64 results on '"Lee Rowen"'
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2. Autoantibodies neutralizing type I IFNs are present in
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Paul, Bastard, Adrian, Gervais, Tom, Le Voyer, Jérémie, Rosain, Quentin, Philippot, Jérémy, Manry, Eleftherios, Michailidis, Hans-Heinrich, Hoffmann, Shohei, Eto, Marina, Garcia-Prat, Lucy, Bizien, Alba, Parra-Martínez, Rui, Yang, Liis, Haljasmägi, Mélanie, Migaud, Karita, Särekannu, Julia, Maslovskaja, Nicolas, de Prost, Yacine, Tandjaoui-Lambiotte, Charles-Edouard, Luyt, Blanca, Amador-Borrero, Alexandre, Gaudet, Julien, Poissy, Pascal, Morel, Pascale, Richard, Fabrice, Cognasse, Jesus, Troya, Sophie, Trouillet-Assant, Alexandre, Belot, Kahina, Saker, Pierre, Garçon, Jacques G, Rivière, Jean-Christophe, Lagier, Stéphanie, Gentile, Lindsey B, Rosen, Elana, Shaw, Tomohiro, Morio, Junko, Tanaka, David, Dalmau, Pierre-Louis, Tharaux, Damien, Sene, Alain, Stepanian, Bruno, Megarbane, Vasiliki, Triantafyllia, Arnaud, Fekkar, James R, Heath, José Luis, Franco, Juan-Manuel, Anaya, Jordi, Solé-Violán, Luisa, Imberti, Andrea, Biondi, Paolo, Bonfanti, Riccardo, Castagnoli, Ottavia M, Delmonte, Yu, Zhang, Andrew L, Snow, Steven M, Holland, Catherine, Biggs, Marcela, Moncada-Vélez, Andrés Augusto, Arias, Lazaro, Lorenzo, Soraya, Boucherit, Boubacar, Coulibaly, Dany, Anglicheau, Anna M, Planas, Filomeen, Haerynck, Sotirija, Duvlis, Robert L, Nussbaum, Tayfun, Ozcelik, Sevgi, Keles, Ahmed A, Bousfiha, Jalila, El Bakkouri, Carolina, Ramirez-Santana, Stéphane, Paul, Qiang, Pan-Hammarström, Lennart, Hammarström, Annabelle, Dupont, Alina, Kurolap, Christine N, Metz, Alessandro, Aiuti, Giorgio, Casari, Vito, Lampasona, Fabio, Ciceri, Lucila A, Barreiros, Elena, Dominguez-Garrido, Mateus, Vidigal, Mayana, Zatz, Diederik, van de Beek, Sabina, Sahanic, Ivan, Tancevski, Yurii, Stepanovskyy, Oksana, Boyarchuk, Yoko, Nukui, Miyuki, Tsumura, Loreto, Vidaur, Stuart G, Tangye, Sonia, Burrel, Darragh, Duffy, Lluis, Quintana-Murci, Adam, Klocperk, Nelli Y, Kann, Anna, Shcherbina, Yu-Lung, Lau, Daniel, Leung, Matthieu, Coulongeat, Julien, Marlet, Rutger, Koning, Luis Felipe, Reyes, Angélique, Chauvineau-Grenier, Fabienne, Venet, Guillaume, Monneret, Michel C, Nussenzweig, Romain, Arrestier, Idris, Boudhabhay, Hagit, Baris-Feldman, David, Hagin, Joost, Wauters, Isabelle, Meyts, Adam H, Dyer, Sean P, Kennelly, Nollaig M, Bourke, Rabih, Halwani, Narjes Saheb, Sharif-Askari, Karim, Dorgham, Jérome, Sallette, Souad Mehlal, Sedkaoui, Suzan, AlKhater, Raúl, Rigo-Bonnin, Francisco, Morandeira, Lucie, Roussel, Donald C, Vinh, Sisse Rye, Ostrowski, Antonio, Condino-Neto, Carolina, Prando, Anastasiia, Bonradenko, András N, Spaan, Laurent, Gilardin, Jacques, Fellay, Stanislas, Lyonnet, Kaya, Bilguvar, Richard P, Lifton, Shrikant, Mane, Mark S, Anderson, Bertrand, Boisson, Vivien, Béziat, Shen-Ying, Zhang, Evangelos, Vandreakos, Olivier, Hermine, Aurora, Pujol, Pärt, Peterson, Trine H, Mogensen, Lee, Rowen, James, Mond, Stéphanie, Debette, Xavier, de Lamballerie, Xavier, Duval, France, Mentré, Marie, Zins, Pere, Soler-Palacin, Roger, Colobran, Guy, Gorochov, Xavier, Solanich, Sophie, Susen, Javier, Martinez-Picado, Didier, Raoult, Marc, Vasse, Peter K, Gregersen, Lorenzo, Piemonti, Carlos, Rodríguez-Gallego, Luigi D, Notarangelo, Helen C, Su, Kai, Kisand, Satoshi, Okada, Anne, Puel, Emmanuelle, Jouanguy, Charles M, Rice, Pierre, Tiberghien, Qian, Zhang, Aurélie, Cobat, Laurent, Abel, and Hind, Hamzeh-Cognasse
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Adult ,Aged, 80 and over ,Adolescent ,Critical Illness ,Infant, Newborn ,COVID-19 ,Infant ,Interferon-alpha ,Middle Aged ,Antibodies, Neutralizing ,Young Adult ,Case-Control Studies ,Child, Preschool ,Immunoglobulin G ,Interferon Type I ,Humans ,Child ,Aged ,Autoantibodies - Abstract
Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4%80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals70 years, 2.3% between 70 and 80 years, and 6.3%80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.
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- 2021
3. Heterogeneous immunological recovery trajectories revealed in post-acute COVID-19
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Clifford Rostomily, Nathan D. Price, Jeffrey A. Bluestone, Julie A. Wallick, Jessi W Li, Sunga Hong, Rachel Liu, Brett Smith, Chen Dg, Li S, Andrew T. Magis, Rachel Ng, Raphael Gottardo, Leroy Hood, Venkata R Duvvuri, Christopher Lausted, Priyanka Baloni, Lesley Jones, Scott D. Boyd, Naeha Subramanian, Yong Zhou, Phil Greenberg, Ana Jimena Pavlovitch-Bedzyk, Mark M. Davis, Jingyi Xie, William R. Berrington, Chengzhen L. Dai, Heather A. Algren, Fan Yang, Sergey A. Kornilov, Chour W, Rick Edmark, Antoni Ribas, Lewis L. Lanier, Jongchan Choi, Shen Dong, Dan Yuan, Jing Zhou, Zhang R, Christos J. Petropoulos, Kai Wang, Murry K, Pamela Troisch, Kelsey Scherler, Wei Wei, Shannon Fallen, Jennifer Hadlock, Anderson Kg, Lee Rowen, Jason D Goldman, Terri Wrin, Sean Mackay, Yu-Ru Su, Lee I, and Heath
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Innate immune system ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Convalescence ,media_common.quotation_subject ,Blood proteins ,Immune system ,Immunology ,Blood plasma ,Medicine ,Cytotoxic T cell ,business ,Viral load ,media_common - Abstract
The immunological picture of how different patients recover from COVID-19, and how those recovery trajectories are influenced by infection severity, remain unclear. We investigated 140 COVID-19 patients from diagnosis to convalescence using clinical data, viral load assessments, and multi-omic analyses of blood plasma and circulating immune cells. Immune-phenotype dynamics resolved four recovery trajectories. One trajectory signals a return to pre-infection healthy baseline, while the other three are characterized by differing fractions of persistent cytotoxic and proliferative T cells, distinct B cell maturation processes, and memory-like innate immunity. We resolve a small panel of plasma proteins that, when measured at diagnosis, can predict patient survival and recovery-trajectory commitment. Our study offers novel insights into post-acute immunological outcomes of COVID-19 that likely influence long-term adverse sequelae.
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- 2021
4. Deciphering Genomes Through Automated Large-scale Sequencing
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Stephen Lasky, Lee Rowen, primary and Hood, Leroy, additional
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- 1999
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5. Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19
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Jenn J. Hadlock, Michael Zager, Rachel Liu, Daniel Chen, Valentin Voillet, Kim Murray, Alan Aderem, Yapeng Su, Jongchan Choi, Philip D. Greenberg, Rongyu Zhang, Yong Zhou, Sui Huang, Alexander M. Xu, Lesley Jones, Raphael Gottardo, Guangrong Qin, Dan Yuan, Chengzhen L. Dai, Jing Zhou, Heather A. Algren, Rick Edmark, Kelsey Scherler, Alissa C. Rothchild, Christopher Lausted, Venkata R Duvvuri, Clifford Rostomily, Naeha Subramanian, Christopher R. Dale, Mark M. Davis, Lewis L. Lanier, Jeffrey A. Bluestone, Jingyi Xie, Sarah Li, Ryan Roper, Jing Li, Brett Smith, Andrew T. Magis, John C. Earls, Sunga Hong, Julie A. Wallick, Sean Mackay, Lee Rowen, Leroy Hood, Priyanka Baloni, Jason D Goldman, Nathan D. Price, James R. Heath, John E. Heath, D. Shane O’Mahony, Sergey A. Kornilov, Shen Dong, Pamela Troisch, Wei Wei, and Kai Wang
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Adult ,Male ,Adolescent ,Cell ,Disease ,Biology ,Severity of Illness Index ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Single-cell analysis ,Severity of illness ,medicine ,Humans ,RNA-Seq ,Aged ,030304 developmental biology ,Aged, 80 and over ,0303 health sciences ,Innate immune system ,SARS-CoV-2 ,COVID-19 ,Genomics ,Middle Aged ,Phenotype ,medicine.anatomical_structure ,Immunology ,Female ,Single-Cell Analysis ,030217 neurology & neurosurgery ,Blood drawing - Abstract
We present an integrated analysis of the clinical measurements, immune cells and plasma multi-omics of 139 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis. We identify a major shift between mild and moderate disease, at which point elevated inflammatory signaling is accompanied by the loss of specific classes of metabolites and metabolic processes. Within this stressed plasma environment at moderate disease, multiple unusual immune cell phenotypes emerge and amplify with increasing disease severity. We condensed over 120,000 immune features into a single axis to capture how different immune cell classes coordinate in response to SARS-CoV-2. This immune-response axis independently aligns with the major plasma composition changes, with clinical metrics of blood clotting, and with the sharp transition between mild and moderate disease. This study suggests that moderate disease may provide the most effective setting for therapeutic intervention., Highlights • Analysis of serial blood from 139 COVID-19 patients reveals immune coordination • A major immunological shift is seen between mild and moderate infection • Moderate and severe cases exhibit inflammation and a sharp drop in blood nutrients • Novel immune cell subsets emerge in moderate cases and increase with severity, Using serial blood draws from hospitalized COVID-19 patients, Su et al. present an extensive single-cell multi-omics dataset covering the first week infection following clinical diagnosis, which includes information on plasma proteins, metabolites, transcriptomic data, immune receptor sequences, secreted proteins, and electronic health record data. Their integrated analysis identifies a major immunological shift between mild and moderate infection, which includes an increase in inflammation, drop in blood nutrients, and the emergence of novel immune cell subpopulations that intensify with disease severity.
