On Ken, additional, Buffalo, Vince, additional, Zerbino, Daniel R., additional, Diekhans, Mark, additional, Nguyen, Ngan, additional, Ariyaratne, Pramila Nuwantha, additional, Sung, Wing-Kin, additional, Ning, Zemin, additional, Haimel, Matthias, additional, Simpson, Jared T., additional, Fonseca, Nuno A., additional, Birol, İnanç, additional, Docking, T. Roderick, additional, Ho, Isaac Y., additional, Rokhsar, Daniel S., additional, Chikhi, Rayan, additional, Lavenier, Dominique, additional, Chapuis, Guillaume, additional, Naquin, Delphine, additional, Maillet, Nicolas, additional, Schatz, Michael C., additional, Kelley, David R., additional, Phillippy, Adam M., additional, Koren, Sergey, additional, Yang, Shiaw-Pyng, additional, Wu, Wei, additional, Chou, Wen-Chi, additional, Srivastava, Anuj, additional, Shaw, Timothy I., additional, Ruby, J. Graham, additional, Skewes-Cox, Peter, additional, Betegon, Miguel, additional, Dimon, Michelle T., additional, Solovyev, Victor, additional, Seledtsov, Igor, additional, Kosarev, Petr, additional, Vorobyev, Denis, additional, Ramirez-Gonzalez, Ricardo, additional, Leggett, Richard, additional, MacLean, Dan, additional, Xia, Fangfang, additional, Luo, Ruibang, additional, Li, Zhenyu, additional, Xie, Yinlong, additional, Liu, Binghang, additional, Gnerre, Sante, additional, MacCallum, Iain, additional, Przybylski, Dariusz, additional, Ribeiro, Filipe J., additional, Yin, Shuangye, additional, Sharpe, Ted, additional, Hall, Giles, additional, Kersey, Paul J., additional, Durbin, Richard, additional, Jackman, Shaun D., additional, Chapman, Jarrod A., additional, Huang, Xiaoqiu, additional, DeRisi, Joseph L., additional, Caccamo, Mario, additional, Li, Yingrui, additional, Jaffe, David B., additional, Green, Richard E., additional, Haussler, David, additional, Korf, Ian, additional, and Paten, Benedict, additional
Published: 2011
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36. High-quality draft assemblies of mammalian genomes from massively parallel sequence data

Author: Gnerre, Sante, primary, MacCallum, Iain, additional, Przybylski, Dariusz, additional, Ribeiro, Filipe J., additional, Burton, Joshua N., additional, Walker, Bruce J., additional, Sharpe, Ted, additional, Hall, Giles, additional, Shea, Terrance P., additional, Sykes, Sean, additional, Berlin, Aaron M., additional, Aird, Daniel, additional, Costello, Maura, additional, Daza, Riza, additional, Williams, Louise, additional, Nicol, Robert, additional, Gnirke, Andreas, additional, Nusbaum, Chad, additional, Lander, Eric S., additional, and Jaffe, David B., additional
Published: 2010
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37. Prospective functional classification of all possible missense variants in PPARG

Author: Majithia, Amit R., Tsuda, Ben, Agostini, Maura, Gnanapradeepan, Keerthana, Rice, Robert, Peloso, Gina, Patel, Kashyap A., Zhang, Xiaolan, Broekema, Marjoleine F., Patterson, Nick, Duby, Marc, Sharpe, Ted, Kalkhoven, Eric, Rosen, Evan D., Barroso, Inês, Ellard, Sian, Kathiresan, Sekar, O’Rahilly, Stephen, Chatterjee, Krishna, Florez, Jose C., Mikkelsen, Tarjei, Savage, David B., and Altshuler, David
Abstract: Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty1,2. For example, mutations in PPARG cause Mendelian lipodystrophy3,4 and increase risk of type 2 diabetes (T2D)5. While approximately one in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning (http://miter.broadinstitute.org). When applied to 55 novel missense variants identified in population-based and clinical sequencing, the classifier annotated six as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.
Published: 2016
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38. Analysis of the African coelacanth genome sheds light on tetrapod evolution