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- 2020
6. Identification of Organ-Enriched Protein Biomarkers of Acute Liver Injury by Targeted Quantitative Proteomics of Blood in Acetaminophen- and Carbon-Tetrachloride-Treated Mouse Models and Acetaminophen Overdose Patients
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Kai Wang, Li Gray, Shizhen Qin, Yong Zhou, Robert L. Moritz, Lee Rowen, Yue Yuan, Laurence McEvoy, Juan Caballero, Munir Pirmohamed, Taek Kyun Kim, Gustavo Glusman, Lucy Hampson, Leroy Hood, Xiaowei Yan, Kevin Park, David S. Campbell, Ulrike Kusebauch, Daniel J. Antoine, and Gilbert S. Omenn
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0301 basic medicine ,Adult ,Proteomics ,acetaminophen overdose ,Quantitative proteomics ,Pharmacology ,Biochemistry ,Toxicology ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,medicine ,Animals ,Humans ,Carbon Tetrachloride ,Acetaminophen ,Aged ,Liver injury ,business.industry ,General Chemistry ,Middle Aged ,medicine.disease ,Blood proteins ,Blot ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Carbon tetrachloride ,Chemical and Drug Induced Liver Injury ,Drug Overdose ,business ,Biomarkers ,Blood Chemical Analysis ,medicine.drug - Abstract
Organ-enriched blood proteins, those produced primarily in one organ and secreted or exported to the blood, potentially afford a powerful and specific approach to assessing diseases in their cognate organs. In this paper, we demonstrate that quantification of organ-enriched proteins in the blood offers a new strategy to find biomarkers for diagnosis and assessment of drug-induced liver injury (and presumably the assessment of other liver diseases). We used selected reaction monitoring (SRM) mass spectrometry to quantify 81 liver-enriched proteins plus three aminotransferases (ALT1, AST1, and AST2) in plasma of C57BL/6J and NOD/ShiLtJ mice exposed to acetaminophen or carbon tetrachloride. Plasma concentrations of 49 liver-enriched proteins were perturbed significantly in response to liver injury induced by one or both toxins. We validated four of these toxin-responsive proteins (ALDOB, ASS1, BHMT and GLUD1) by Western blotting. By both assays, these four proteins constitute liver injury markers superior to currently employed markers such as ALT and AST. A similar approach was also successful in human serum where we had analyzed 66 liver-enriched proteins in acetaminophen overdose patients. Of these, 23 proteins were elevated in patients; 15 of 23 overlapped with the concentration-increased proteins in the mouse study. A combination of 5 human proteins, AGXT, ALDOB, CRP, FBP1, and MMP9, provides the best diagnostic performance to distinguish acetaminophen overdose patients from controls (sensitivity: 0.85, specificity: 0.84, accuracy: 85%). These five blood proteins are candidates for detecting acetaminophen-induced liver injury using next-generation diagnostic devices (e.g, microfluidic ELIZA assays).
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- 2016
7. Molecular Dissection of Prethymic Progenitor Entry into the T Lymphocyte Developmental Pathway
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Elizabeth Sharon David-Fung, Tom Taghon, Ellen V. Rothenberg, Jonathan E. Moore, C. Chace Tydell, and Lee Rowen
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Lineage (genetic) ,T cell ,Molecular Sequence Data ,Immunology ,Notch signaling pathway ,Mice, Transgenic ,Mice, SCID ,Thymus Gland ,Biology ,Mice ,Fetus ,T-Lymphocyte Subsets ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,Cell Lineage ,Progenitor cell ,Cells, Cultured ,Receptors, Notch ,Gene Expression Profiling ,Lymphopoiesis ,Tumor Suppressor Proteins ,Intracellular Signaling Peptides and Proteins ,GATA3 ,Membrane Proteins ,Cell Differentiation ,T lymphocyte ,Hematopoietic Stem Cells ,Molecular biology ,Coculture Techniques ,Up-Regulation ,DNA-Binding Proteins ,Mice, Inbred C57BL ,Repressor Proteins ,medicine.anatomical_structure ,Stem cell ,Signal Transduction - Abstract
Notch signaling activates T lineage differentiation from hemopoietic progenitors, but relatively few regulators that initiate this program have been identified, e.g., GATA3 and T cell factor-1 (TCF-1) (gene name Tcf7). To identify additional regulators of T cell specification, a cDNA library from mouse Pro-T cells was screened for genes that are specifically up-regulated in intrathymic T cell precursors as compared with myeloid progenitors. Over 90 genes of interest were identified, and 35 of 44 tested were confirmed to be more highly expressed in T lineage precursors relative to precursors of B and/or myeloid lineage. To a remarkable extent, however, expression of these T lineage-enriched genes, including zinc finger transcription factor, helicase, and signaling adaptor genes, was also shared by stem cells (Lin−Sca-1+Kit+CD27−) and multipotent progenitors (Lin−Sca-1+Kit+CD27+), although down-regulated in other lineages. Thus, a major fraction of these early T lineage genes are a regulatory legacy from stem cells. The few genes sharply up-regulated between multipotent progenitors and Pro-T cell stages included those encoding transcription factors Bcl11b, TCF-1 (Tcf7), and HEBalt, Notch target Deltex1, Deltex3L, Fkbp5, Eva1, and Tmem131. Like GATA3 and Deltex1, Bcl11b, Fkbp5, and Eva1 were dependent on Notch/Delta signaling for induction in fetal liver precursors, but only Bcl11b and HEBalt were up-regulated between the first two stages of intrathymic T cell development (double negative 1 and double negative 2) corresponding to T lineage specification. Bcl11b was uniquely T lineage restricted and induced by Notch/Delta signaling specifically upon entry into the T lineage differentiation pathway.
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- 2007
8. T1DBase, a community web-based resource for type 1 diabetes research
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Gustavo Glusman, Vincent H. Everett, Alex C. Lam, Erin Helton, Josyf C. Mychaleckyj, Geoffrey E. Dolman, Nathan Goodman, Davide Laneri, Linda S. Wicker, Christopher C. Cavnor, John A. Todd, Barry C. Healy, Daisy Flamez, Oliver S. Burren, Lee Rowen, Neil Walker, David B. Burdick, Yang Wang, Helen Schuilenburg, Decio L. Eizirik, and Luc J. Smink
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medicine.medical_specialty ,INDUCED GENES ,Biomedical Research ,DATABASE ,Gene Expression ,Genomics ,Context (language use) ,Genome browser ,Biology ,MOUSE ,Genome ,03 medical and health sciences ,Islets of Langerhans ,Mice ,User-Computer Interface ,0302 clinical medicine ,Molecular genetics ,Databases, Genetic ,Genetics ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,KEGG ,AUTOIMMUNE-DISEASE ,Gene ,030304 developmental biology ,0303 health sciences ,Internet ,IDENTIFICATION ,Biology and Life Sciences ,ASSOCIATION ,Genome project ,Articles ,NETWORKS ,3. Good health ,Rats ,GENOME ,Disease Models, Animal ,Diabetes Mellitus, Type 1 ,030220 oncology & carcinogenesis ,RAT ,PANCREATIC BETA-CELLS ,Database Management Systems - Abstract
T1DBase (http://T1DBase.org) is a public website and database that supports the type 1 diabetes (T1D) research community. The site is currently focused on the molecular genetics and biology of T1D susceptibility and pathogenesis. It includes the following datasets: annotated genome sequence for human, rat and mouse; information on genetically identified T1D susceptibility regions in human, rat and mouse, and genetic linkage and association studies pertaining to T1D; descriptions of NOD mouse congenic strains; the Beta Cell Gene Expression Bank, which reports expression levels of genes in beta cells under various conditions, and annotations of gene function in beta cells; data on gene expression in a variety of tissues and organs; and biological pathways from KEGG and BioCarta. Tools on the site include the GBrowse genome browser, site-wide context dependent search, Connect-the-Dots for connecting gene and other identifiers from multiple data sources, Cytoscape for visualizing and analyzing biological networks, and the GESTALT workbench for genome annotation. All data are open access and all software is open source.
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- 2004
9. The human GRINL1A gene defines a complex transcription unit, an unusual form of gene organization in eukaryotes☆
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Brian Birditt, Raymond S. Roginski, Bhaskara K. Mohan Raj, and Lee Rowen
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Genetics ,DNA, Complementary ,Transcription, Genetic ,Molecular Sequence Data ,Alternative splicing ,RNA polymerase II ,Exons ,Biology ,Exon shuffling ,genomic DNA ,Exon ,Eukaryotic Cells ,Exon trapping ,Receptors, Glutamate ,Gene Order ,biology.protein ,Humans ,Protein Isoforms ,RNA Polymerase II ,RNA, Messenger ,Tandem exon duplication ,Gene - Abstract
Sequencing of genomic DNA and cloned transcripts from the 200-kb human GRINL1A gene on chromosome 15 revealed a complex gene structure comprising at least 28 exons. In one gene model, transcription begins at exon 1 and ends at exon 15b. Another gene model begins transcription at exon 20 and terminates at exon 23, 24, or 28. In a third gene model, transcription begins at exon 1 and ends at exon 23, thus conjoining two apparently discrete genes into a third combined gene. Exon 15 can function as a terminating exon or as an alternatively spliced internal exon, or it can be skipped altogether. Exons 11, 14, 15a, 16, 17, 18, 19, 20a, and 20f are found only in transcripts that do not terminate at exon 15b. Combined transcripts that convert two genes into a third provide evidence for an unusual form of gene organization and expression that we call the complex transcription unit (CTU). Organization of exons into a CTU increases the extractable information content of a segment of genomic DNA and constitutes a potentially significant mechanism for augmenting the proteome of a genome.
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- 2004
10. Genetic Divergence of the Rhesus Macaque Major Histocompatibility Complex
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Gustavo Glusman, Daniel E. Geraghty, Lee Rowen, Riza Daza-Vamenta, and Brandon L. Guthrie
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Chromosomes, Artificial, Bacterial ,Molecular Sequence Data ,Genomics ,Major histocompatibility complex ,Evolution, Molecular ,Major Histocompatibility Complex ,Antigen ,MHC class I ,Genetics ,Animals ,Humans ,Letters ,Phylogeny ,Genetics (clinical) ,Genetic diversity ,Base Sequence ,biology ,MHC Class I Gene ,Genetic Variation ,Sequence Analysis, DNA ,Physical Chromosome Mapping ,biology.organism_classification ,Macaca mulatta ,Genetic divergence ,Rhesus macaque ,Haplotypes ,Evolutionary biology ,biology.protein - Abstract
The major histocompatibility complex (MHC) is comprised of the class I, class II, and class III regions, including the MHC class I and class II genes that play a primary role in the immune response and serve as an important model in studies of primate evolution. Although nonhuman primates contribute significantly to comparative human studies, relatively little is known about the genetic diversity and genomics underlying nonhuman primate immunity. To address this issue, we sequenced a complete rhesus macaque MHC spanning over 5.3 Mb, and obtained an additional 2.3 Mb from a second haplotype, including class II and portions of class I and class III. A major expansion of from six class I genes in humans to as many as 22 active MHC class I genes in rhesus and levels of sequence divergence some 10-fold higher than a similar human comparison were found, averaging from 2% to 6% throughout extended portions of class I and class II. These data pose new interpretations of the evolutionary constraints operating between MHC diversity and T-cell selection by contrasting with models predicting an optimal number of antigen presenting genes. For the clinical model, these data and derivative genetic tools can be implemented in ongoing genetic and disease studies that involve the rhesus macaque.
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- 2004
11. Analysis of the Gene-Dense Major Histocompatibility Complex Class III Region and Its Comparison to Mouse
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Shizhen Qin, Tao Xie, Begoña Aguado, R. Duncan Campbell, Mary Ellen Ahearn, Lee Rowen, Leroy Hood, and Anup Madan
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RNA, Untranslated ,Molecular Sequence Data ,Interspersed repeat ,Biology ,Genome ,Conserved sequence ,Conserved non-coding sequence ,Evolution, Molecular ,Major Histocompatibility Complex ,Mice ,Intergenic region ,Genetics ,Animals ,Humans ,Letters ,Gene ,Conserved Sequence ,Genetics (clinical) ,Polymorphism, Genetic ,Intron ,Proteins ,Sequence Analysis, DNA ,Alternative Splicing ,Genes ,Protein Biosynthesis ,Human genome - Abstract
In mammals, the Major Histocompatibility Complex class I and II gene clusters are separated by an approximately 700-kb stretch of sequence called the MHC class III region, which has been associated with susceptibility to numerous diseases. To facilitate understanding of this medically important and architecturally interesting portion of the genome, we have sequenced and analyzed both the human and mouse class III regions. The cross-species comparison has facilitated the identification of 60 genes in human and 61 in mouse, including a potential RNA gene for which the introns are more conserved across species than the exons. Delineation of global organization, gene structure, alternative splice forms, protein similarities, and potential cis-regulatory elements leads to several conclusions: (1) The human MHC class III region is the most gene-dense region of the human genome:14% of the sequence is coding, approximately 72% of the region is transcribed, and there is an average of 8.5 genes per 100 kb. (2) Gene sizes, number of exons, and intergenic distances are for the most part similar in both species, implying that interspersed repeats have had little impact in disrupting the tight organization of this densely packed set of genes. (3) The region contains a heterogeneous mixture of genes, only a few of which have a clearly defined and proven function. Although many of the genes are of ancient origin, some appear to exist only in mammals and fish, implying they might be specific to vertebrates. (4) Conserved noncoding sequences are found primarily in or near the 5'-UTR or the first intron of genes, and seldom in the intergenic regions. Many of these conserved blocks are likely to be cis-regulatory elements.
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- 2003
12. The DNA sequence and analysis of human chromosome 14
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Roland Heilig, Ralph Eckenberg, Jean-Louis Petit, Núria Fonknechten, Corinne Da Silva, Laurence Cattolico, Michaël Levy, Valérie Barbe, Véronique de Berardinis, Abel Ureta-Vidal, Eric Pelletier, Virginie Vico, Véronique Anthouard, Lee Rowen, Anup Madan, Shizhen Qin, Hui Sun, Hui Du, Kymberlie Pepin, François Artiguenave, Catherine Robert, Corinne Cruaud, Thomas Brüls, Olivier Jaillon, Lucie Friedlander, Gaelle Samson, Philippe Brottier, Susan Cure, Béatrice Ségurens, Franck Anière, Sylvie Samain, Hervé Crespeau, Nissa Abbasi, Nathalie Aiach, Didier Boscus, Rachel Dickhoff, Monica Dors, Ivan Dubois, Cynthia Friedman, Michel Gouyvenoux, Rose James, Anuradha Madan, Barbara Mairey–Estrada, Sophie Mangenot, Nathalie Martins, Manuela Ménard, Sophie Oztas, Amber Ratcliffe, Tristan Shaffer, Barbara Trask, Benoit Vacherie, Chadia Bellemere, Caroline Belser, Marielle Besnard-Gonnet, Delphine Bartol–Mavel, Magali Boutard, Stéphanie Briez-Silla, Stephane Combette, Virginie Dufossé-Laurent, Carolyne Ferron, Christophe Lechaplais, Claudine Louesse, Delphine Muselet, Ghislaine Magdelenat, Emilie Pateau, Emmanuelle Petit, Peggy Sirvain-Trukniewicz, Arnaud Trybou, Nathalie Vega-Czarny, Elodie Bataille, Elodie Bluet, Isabelle Bordelais, Maria Dubois, Corinne Dumont, Thomas Guérin, Sébastien Haffray, Rachid Hammadi, Jacqueline Muanga, Virginie Pellouin, Dominique Robert, Edith Wunderle, Gilbert Gauguet, Alice Roy, Laurent Sainte-Marthe, Jean Verdier, Claude Verdier-Discala, LaDeana Hillier, Lucinda Fulton, John McPherson, Fumihiko Matsuda, Richard Wilson, Claude Scarpelli, Gábor Gyapay, Patrick Wincker, William Saurin, Francis Quétier, Robert Waterston, Leroy Hood, and Jean Weissenbach
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Chromosomes, Human, Pair 14 ,Base Composition ,Multidisciplinary ,Molecular Sequence Data ,Immunity ,Reproducibility of Results ,Genomics ,Sequence Analysis, DNA ,Physical Chromosome Mapping ,DNA, Mitochondrial ,DNA, Ribosomal ,Synteny ,Mice ,Open Reading Frames ,Genes ,Animals ,Humans ,Chromosomes, Artificial ,CpG Islands ,5' Untranslated Regions ,Pseudogenes ,Microsatellite Repeats - Abstract
Chromosome 14 is one of five acrocentric chromosomes in the human genome. These chromosomes are characterized by a heterochromatic short arm that contains essentially ribosomal RNA genes, and a euchromatic long arm in which most, if not all, of the protein-coding genes are located. The finished sequence of human chromosome 14 comprises 87,410,661 base pairs, representing 100% of its euchromatic portion, in a single continuous segment covering the entire long arm with no gaps. Two loci of crucial importance for the immune system, as well as more than 60 disease genes, have been localized so far on chromosome 14. We identified 1,050 genes and gene fragments, and 393 pseudogenes. On the basis of comparisons with other vertebrate genomes, we estimate that more than 96% of the chromosome 14 genes have been annotated. From an analysis of the CpG island occurrences, we estimate that 70% of these annotated genes are complete at their 5' end.
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- 2003
13. Quod erat faciendum: sequence analysis of the H2-D and H2-Q regions of 129/SvJ mice
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Kirsten Fischer Lindahl, Anup Madan, Shizhen Qin, Leroy Hood, Attila Kumánovics, and Lee Rowen
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Genetics ,Chromosomes, Artificial, Bacterial ,biology ,Sequence analysis ,Molecular Sequence Data ,Immunology ,Haplotype ,H-2 Antigens ,Genes, MHC Class I ,Locus (genetics) ,Sequence Analysis, DNA ,D region ,Major histocompatibility complex ,Mice ,Multigene Family ,Gene duplication ,biology.protein ,Animals ,Amino Acid Sequence ,Allele ,Gene - Abstract
The H2-D and -Q regions of the mouse major histocompatibility complex (Mhc or H2) have been sequenced from strain 129/SvJ (haplotype bc), revealing a D/Q region different from all other investigated haplotypes, including the closely related b haplotype. The 300-kb class I-rich region consists of the classical class I, H2-D, and 11 non-classical class I genes. The Q region was formed by two series of tandem duplications. Comparison of the segment between the D and Q1 genes with the H2-K region provides evidence that class I genes were translocated from the K region to the D region, and gives a new explanation for the weak locus specificity of the H-K and H2-D alleles.