Author: Amemiya, Chris T., Alföldi, Jessica, Lee, Alison P., Fan, Shaohua, Philippe, Hervé, MacCallum, Iain, Braasch, Ingo, Manousaki, Tereza, Schneider, Igor, Rohner, Nicolas, Organ, Chris, Chalopin, Domitille, Smith, Jeramiah J., Robinson, Mark, Dorrington, Rosemary A., Gerdol, Marco, Aken, Bronwen, Biscotti, Maria Assunta, Barucca, Marco, Baurain, Denis, Berlin, Aaron M., Blatch, Gregory L., Buonocore, Francesco, Burmester, Thorsten, Campbell, Michael S., Canapa, Adriana, Cannon, John P., Christoffels, Alan, De Moro, Gianluca, Edkins, Adrienne L., Fan, Lin, Fausto, Anna Maria, Feiner, Nathalie, Forconi, Mariko, Gamieldien, Junaid, Gnerre, Sante, Gnirke, Andreas, Goldstone, Jared V., Haerty, Wilfried, Hahn, Mark E., Hesse, Uljana, Hoffmann, Steve, Johnson, Jeremy, Karchner, Sibel I., Kuraku, Shigehiro, Lara, Marcia, Levin, Joshua Z., Litman, Gary W., Mauceli, Evan, Miyake, Tsutomu, Mueller, M. Gail, Nelson, David R., Nitsche, Anne, Olmo, Ettore, Ota, Tatsuya, Pallavicini, Alberto, Panji, Sumir, Picone, Barbara, Ponting, Chris P., Prohaska, Sonja J., Przybylski, Dariusz, Saha, Nil Ratan, Ravi, Vydianathan, Ribeiro, Filipe J., Sauka-Spengler, Tatjana, Scapigliati, Giuseppe, Searle, Stephen M. J., Sharpe, Ted, Simakov, Oleg, Stadler, Peter F., Stegeman, John J., Sumiyama, Kenta, Tabbaa, Diana, Tafer, Hakim, Turner-Maier, Jason, van Heusden, Peter, White, Simon, Williams, Louise, Yandell, Mark, Brinkmann, Henner, Volff, Jean-Nicolas, Tabin, Clifford J., Shubin, Neil, Schartl, Manfred, Jaffe, David, Postlethwait, John H., Venkatesh, Byrappa, Di Palma, Federica, Lander, Eric S., Meyer, Axel, and Lindblad-Toh, Kerstin
Abstract: It was a zoological sensation when a living specimen of the coelacanth was first discovered in 1938, as this lineage of lobe-finned fish was thought to have gone extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features . Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain, and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues demonstrate the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.
Published: 2013
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39. Author Correction: A structural variation reference for medical and population genetics.

Author: Collins, Ryan L., Brand, Harrison, Karczewski, Konrad J., Zhao, Xuefang, Alföldi, Jessica, Francioli, Laurent C., Khera, Amit V., Lowther, Chelsea, Gauthier, Laura D., Wang, Harold, Watts, Nicholas A., Solomonson, Matthew, O'Donnell-Luria, Anne, Baumann, Alexander, Munshi, Ruchi, Walker, Mark, Whelan, Christopher W., Huang, Yongqing, Brookings, Ted, and Sharpe, Ted
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03176-6. [ABSTRACT FROM AUTHOR]
Published: 2021
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40. The genomic substrate for adaptive radiation in African cichlid fish

Author: Yin, Shuangye, Ponting, Chris P., Lander, Eric S., Noh, Hyun Ji, Hofmann, Hans A., Young, Sarah, Ron, Micha, Galibert, Francis, Johnson, Jeremy, Di Palma, Federica, Russell, Pamela, Fernald, Russell D., Lim, Zhi Wei, Alcazar, Rosa, Ozouf-Costaz, Catherine, Gante, Hugo F., Guyon, Richard, Salzburger, Walter, Bezault, Etienne, Carleton, Karen L., Williams, Louise, Meyer, Axel, Greuter, Lucie, Okada, Norihiro, Searle, Steve, Przybylski, Dariusz, Lee, Alison P., Turner-Maier, Jason, Eshel, Orly, Simakov, Oleg, Aken, Bronwen, Ribeiro, Filipe J., Lara, Marcia, Hourlier, Thibaut, Venkatesh, Byrappa, Ng, Alvin Y., Streelman, J. Todd, Brawand, David, Miska, Eric A., Lindblad-Toh, Kerstin, Swofford, Ross, Haerty, Wilfried, Keller, Irene, Rakotomanga, Michaelle, Gnerre, Sante, Gaffney, Leslie, Santos, M. Emilia, Sanchez-Pulido, Luis, Amemiya, Chris, Conte, Matthew A., Li, Yang I., Renn, Suzy C. P., Azzouzi, Naoual, Harris, Rayna M., Sharpe, Ted, Barloy-Hubler, Frederique, Wagner, Catherine, Kocher, Thomas D., Malinsky, Milan, Seehausen, Ole, Penman, David J., Berlin, Aaron, Nishihara, Hidenori, Mwaiko, Salome, Hulata, Gideon, Bloomquist, Ryan, Fan, Shaohua, Tan, Frederick J., Baroiller, Jean-François, MacCallum, Iain, D'Cotta, Helena, Alföldi, Jessica, Nikaido, Masato, Jaffe, David B., and Haddad, Natalie S.
Subjects: 570 Life sciences, biology, 14. Life underwater, human activities
Abstract: Cichlid fishes are famous for large, diverse and replicated adaptive radiations in the Great Lakes of East Africa. To understand the molecular mechanisms underlying cichlid phenotypic diversity, we sequenced the genomes and transcriptomes of five lineages of African cichlids: the Nile tilapia (Oreochromis niloticus), an ancestral lineage with low diversity; and four members of the East African lineage: Neolamprologus brichardi/pulcher (older radiation, Lake Tanganyika), Metriaclima zebra (recent radiation, Lake Malawi), Pundamilia nyererei (very recent radiation, Lake Victoria), and Astatotilapia burtoni (riverine species around Lake Tanganyika). We found an excess of gene duplications in the East African lineage compared to tilapia and other teleosts, an abundance of non-coding element divergence, accelerated coding sequence evolution, expression divergence associated with transposable element insertions, and regulation by novel microRNAs. In addition, we analysed sequence data from sixty individuals representing six closely related species from Lake Victoria, and show genome-wide diversifying selection on coding and regulatory variants, some of which were recruited from ancient polymorphisms. We conclude that a number of molecular mechanisms shaped East African cichlid genomes, and that amassing of standing variation during periods of relaxed purifying selection may have been important in facilitating subsequent evolutionary diversification.