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- 2002
14. Whole-Genome Shotgun Assembly and Analysis of the Genome ofFugu rubripes
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Gustavo Glusman, Daniel S. Rokhsar, Chris Detter, Greg Elgar, Paramvir S. Dehal, Susan Lucas, Sarah Smith, Melody S. Clark, Dmitry Pruss, Sean V. Tavtigian, Jarrod Chapman, Trevor Hawkins, Byrappa Venkatesh, Paul Predki, Y. H. Tan, Elia Stupka, Isaac Ho, Shawn Hoon, Justin Powell, Holly Baden, Tania Oh, Jared C. Roach, Marie Wong, Sam Rash, Leroy Hood, Nik Putnam, Arian F.A. Smit, Cheryl Evans, Paul G. Richardson, Jer Ming Chia, Alice Tay, Norman A. Doggett, Frans Verhoef, Maarten D. Sollewijn Gelpke, Mary Barnstead, Yvonne J. K. Edwards, Samuel Aparicio, Andrey Zharkikh, Alan Christoffels, Sydney Brenner, and Lee Rowen
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Fish Proteins ,Proteome ,Takifugu rubripes ,Locus (genetics) ,Synteny ,Genome ,Evolution, Molecular ,Gene Duplication ,Gene Order ,Animals ,Humans ,Repeated sequence ,Gene ,Conserved Sequence ,Repetitive Sequences, Nucleic Acid ,Genetics ,Multidisciplinary ,biology ,Genome, Human ,Fugu ,Shotgun sequencing ,fungi ,Computational Biology ,Proteins ,Exons ,Genomics ,Sequence Analysis, DNA ,Physical Chromosome Mapping ,biology.organism_classification ,Biological Evolution ,Introns ,Takifugu ,DNA Transposable Elements ,Human genome - Abstract
The compact genome ofFugu rubripeshas been sequenced to over 95% coverage, and more than 80% of the assembly is in multigene-sized scaffolds. In this 365-megabase vertebrate genome, repetitive DNA accounts for less than one-sixth of the sequence, and gene loci occupy about one-third of the genome. As with the human genome, gene loci are not evenly distributed, but are clustered into sparse and dense regions. Some “giant” genes were observed that had average coding sequence sizes but were spread over genomic lengths significantly larger than those of their human orthologs. Although three-quarters of predicted human proteins have a strong match toFugu, approximately a quarter of the human proteins had highly diverged from or had no pufferfish homologs, highlighting the extent of protein evolution in the 450 million years since teleosts and mammals diverged. Conserved linkages betweenFuguand human genes indicate the preservation of chromosomal segments from the common vertebrate ancestor, but with considerable scrambling of gene order.
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- 2002
15. A Provisional Regulatory Gene Network for Specification of Endomesoderm in the Sea Urchin Embryo
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Pei Yun Lee, Maria Ina Arnone, Gabriele Amore, R. Andrew Cameron, Cesar Arenas-Mena, David R. McClay, Veronica F. Hinman, Andrew Ransick, Eric H. Davidson, Leroy Hood, Ochan Otim, Jonathan P. Rast, Chiou-Hwa Yuh, Hamid Bolouri, Peter J.C. Clarke, Paola Oliveri, Alistair G. Rust, Takuya Minokawa, Lee Rowen, Cristina Calestani, Zhengjun Pan, Roger Revilla, C. Titus Brown, Maria J. Schilstra, and Carolina B. Livi
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Morpholino ,Gene regulatory network ,Computational biology ,Biology ,Models, Biological ,Mesoderm ,03 medical and health sciences ,Endomesoderm ,0302 clinical medicine ,Genes, Regulator ,Animals ,RNA, Messenger ,Gene ,Molecular Biology ,030304 developmental biology ,Regulator gene ,Regulation of gene expression ,Genetics ,sea urchin embryo ,0303 health sciences ,Endoderm ,Cell Biology ,engrailed ,Sea Urchins ,FOS: Biological sciences ,embryonic structures ,gene network ,Ectopic expression ,gene regulation ,030217 neurology & neurosurgery ,69999 Biological Sciences not elsewhere classified ,Developmental Biology - Abstract
We present the current form of a provisional DNA sequence-based regulatory gene network that explains in outline how endomesodermal specification in the sea urchin embryo is controlled. The model of the network is in a continuous process of revision and growth as new genes are added and new experimental results become available; see http://www.its.caltech.edu/~mirsky/endomeso.htm (End-mes Gene Network Update) for the latest version. The network contains over 40 genes at present, many newly uncovered in the course of this work, and most encoding DNA-binding transcriptional regulatory factors. The architecture of the network was approached initially by construction of a logic model that integrated the extensive experimental evidence now available on endomesoderm specification. The internal linkages between genes in the network have been determined functionally, by measurement of the effects of regulatory perturbations on the expression of all relevant genes in the network. Five kinds of perturbation have been applied: (1) use of morpholino antisense oligonucleotides targeted to many of the key regulatory genes in the network; (2) transformation of other regulatory factors into dominant repressors by construction of Engrailed repressor domain fusions; (3) ectopic expression of given regulatory factors, from genetic expression constructs and from injected mRNAs; (4) blockade of the beta-catenin/Tcf pathway by introduction of mRNA encoding the intracellular domain of cadherin; and (5) blockade of the Notch signaling pathway by introduction of mRNA encoding the extracellular domain of the Notch receptor. The network model predicts the cis-regulatory inputs that link each gene into the network. Therefore, its architecture is testable by cis-regulatory analysis. Strongylocentrotus purpuratus and Lytechinus variegatus genomic BAC recombinants that include a large number of the genes in the network have been sequenced and annotated. Tests of the cis-regulatory predictions of the model are greatly facilitated by interspecific computational sequence comparison, which affords a rapid identification of likely cis-regulatory elements in advance of experimental analysis. The network specifies genomically encoded regulatory processes between early cleavage and gastrula stages. These control the specification of the micromere lineage and of the initial veg(2) endomesodermal domain; the blastula-stage separation of the central veg(2) mesodermal domain (i.e., the secondary mesenchyme progenitor field) from the peripheral veg(2) endodermal domain; the stabilization of specification state within these domains; and activation of some downstream differentiation genes. Each of the temporal-spatial phases of specification is represented in a subelement of the network model, that treats regulatory events within the relevant embryonic nuclei at particular stages.
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- 2002
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16. Genomic analysis of orthologous mouse and human olfactory receptor loci
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Richard Axel, Robert P. Lane, Maria Athanasiou, Leroy Hood, Tyler Cutforth, Glen A. Evans, Janet M. Young, Cynthia Friedman, Lee Rowen, and Barbara J. Trask
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Molecular Sequence Data ,Mice, Inbred Strains ,Biology ,Receptors, Odorant ,Polymerase Chain Reaction ,Homology (biology) ,Evolution, Molecular ,Mice ,Open Reading Frames ,medicine ,Animals ,Humans ,Gene family ,Coding region ,Gene ,Phylogeny ,Synteny ,Comparative genomics ,Genetics ,Multidisciplinary ,Olfactory receptor ,Chromosome Mapping ,Exons ,Biological Sciences ,medicine.anatomical_structure ,Multigene Family ,Human genome ,5' Untranslated Regions - Abstract
Olfactory receptor (OR) genes represent approximately 1% of genomic coding sequence in mammals, and these genes are clustered on multiple chromosomes in both the mouse and human genomes. We have taken a comparative genomics approach to identify features that may be involved in the dynamic evolution of this gene family and in the transcriptional control that results in a single OR gene expressed per olfactory neuron. We sequenced approximately 350 kb of the murine P2 OR cluster and used synteny, gene linkage, and phylogenetic analysis to identify and sequence approximately 111 kb of an orthologous cluster in the human genome. In total, 18 mouse and 8 human OR genes were identified, including 7 orthologs that appear to be functional in both species. Noncoding homology is evident between orthologs and generally is confined within the transcriptional unit. We find no evidence for common regulatory features shared among paralogs, and promoter regions generally do not contain strong promoter motifs. We discuss these observations, as well as OR clustering, in the context of evolutionary expansion and transcriptional regulation of OR repertoires.
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- 2001
17. A physical map of the human genome
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Anuradha Madan, S. Naylor, Kami Dixon, Wonhee Jang, John Douglas Mcpherson, Asao Fujiyama, Simon G. Gregory, Jacquelyn R. Idol, Takashi Sasaki, David Haussler, Hong Seok Park, Jun Kudoh, Ai Shintani, Erica Sodergren, Barbara J. Trask, Norma J. Nowak, Gerald Nyakatura, Gregory D. Schuler, Shinsei Minoshima, Raluca Yonescu, J. Harley Gorrell, Roland Heilig, Vivian G. Cheung, Steve Scherer, Kazunori Shibuya, Hsiu Chuan Chen, Olivia Velasquez, Scot Kennedy, Leroy Hood, Richard Reinhardt, Lucía Ramírez, Richard M. Myers, Atsushi Toyoda, Tetsushi Yada, Nobuyoshi Shimizu, Eric D. Green, Dawn Garcia, Owen T. McCann, Kate Montgomery, Asif T. Chinwalla, Elaine R. Mardis, Peter Seranski, Valerie Maduro, W. James Kent, Cynthia Friedman, Kazutoyo Osoegawa, Carol Scott, Juliane Ramser, Marco A. Marra, Caryn Wagner-McPherson, William B. Barbazuk, Thomas Reid, Mandeep Sekhon, Lee Rowen, Nancy E. Stone, Richard A. Gibbs, Lisa French, Trevor Hawkins, J. de Jong, Jin Shang, Tamara A. Kucaba, Robert H. Waterston, Adam Whittaker, Jeremy Schmutz, Richard K. Wilson, Kristine M. Wylie, Masahira Hattori, Atsushi Shimizu, Ilan R. Kirsch, Jean Weissenbach, Céline Hoff, Julie R. Korenberg, Markus Schilhabel, Sanja Rogic, David R. Bentley, Shuichi Asakawa, Paul E. Tabor, Terrence S. Furey, Kerstin P. Clerc-Blankenburg, Raju Kucherlapati, Joseph J. Catanese, Shizhen Qin, Annemarie Poustka, Suzanne Emerling, Reiner Siebert, Brigitte Schlegelberger, Hans Lehrach, Monica Dors, Thomas Brüls, Hillary Massa, R Evans, Steven J.M. Jones, Gernot Gloeckner, Elbert Branscomb, Andrew Dunham, Jane L. Holden, Xiao Ning Chen, Ashley Miller, Jan Fang Cheng, André Rosenthal, John W. Wallis, Eunice Lee, Gaiping Wen, Sean Humphray, Carol Soderlund, Robert S. Fulton, Yoshiyuki Sakaki, David R. Cox, Norman A. Doggett, Kazuhiko Kawasaki, Anne S. Olsen, Graeme Bethel, and LaDeana W. Hillier
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Genetics ,Cancer genome sequencing ,Whole genome sequencing ,Chromosomes, Artificial, Bacterial ,Multidisciplinary ,Contig ,Genome, Human ,Computational biology ,Genome project ,Biology ,ENCODE ,DNA Fingerprinting ,Genome ,Chimpanzee genome project ,Contig Mapping ,Gene Duplication ,Humans ,Cloning, Molecular ,In Situ Hybridization, Fluorescence ,Repetitive Sequences, Nucleic Acid ,Reference genome - Abstract
The human genome is by far the largest genome to be sequenced, and its size and complexity present many challenges for sequence assembly. The International Human Genome Sequencing Consortium constructed a map of the whole genome to enable the selection of clones for sequencing and for the accurate assembly of the genome sequence. Here we report the construction of the whole-genome bacterial artificial chromosome (BAC) map and its integration with previous landmark maps and information from mapping efforts focused on specific chromosomal regions. We also describe the integration of sequence data with the map.
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- 2001
18. Characterization of C14orf4, a Novel Intronless Human Gene Containing a Polyglutamine Repeat, Mapped to the ARVD1 Critical Region
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Natascia Tiso, Andrea Nava, Alessandra Rampazzo, Gian Antonio Danieli, Gianluca Occhi, Stefania Bortoluzzi, Francesca Pivotto, Lee Rowen, and Lee Hood
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DNA, Complementary ,Ventricular Dysfunction, Right ,TATA box ,Molecular Sequence Data ,Hypothetical protein ,Biophysics ,CAAT box ,Biology ,Polymerase Chain Reaction ,Biochemistry ,Open Reading Frames ,LINKAGE ,Animals ,Humans ,Amino Acid Sequence ,Nuclear protein ,Caenorhabditis elegans ,Molecular Biology ,Gene ,Repetitive Sequences, Nucleic Acid ,Chromosomes, Human, Pair 14 ,Arrhythmogenic Right Ventricular Dysplasia/genetics ,Genetics ,Base Sequence ,Sequence Homology, Amino Acid ,Reverse Transcriptase Polymerase Chain Reaction ,Chromosome Mapping ,Nuclear Proteins ,Promoter ,DNA ,Cell Biology ,Molecular biology ,RING finger domain ,Drosophila melanogaster ,cardiomyopathy ,Cardiomyopathies ,Carrier Proteins ,Peptides ,Sequence Alignment ,GC-content - Abstract
Within the ARVD1 (arrhythmogenic right ventricular dysplasia/cardiomyopathy, type 1) critical region, mapped to 14q24.3, we detected an intronless gene of 4859 bp, predominantly expressed in the heart tissue. This gene encodes a 796-amino-acid, proline-rich protein showing polyglutamine and polyalanine tracks with variable length at the N-terminus and a C3HC4 RING finger domain at the C-terminus. CREB and AP-2 binding sites are present in the promoter region. The 5′ flanking region contains neither a TATA box nor a CAAT box, but it is high in GC content and includes several Sp1 binding sites. Protein similarity searches revealed a significant match between the C-terminus and a human hypothetical protein, whose gene is located on the chromosome 19 long arm. The predicted protein shows PEST sequences, suggesting its rapid degradation. The novel intronless gene, provisionally named C14orf4 and probably encoding a nuclear protein, was excluded from being the ARVD1 gene.
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- 2000
19. BTL-II : a polymorphic locus with homology to the butyrophilin gene family, located at the border of the major histocompatibility complex class II and class III regions in human and mouse
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M. Stammers, John Trowsdale, Lee Rowen, Stephan Beck, and David A. Rhodes
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Genes, MHC Class II ,Molecular Sequence Data ,Immunology ,Locus (genetics) ,Biology ,Major histocompatibility complex ,Homology (biology) ,Major Histocompatibility Complex ,Mice ,Exon ,Butyrophilin ,Genetics ,Animals ,Humans ,Gene family ,Tissue Distribution ,Amino Acid Sequence ,Cloning, Molecular ,Peptide sequence ,Gene ,Phylogeny ,Membrane Glycoproteins ,Polymorphism, Genetic ,Butyrophilins ,Sequence Homology, Amino Acid ,Exons ,Sequence Analysis, DNA ,Inflammatory Bowel Diseases ,Intestines ,Multigene Family ,biology.protein - Abstract
Comparison of human and mouse genomic sequence at the border of the major histocompatibility complex (MHC) class II and class III regions revealed a locus encoding six exons with homology to the butyrophilin gene family and the location of a previously described gene, testis-specific basic protein (TSBP). We named the new locus BTL-II, for butyrophilin-like MHC class II associated. The six discernable exons of the BTL-II locus encode a small hydrophobic amino acid sequence (which may be a signal peptide), two immunoglobulin domains, a small 7-amino acid, heptad repeat-like exon, and a further two immunoglobulin domains. In mouse, an additional butyrophilin-like gene (NG10) is situated adjacent to BTL-II. Expression studies of the BTL-II locus in mouse showed that it is expressed in a range of gut tissues. We demonstrate that like many other genes from the MHC, BTL-II is polymorphic in a selection of diverse HLA haplotypes. In the light of the newly discovered locus, we revisit and discuss the possible origin of the butyrophilin gene family.
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- 2000
20. Genetic Modulation of T Cell Receptor Gene Segment Usage during Somatic Recombination
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Douglas B. Burtrum, David G. Schatz, Howard T. Petrie, Lee Rowen, and Ferenc Livak
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Mitotic crossover ,T-Lymphocytes ,Immunology ,Biology ,Kidney ,DNA, Ribosomal ,Polymerase Chain Reaction ,Mice ,thymus ,Gene cluster ,Consensus Sequence ,Recombinase ,Immunology and Allergy ,Recombination signal sequences ,Animals ,Somatic recombination ,Floxing ,DNA Primers ,Genetics ,Recombination, Genetic ,Recombinase activity ,Base Sequence ,Brief Definitive Report ,VDJ recombination ,repertoire selection ,Mice, Inbred C57BL ,Genes, T-Cell Receptor ,T-Cell Receptor Gene ,recombination signal sequence ,T cell receptor β locus ,Genes, T-Cell Receptor beta - Abstract
Lymphocyte antigen receptors are not encoded by germline genes, but rather are produced by combinatorial joining between clusters of gene segments in somatic cells. Within a given cluster, gene segment usage during recombination is thought to be largely random, with biased representation in mature T lymphocytes resulting from protein-mediated selection of a subset of the total repertoire. Here we show that T cell receptor Dβ and Jβ gene segment usage is not random, but is patterned at the time of recombination. The hierarchy of gene segment usage is independent of gene segment proximity, but rather is influenced by the ability of the flanking recombination signal sequences (RSS) to bind the recombinase and/or to form a paired synaptic complex. Importantly, the relative frequency of gene segment usage established during recombination is very similar to that found after protein-mediated selection, suggesting that in addition to targeting recombinase activity, the RSS may have evolved to bias the naive repertoire in favor of useful gene products.
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- 2000
21. The Human Genome Project: big science transforms biology and medicine
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Leroy Hood and Lee Rowen
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0303 health sciences ,Opinion ,Translational bioinformatics ,Computer science ,Systems biology ,Human Brain Project ,Bioinformatics ,Genome ,Data science ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,ComputingMethodologies_PATTERNRECOGNITION ,030220 oncology & carcinogenesis ,Genetics ,Human proteome project ,Molecular Medicine ,Human genome ,1000 Genomes Project ,International HapMap Project ,Molecular Biology ,Genetics (clinical) ,030304 developmental biology - Abstract
The Human Genome Project has transformed biology through its integrated big science approach to deciphering a reference human genome sequence along with the complete sequences of key model organisms. The project exemplifies the power, necessity and success of large, integrated, cross-disciplinary efforts - so-called ‘big science’ - directed towards complex major objectives. In this article, we discuss the ways in which this ambitious endeavor led to the development of novel technologies and analytical tools, and how it brought the expertise of engineers, computer scientists and mathematicians together with biologists. It established an open approach to data sharing and open-source software, thereby making the data resulting from the project accessible to all. The genome sequences of microbes, plants and animals have revolutionized many fields of science, including microbiology, virology, infectious disease and plant biology. Moreover, deeper knowledge of human sequence variation has begun to alter the practice of medicine. The Human Genome Project has inspired subsequent large-scale data acquisition initiatives such as the International HapMap Project, 1000 Genomes, and The Cancer Genome Atlas, as well as the recently announced Human Brain Project and the emerging Human Proteome Project.