41. Prospective functional classification of all possible missense variants in PPARG

Author: Majithia, Amit R, Tsuda, Ben, Agostini, Maura, Gnanapradeepan, Keerthana, Rice, Robert, Peloso, Gina, Patel, Kashyap A, Zhang, Xiaolan, Broekema, Marjoleine F, Patterson, Nick, Duby, Marc, Sharpe, Ted, Kalkhoven, Eric, Rosen, Evan D, Barroso, Inês, Ellard, Sian, UK Monogenic Diabetes Consortium, Kathiresan, Sekar, Myocardial Infarction Genetics Consortium, O'Rahilly, Stephen, UK Congenital Lipodystrophy Consortium, Chatterjee, Krishna, Florez, Jose C, Mikkelsen, Tarjei, Savage, David B, and Altshuler, David
Subjects: Male, PPAR gamma, Amino Acid Substitution, Diabetes Mellitus, Type 2, Lipodystrophy, Case-Control Studies, Macrophages, Mutation, Missense, Myocardial Infarction, Humans, Female, Prospective Studies, 3. Good health
Abstract: Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty. For example, mutations in PPARG cause Mendelian lipodystrophy and increase risk of type 2 diabetes (T2D). Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single-amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning. When applied to 55 new missense variants identified in population-based and clinical sequencing, the classifier annotated 6 variants as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.

42. Novel origins of copy number variation in the dog genome.

Author: Berglund J, Nevalainen EM, Molin AM, Perloski M, André C, Zody MC, Sharpe T, Hitte C, Lindblad-Toh K, Lohi H, and Webster MT
Subjects: Animals, Breeding, Comparative Genomic Hybridization, Female, Genetic Loci, Genomic Instability, Genotype, Male, Phenotype, Reproducibility of Results, DNA Copy Number Variations, Dogs genetics, Genome
Abstract: Background: Copy number variants (CNVs) account for substantial variation between genomes and are a major source of normal and pathogenic phenotypic differences. The dog is an ideal model to investigate mutational mechanisms that generate CNVs as its genome lacks a functional ortholog of the PRDM9 gene implicated in recombination and CNV formation in humans. Here we comprehensively assay CNVs using high-density array comparative genomic hybridization in 50 dogs from 17 dog breeds and 3 gray wolves., Results: We use a stringent new method to identify a total of 430 high-confidence CNV loci, which range in size from 9 kb to 1.6 Mb and span 26.4 Mb, or 1.08%, of the assayed dog genome, overlapping 413 annotated genes. Of CNVs observed in each breed, 98% are also observed in multiple breeds. CNVs predicted to disrupt gene function are significantly less common than expected by chance. We identify a significant overrepresentation of peaks of GC content, previously shown to be enriched in dog recombination hotspots, in the vicinity of CNV breakpoints., Conclusions: A number of the CNVs identified by this study are candidates for generating breed-specific phenotypes. Purifying selection seems to be a major factor shaping structural variation in the dog genome, suggesting that many CNVs are deleterious. Localized peaks of GC content appear to be novel sites of CNV formation in the dog genome by non-allelic homologous recombination, potentially activated by the loss of PRDM9. These sequence features may have driven genome instability and chromosomal rearrangements throughout canid evolution.
Published: 2012
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