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- 2013
22. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
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Elizabeth T. DeChene, Fang Fang, Javier Llorca, Gustavo Glusman, Xiting Yan, Catherine A. Brownstein, Kim L. McBride, Jason Sager, Kai Wang, Kelli K. Ryckman, Nic Meyer, Ofer Isakov, Michael M. Segal, Peining Li, Gholson J. Lyon, Edwin M. Stone, Katherine C. Flannery, Thomas B. Bair, Ingrid A. Holm, Marc S. Williams, Barry Moore, Soumya Raychaudhuri, Shuba Krishna, Timothy W. Yu, Kasper Lage, Saloni Agrawal, Eran Halperin, Mortiz Menzel, Michael F. Murray, Adam P. DeLuca, Martin G. Reese, Mark Yandell, Mengjie Chen, Donald J. Corsmeier, Mark E. Samuels, Luca Lovrečić, Matthew S. Lebo, Ignacio Varela, Oleg A. Shchelochkov, Jacek Majewski, David L. Newsom, Francisco M. De La Vega, Sven Perner, Anne E. Kwitek, Peter White, Katherine D. Mathews, Mikael Huss, Sabrina W. Yum, Janeen L. Andorf, Zayed Albertyn, Juan M. García-Lobo, Hatice Duzkale, Saskia Biskup, Jian Huang, Komal S. Sandhu, Daniel Nilsson, Anna Wedell, Bruce E. Bray, Kevin T. Booth, Bernward Klocke, Sarah L. Sawyer, Tune H. Pers, Lu Zhang, Asif Javed, David M. Margulies, Paz Polak, Juan Caballero, Kathryn Blair, Alexander T. Rakowsky, Yong Kong, Livija Medne, Huntington F. Willard, Rama Sompallae, Cong Li, Måns Magnusson, Max Schubach, Ying Huang, Paul I.W. de Bakker, Anja Palandačić, Tara Maga, Fulya Taylan, Pamela Trapane, Emily N. Price, Lovelace J. Luquette, Hongyu Zhao, Yu Bai, Barry Merriman, Alexander Hahn, Hannah C. Cox, Erik Edens, Devon Lamb-Thrush, Terry A. Braun, Dennis E. Bulman, Pauline C. Ng, Monkol Lek, Peter Szolovits, Can Yang, Renee Temme, María Cruz Rodríguez, Karin Panzer, Sara Vestecka, Gail E. Herman, Rachel Soemedi, Edward S. Kiruluta, Isaac S. Kohane, Peter Neupert, Jorge Barrera, E. Ann Black-Ziegelbein, Nathan O. Stitziel, Jillian S. Parboosingh, Ignaty Leshchiner, Sara Fitzgerald-Butt, Jared C. Roach, Monica A. Giovanni, Vamsi Veeramachaneni, Christian Gilissen, Steven A. Moore, Michele Cargill, Deniz Kural, David A. Stevenson, Aiden Eliot Shearer, Andrey Alexeyenko, Murat Gunel, Daniel R. Richards, Richard J.H. Smith, Alan H. Beggs, Nils Homer, Jonathan W. Heusel, Val C. Sheffield, Ivan Adzhubey, Bartha Maria Knoppers, Yan Zhang, Jon M. Sorenson, Greg Lennon, William G. Fairbrother, Domingo González-Lamuño, Todd E. Scheetz, Noam Shomron, Benjamin W. Darbro, Colleen A. Campbell, Christopher A. Cassa, Christopher R. Pierson, Christian R. Marshall, F. Anthony San Lucas, Elaine Lyon, Sarah K. Savage, Jessica M. Lindvall, Borut Peterlin, Peter Freisinger, Jeremy Schwartzentruber, Gerard Tromp, Eitan Friedman, Daniel G. MacArthur, Richard S. Finkel, Piotr Dworzynski, Robert E. Handsaker, A. Micheil Innes, Jochen Supper, David McCallie, Bregje W.M. van Bon, Aaron D. Bossler, Lee Rowen, Mario Deng, Laurent C. Francioli, Michael Cariaso, Shamil R. Sunyaev, Diana L. Kolbe, Nancy J. Mendelsohn, Denise E. Mauldin, Helger G. Yntema, Alexander G. Bassuk, Joseph A. Majzoub, Marcel R. Nelen, Paul M. K. Gordon, Zhengyuan Wang, Claudia Gugenmus, Aleš Maver, Heather M. McLaughlin, Meghan C. Towne, Ali Torkamani, Hela Azaiez, Karen Eilbeck, Thomas H. Wassink, Reece K. Hart, Henrik Stranneheim, Austin C. Alexander, Douglas J. Van Daele, Seth A. Ament, Manuel L. Gonzalez-Garay, Lin Hou, Birgit Funke, Kym M. Boycott, Heidi L. Rehm, Weidong Zhang, Alexander Hoischen, Martin Braun, Xiaowei Chen, C. Thomas Caskey, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Szolovits, Peter, Universidad de Cantabria, Thermo Fisher Scientific, Harvard Medical School, Boston Children’s Hospital, and Beijing Genomics Institute
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Heart Defects, Congenital ,Male ,Best practice ,Genomics ,ComputingMilieux_LEGALASPECTSOFCOMPUTING ,Biology ,Bioinformatics ,Genome ,DNA sequencing ,law.invention ,law ,Databases, Genetic ,medicine ,Humans ,Genetic Testing ,Child ,Exome ,Genetic testing ,Whole genome sequencing ,medicine.diagnostic_test ,Research ,Financing, Organized ,Sequence Analysis, DNA ,Data science ,CLARITY ,Female ,Myopathies, Structural, Congenital - Abstract
This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al., [Background]: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. [Results]: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. [Conclusions]: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups., This work was supported by funds provided through the Gene Partnership and the Manton Center for Orphan Disease Research at Boston Children’s Hospital and the Center for Biomedical Informatics at Harvard Medical School and by generous donations in-kind of genomic sequencing services by Life Technologies (Carlsbad, CA, USA) and Complete Genomics (Mountain View, CA, USA).
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- 2013
23. The Complete 685-Kilobase DNA Sequence of the Human β T Cell Receptor Locus
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Ben F. Koop, Leroy Hood, and Lee Rowen
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DNA, Complementary ,RNA Splicing ,Receptors, Antigen, T-Cell, alpha-beta ,Pseudogene ,Molecular Sequence Data ,Interspersed repeat ,Locus (genetics) ,Biology ,Translocation, Genetic ,DNA sequencing ,Gene mapping ,Complementary DNA ,Humans ,Amino Acid Sequence ,Promoter Regions, Genetic ,Gene ,Repetitive Sequences, Nucleic Acid ,Genetics ,Polymorphism, Genetic ,Multidisciplinary ,Base Sequence ,Nucleic acid sequence ,Genetic Variation ,Exons ,Biological Evolution ,Molecular biology ,Introns ,Multigene Family ,Trypsinogen ,Chromosomes, Human, Pair 9 ,Chromosomes, Human, Pair 7 ,Pseudogenes - Abstract
The human beta T cell receptor (TCR) locus, comprising a complex family of genes, has been sequenced. The locus contains two types of coding elements--TCR elements (65 variable gene segments and two clusters of diversity, joining, and constant segments) and eight trypsinogen genes --that constitute 4.6 percent of the DNA. Genome-wide interspersed repeats and locus-specific repeats span 30 and 47 percent, respectively, of the 685-kilobase sequence. A comparison of the germline variable elements with their approximately 300 complementary DNA counterparts reveals marked differential patterns of variable gene expression, the importance of exonuclease activity in generating TCR diversity, and the predominant tendency for only functional variable elements to be present in complementary DNA libraries.
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- 1996
24. The Human T-Cell Receptor TCRAC/TCRDC (Cα/Cdelta;) Region: Organization, Sequence, and Evolution of 97.6 kb of DNA
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Chia Lam Kuo, Stephen Howard, Purnima Deshpande, Donald Seto, Kai Wang, Ben F. Koop, Wei Shan, Lee Rowen, Leroy Hood, and Johannes A. Lenstra
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RNA Splicing ,Receptors, Antigen, T-Cell, alpha-beta ,Pseudogene ,Molecular Sequence Data ,Sequence Homology ,Biology ,Gene Rearrangement, T-Lymphocyte ,DNA sequencing ,Homology (biology) ,Mice ,Species Specificity ,Complementary DNA ,Consensus Sequence ,Genetics ,Animals ,Humans ,Coding region ,Amino Acid Sequence ,Gene ,Repetitive Sequences, Nucleic Acid ,Genomic organization ,Base Sequence ,Nucleic acid sequence ,Chromosome Mapping ,Receptors, Antigen, T-Cell, gamma-delta ,DNA ,Biological Evolution ,Molecular biology ,Enhancer Elements, Genetic ,Genes ,Sequence Alignment ,Pseudogenes - Abstract
We sequenced and analyzed 97.6 kb of new DNA sequence containing the human TCRAC (C alpha) and TCRDC (C delta) genes as well as the TCRDV3 (V delta 3) and 61 different TCRAJ (J alpha) gene segments and compared its organization and structure to the previously described mouse T-cell receptor TCRAC/TCRDC (C alpha/C delta) region. A comprehensive nomenclature, consistent with the IUIS nomenclature committee recommendations, for both human and mouse TCRAJ gene segments is presented. In the human sequence, we identified 20 new TCRAJ gene segments and obtained the germline sequence for 23 additional TCRAJ gene segments known from cDNA clones. Using the sequence data obtained from the human TCRAC/TCRDC region, we have extended a polymerase chain reaction-based assay to test for the expression of the individual TCRAJ gene segments. At least five TCRAJ pseudogene segments were identified by sequence criteria. Like the murine TCRAC/TCRDC sequence, this sequence contains a high level of coding sequence, with over 6.6% of the total sequence being transcribed. Comparison of the human sequence with the previously reported mouse DNA sequence reveals homologous counterparts for the variable and joining (J) gene segments and both constant genes. Eleven new J pseudogene segments have been identified in the mouse TCRAC/TCRDC sequence through the use of human and mouse sequence comparisons. In terms of structure and organization, this region of the human and mouse genome appears to be remarkably conserved.
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- 1994
25. Analysis of Genetic Inheritance in a Family Quartet by Whole Genome Sequencing
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Radoje Drmanac, Michael J. Bamshad, Jay Shendure, Krishna Pant, Arian F.A. Smit, Lee Rowen, Gustavo Glusman, David J. Galas, Nathan Goodman, Robert Hubley, Jared C. Roach, Lynn B. Jorde, Chad D. Huff, Leroy Hood, and Paul Shannon
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Male ,Candidate gene ,Mutation rate ,Oxidoreductases Acting on CH-CH Group Donors ,Sequence analysis ,Dihydroorotate Dehydrogenase ,Inheritance Patterns ,Limb Deformities, Congenital ,Genes, Recessive ,Biology ,Genome ,Polymorphism, Single Nucleotide ,Article ,Nuclear Family ,Humans ,Abnormalities, Multiple ,Crossing Over, Genetic ,Gene ,Nuclear family ,Alleles ,Genetic Association Studies ,Genes, Dominant ,Whole genome sequencing ,Genetics ,Multidisciplinary ,Genome, Human ,Axonemal Dyneins ,Sequence Analysis, DNA ,Syndrome ,Pedigree ,Mutation ,Human genome ,Female ,Algorithms ,Mandibulofacial Dysostosis ,Ciliary Motility Disorders - Abstract
Runs in the Family The power to detect mutations involved in disease by genome sequencing is enhanced when combined with the ability to discover specific mutations that may have arisen between offspring and parents. Roach et al. (p. 636 , published online 10 March) present the sequence of a family with two offspring affected with two genetic disorders: Miller syndrome and primary ciliary dyskinesia. Sequence analysis of the children and their parents not only showed that the intergenerational mutation rate was lower than anticipated but also revealed recombination sites and the occurrence of rare polymorphisms.
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- 2010
26. Systems biology at the Institute for Systems Biology
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Lee Rowen, Leroy Hood, David J. Galas, and John D. Aitchison
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Halobacterium salinarum ,Systems biology ,Emergent systems ,Computational biology ,Saccharomyces cerevisiae ,Biology ,Biochemistry ,Genetics ,Peroxisomes ,Animals ,Humans ,Complex systems biology ,Molecular Biology ,Biological computation ,Information Science ,Inflammation ,Mathematical and theoretical biology ,Hierarchy ,Internet ,Management science ,Modelling biological systems ,Research ,Systems Biology ,Academies and Institutes ,Immunity ,Visualization - Abstract
Systems biology represents an experimental approach to biology that attempts to study biological systems in a holistic rather than an atomistic manner. Ideally this involves gathering dynamic and global data sets as well as phenotypic data from different levels of the biological information hierarchy, integrating them and modeling them graphically and/or mathematically to generate mechanistic explanations for the emergent systems properties. This requires that the biological frontiers drive the development of new measurement and visualization technologies and the pioneering of new computational and mathematical tools-all of which requires a cross-disciplinary environment composed of biologists, chemists, computer scientists, engineers, mathematicians, physicists, and physicians speaking common discipline languages. The Institute for Systems Biology has aspired to pioneer and seamlessly integrate each of these concepts.
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- 2008
27. Sequencing the Human Genome: A Historical Perspective on Challenges for Systems Integration
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Lee Rowen
- Subjects
Funding Agency ,Resource (project management) ,Data sequences ,Shotgun sequencing ,business.industry ,Political science ,Chromosomal Territory ,Library science ,System integration ,Human genome ,Bioinformatics ,business ,Genome - Abstract
The sequence of the human genomewas declared finished on April 14, 2003. Analyses have been published in the journal Nature for chromosomes 6, 7, 14, 20, 21, 22 andY, with the other chromosomes to followin 2004. Although the Human Genome Project officially began in 1990, most of the publicly accessible sequence data were produced by 20 genome centers in six countries between 1999 and 2002. This group of centers, called the International Human Genome Sequencing Consortium, coordinated their mapping and sequencing efforts and freely shared materials, data and procedures [23]. The International Consortium in turn was supported by a network of funding agency program directors, database managers, resource providers, instrumentation/protocol developers, and conference organizers. In all, several thousand people made sure that the human genome got sequenced, and the world is rightly celebrating their accomplishment.
- Published
- 2007
28. Analysis of the DNA sequence and duplication history of human chromosome 15
- Author
-
Sandra Stewart, Amardeep Kaur, Evan Mauceli, Kerri Topham, Harindra Arachchi, Brian Birditt, Jerome Naylor, Toby Bloom, Sarah Young, Anup Madan, Reinhard Engels, Manuel Garber, Sabrina M. Stone, Anuradha Madan, Amber L Ratcliffe, Ryan Nesbitt, Amr Abouelleil, Keith O'Neill, Scott Bloom, Katherine M. B. Sneddon, Dascena Vincent, Lester Dorris, Steven Rounsley, Jennifer L. Hall, Michael Fitzgerald, David B. Jaffe, Grace Hensley, Gary Gearin, Devin P. Locke, Asha Kamat, Ericka M. Johnson, Jonathan Butler, Sinéad B. O'Leary, Jeremy Burke, Lida Baradarani, Jean L. Chang, Kurt DeArellano, Michael Kamal, Andrew Zimmer, Annie Lui, Eric S. Lander, Charles A. Whittaker, Monica Dors, Chad Nusbaum, David DeCaprio, Chinnappa D. Kodira, Leroy Hood, Robert Nicol, Ted Sharpe, Evan E. Eichler, Nissa Abbasi, Christina A. Cuomo, Glen Munson, Mark L. Borowsky, Shunguang Wang, Michael C. Zody, Shizhen Qin, Charlien Jones, Peter Fleetwood, Xinwei She, Pendexter Macdonald, Ken Dewar, April Cook, Xiaoping Yang, Bruce W. Birren, Jessica Fahey, Cynthia Friedman, Carrie Sougnez, and Lee Rowen
- Subjects
Molecular Sequence Data ,Biology ,Synteny ,Evolution, Molecular ,Chromosome 16 ,Chromosome 19 ,Gene Duplication ,Animals ,Humans ,Conserved Sequence ,Phylogeny ,Segmental duplication ,Genetics ,Chromosome 7 (human) ,Chromosomes, Human, Pair 15 ,Multidisciplinary ,Polymorphism, Genetic ,Genome, Human ,Sequence Analysis, DNA ,Macaca mulatta ,Chromosome 17 (human) ,Chromosome 4 ,Genes ,Haplotypes ,Multigene Family ,Chromosome 21 ,Chromosome 22 - 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 duplications 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
- 2005
29. Gene Structure and Organization
- Author
-
Lee Rowen
- Subjects
Genetics ,Genome evolution ,Exon trapping ,Pseudogene ,Gene density ,Human genome ,Genome project ,Biology ,ENCODE ,human activities ,Genome - Abstract
The sequence of the human genome enables a delineation of genes and analysis of their structural properties and organization in the context of the chromosome. Keywords: gene; genome; transcript; intron; exon
- Published
- 2005
30. The evolution of vertebrate Toll-like receptors
- Author
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Jared C. Roach, Gustavo Glusman, Maureen K. Purcell, Amardeep Kaur, Leroy Hood, Kelly D. Smith, Lee Rowen, and Alan Aderem
- Subjects
Takifugu rubripes ,Sequence analysis ,Pseudogene ,Molecular Sequence Data ,Receptors, Cell Surface ,Takifugu ,Evolution, Molecular ,Species Specificity ,Phylogenetics ,biology.animal ,Animals ,Phylogeny ,Genetics ,Multidisciplinary ,Concerted evolution ,Membrane Glycoproteins ,biology ,Base Sequence ,Models, Genetic ,Toll-Like Receptors ,Vertebrate ,Computational Biology ,Genomics ,Sequence Analysis, DNA ,Biological Sciences ,biology.organism_classification ,Toll-Like Receptor 1 ,Gene Components ,Multigene Family ,Vertebrates ,TLR10 - Abstract
The complete sequences of Takifugu Toll-like receptor (TLR) loci and gene predictions from many draft genomes enable comprehensive molecular phylogenetic analysis. Strong selective pressure for recognition of and response to pathogen-associated molecular patterns has maintained a largely unchanging TLR recognition in all vertebrates. There are six major families of vertebrate TLRs. This repertoire is distinct from that of invertebrates. TLRs within a family recognize a general class of pathogen-associated molecular patterns. Most vertebrates have exactly one gene ortholog for each TLR family. The family including TLR1 has more species-specific adaptations than other families. A major family including TLR11 is represented in humans only by a pseudogene. Coincidental evolution plays a minor role in TLR evolution. The sequencing phase of this study produced finished genomic sequences for the 12 Takifugu rubripes TLRs. In addition, we have produced >70 gene models, including sequences from the opossum, chicken, frog, dog, sea urchin, and sea squirt.
- Published
- 2005
31. Interchromosomal segmental duplications explain the unusual structure of PRSS3, the gene for an inhibitor-resistant trypsinogen
- Author
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Cynthia Friedman, Lee Rowen, Leroy Hood, Scott Bloom, Barbara J. Trask, Amardeep Kaur, Eleanor M. Williams, Gustavo Glusman, Cecilie Boysen, Elena V. Linardopoulou, Shizhen Qin, Mary Ellen Ahearn, Kai Wang, and Jason Seto
- Subjects
Genetics ,Trypsinogen ,Quantitative Trait Loci ,Exons ,Biology ,Evolution, Molecular ,Exon ,chemistry.chemical_compound ,Fusion transcript ,chemistry ,Gene duplication ,PRSS2 ,Gene family ,Chromosomes, Human ,Humans ,Trypsin ,PRSS3 ,Selection, Genetic ,Trypsin Inhibitors ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Segmental duplication - Abstract
Homo sapiens possess several trypsinogen or trypsinogen-like genes of which three (PRSS1, PRSS2, and PRSS3) produce functional trypsins in the digestive tract. PRSS1 and PRSS2 are located on chromosome 7q35, while PRSS3 is found on chromosome 9p13. Here, we report a variation of the theme of new gene creation by duplication: the PRSS3 gene was formed by segmental duplications originating from chromosomes 7q35 and 11q24. As a result, PRSS3 transcripts display two variants of exon 1. The PRSS3 transcript whose gene organization most resembles PRSS1 and PRSS2 encodes a functional protein originally named mesotrypsinogen. The other variant is a fusion transcript, called trypsinogen IV. We show that the first exon of trypsinogen IV is derived from the noncoding first exon of LOC120224, a chromosome 11 gene. LOC120224 codes for a widely conserved transmembrane protein of unknown function. Comparative analyses suggest that these interchromosomal duplications occurred after the divergence of Old World monkeys and hominids. PRSS3 transcripts consist of a mixed population of mRNAs, some expressed in the pancreas and encoding an apparently functional trypsinogen and others of unknown function expressed in brain and a variety of other tissues. Analysis of the selection pressures acting on the trypsinogen gene family shows that, while the apparently functional genes are under mild to strong purifying selection overall, a few residues appear under positive selection. These residues could be involved in interactions with inhibitors.
- Published
- 2005
32. The organization and evolution of the dipteran and hymenopteran Down syndrome cell adhesion molecule (Dscam) genes
- Author
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Brenton R. Graveley, Lee Rowen, Amardeep Kaur, Dorian Gunning, S. Lawrence Zipursky, and James C. Clemens
- Subjects
Gene isoform ,animal structures ,Genes, Insect ,Evolution, Molecular ,Exon ,DSCAM ,Anopheles ,Melanogaster ,Animals ,Drosophila Proteins ,Molecular Biology ,Gene ,Letter to the Editor ,Genetics ,Recombination, Genetic ,biology ,Diptera ,Alternative splicing ,fungi ,Proteins ,DNA ,Exons ,Bees ,biology.organism_classification ,Hymenoptera ,Drosophila melanogaster ,Insect Proteins ,Drosophila ,Cell Adhesion Molecules ,Drosophila Protein - Abstract
The Drosophila melanogaster Down syndrome cell adhesion molecule (Dscam) gene encodes an axon guidance receptor and can generate 38,016 different isoforms via the alternative splicing of 95 variable exons. Dscam contains 10 immunoglobulin (Ig), six Fibronectin type III, a transmembrane (TM), and cytoplasmic domains. The different Dscam isoforms vary in the amino acid sequence of three of the Ig domains and the TM domain. Here, we have compared the organization of the Dscam gene from three members of the Drosophila subgenus (D. melanogaster, D. pseudoobscura, and D. virilis), the mosquito Anopheles gambiae, and the honeybee Apis mellifera. Each of these organisms contains numerous alternative exons and can potentially synthesize tens of thousands of isoforms. Interestingly, most of the alternative exons in one species are more similar to one another than to the corresponding alternative exons in the other species. These observations provide strong evidence that many of the alternative exons have arisen by reiterative exon duplication and deletion events. In addition, these findings suggest that the expression of a large Dscam repertoire is more important for the development and function of the insect nervous system than the actual sequence of each isoform.
- Published
- 2004
33. Majority of divergence between closely related DNA samples is due to indels
- Author
-
R. Andrew Cameron, John C. Williams, Lee Rowen, and Roy J. Britten
- Subjects
DNA, Bacterial ,Chromosomes, Artificial, Bacterial ,Pan troglodytes ,Biology ,medicine.disease_cause ,Escherichia coli O157 ,Evolution, Molecular ,chemistry.chemical_compound ,Sequence Homology, Nucleic Acid ,medicine ,Animals ,Humans ,Indel ,Sequence (medicine) ,Smith–Waterman algorithm ,Genetics ,Mutation ,Multidisciplinary ,Polymorphism, Genetic ,Phylogenetic tree ,food and beverages ,DNA ,Biological Sciences ,chemistry ,Sea Urchins ,Human genome ,Chromosome 22 ,Caltech Library Services - Abstract
utations in the DNA are the source of variation in Darwinian evolution. Therefore it is likely that the exam- ination of DNA differences between closely related species or among polymorphic variations in DNA of a given species will give insight into the nature of the mutations and the process of evolution. In the present paper, published and unpublished data are summarized for examples from several distantly related phylogenetic groups, and the data show that indels dominate the process of early divergence. There is a continuing problem in these data of the upper limit in the size of detected gaps and bias against larger ones. The groups sampled are apes (chimp-human DNA comparison), sea urchins (Strongylocentrotus purpuratus polymorphism), bacteria (Escherichia coli substrain compari- son), insects (Drosophila polymorphism), nematodes (Caeno- rhabditis elegans polymorphism), and plants (Arabidopsis poly- morphism). It is also noted that human genetic diseases are frequently caused by indels. The first part of the paper summa- rizes the results for samples of chimp DNA compared with the human genome sequence. Then an example of sea urchin polymorphism is briefly described. Initial comparison of two strains of E. coli O157:H7 is described. Finally, the published polymorphism data are reviewed and brought together with the data reported here to draw the conclusion that indel formation is a major and significant evolutionary process. to align the complete chimp BAC sequence with the human genome, regardless of the presence of repeated sequences, which typically consist of about half of the BAC sequence. The repeated sequences, naturally, sometimes complicate the align- ment process. The National Institutes of Health program ''BLAST the Human Genome'' was used to find the most promising region of the human genome for alignment with each particular chimp BAC sequence. This program works well because the human repetitive sequences are filtered out during the comparisons and then apparently reinserted for mapping the results. Usually only one region of the human genome shows a full or nearly full alignment with a chimp BAC sequence, whereas other regions show short or fragmentary alignments. Where duplications of long regions have occurred as on chromosome 22 there is uncertainty and we have not included these comparisons. For the next stage in the analysis a program has been written that almost always accurately detects mismatches and gaps in the alignment. It is called GAPD for gap detection or gap determination and is described in the next few sentences. Standard sequence com- parison programs such as Smith Waterman are used to find the human sequence that aligns with the start of the chimp BAC. From this aligned start GAPD goes nucleotide by nucleotide checking for mismatches. If a mismatch is seen, then a check is made of the succeeding 10 nucleotides, and if at least 6 of these match, the original mismatch is taken to be due to a base substitution. There is a possibility that there is a local region with
- Published
- 2003
34. Patchy Interspecific Sequence Similarities Efficiently Identify Positive cis-Regulatory Elements in the Sea Urchin
- Author
-
Eric H. Davidson, Carolina B. Livi, Peter J.C. Clarke, Lee Rowen, C. Titus Brown, and Chiou-Hwa Yuh
- Subjects
Chromosomes, Artificial, Bacterial ,Base pair ,Genetic Vectors ,Gene regulatory network ,computational genomics ,Regulatory Sequences, Nucleic Acid ,Biology ,Conserved sequence ,chemistry.chemical_compound ,Species Specificity ,Animals ,Molecular Biology ,Gene ,In Situ Hybridization ,sea urchin embryo ,Genetics ,Expression vector ,FamilyRelations ,DNA ,Cell Biology ,biology.organism_classification ,Strongylocentrotus purpuratus ,genomic DNA ,cis-regulatory sequence ,chemistry ,otx gene ,Sea Urchins ,embryonic structures ,Developmental Biology - Abstract
We demonstrate that interspecific sequence conservation can provide a systematic guide to the identification of functional cis-regulatory elements within a large expanse of genomic DNA. The test was carried out on the otx gene of Strongylocentrotus purpuratus. This gene plays a major role in the gene regulatory network that underlies endomesoderm specification in the embryo. The cis-regulatory organization of the otx gene is expected to be complex, because the gene has three different start sites (X. Li, C.-K. Chuang, C.-A. Mao, L. M. Angerer, and W. H. Klein, 1997, Dev. Biol. 187, 253–266), and it is expressed in many different spatial domains of the embryo. BAC recombinants containing the otx gene were isolated from Strongylocentrotus purpuratus and Lytechinus variegatus libraries, and the ordered sequence of these BACs was obtained and annotated. Sixty kilobases of DNA flanking the gene, and included in the BAC sequence from both species, were scanned computationally for short conserved sequence elements. For this purpose, we used a newly constructed software package assembled in our laboratory, “FamilyRelations.” This tool allows detection of sequence similarities above a chosen criterion within sliding windows set at 20–50 bp. Seventeen partially conserved regions, most a few hundred base pairs long, were amplified from the S. purpuratus BAC DNA by PCR, inserted in an expression vector driving a CAT reporter, and tested for cis-regulatory activity by injection into fertilized S. purpuratus eggs. The regulatory activity of these constructs was assessed by whole-mount in situ hybridization (WMISH) using a probe against CAT mRNA. Of the 17 constructs, 11 constructs displayed spatially restricted regulatory activity, and 6 were inactive in this test. The domains within which the cis-regulatory constructs were expressed are approximately consistent with results from a WMISH study on otx expression in the embryo, in which we used probes specific for the mRNAs generated from each of the three transcription start sites. Four separate cis-regulatory elements that specifically produce endomesodermal expression were identified, as well as ubiquitously active elements, and ectoderm-specific elements. We confirm predictions from other work with respect to target sites for specific transcription factors within the elements that express in the endoderm.
- Published
- 2002
35. Analysis of the human neurexin genes: alternative splicing and the generation of protein diversity
- Author
-
Dana L. Philipps, Brian Birditt, Amardeep Kaur, Anup Madan, Richard K. Wilson, Leroy Hood, Lee Rowen, Shizhen Qin, Brenton R. Graveley, Janet M. Young, and Patrick Minx
- Subjects
Gene isoform ,Genetics ,integumentary system ,Base Sequence ,fungi ,Alternative splicing ,Molecular Sequence Data ,Neurexin ,Sequence Homology ,Promoter ,Nerve Tissue Proteins ,Sequence Analysis, DNA ,Biology ,Genome ,Alternative Splicing ,Gene Expression Regulation ,Gene expression ,Humans ,Human genome ,Gene ,Neural Cell Adhesion Molecules - Abstract
The neurexins are neuronal proteins that function as cell adhesion molecules during synaptogenesis and in intercellular signaling. Although mammalian genomes contain only three neurexin genes, thousands of neurexin isoforms may be expressed through the use of two alternative promoters and alternative splicing at up to five different positions in the pre-mRNA. To begin understanding how the expression of the neurexin genes is regulated, we have determined the complete nucleotide sequence of all three human neurexin genes: NRXN1, NRXN2, and NRXN3. Unexpectedly, two of these, NRXN1 ( approximately 1.1 Mb) and NRXN3 ( approximately 1.7 Mb), are among the largest known human genes. In addition, we have identified several conserved intronic sequence elements that may participate in the regulation of alternative splicing. The sequences of these genes provide insight into the mechanisms used to generate the diversity of neurexin protein isoforms and raise several interesting questions regarding the expression mechanism of large genes.
- Published
- 2002
36. A genomic regulatory network for development
- Author
-
Roger Revilla, Carolina B. Livi, Andrew Ransick, Maria Ina Arnone, Maria J. Schilstra, Paola Oliveri, R. Andrew Cameron, Veronica F. Hinman, Zheng Jun Pan, Eric H. Davidson, Cesar Arenas-Mena, Chiou-Hwa Yuh, Cristina Calestani, Leroy Hood, Alistair G. Rust, David R. McClay, Gabriele Amore, Hamid Bolouri, Peter J.C. Clarke, Jonathan P. Rast, Pei Yun Lee, Lee Rowen, Takuya Minokawa, Ochan Otim, and C. Titus Brown
- Subjects
Mesoderm ,animal structures ,Embryonic Development ,Systems Theory ,Computational biology ,Biology ,Regulatory Sequences, Nucleic Acid ,Models, Biological ,Genes, Regulator ,medicine ,Morphogenesis ,Animals ,Cell Lineage ,Gene ,Regulator gene ,Genetics ,Regulation of gene expression ,Multidisciplinary ,Genome ,Models, Genetic ,Gene Expression Profiling ,Stem Cells ,Endoderm ,Computational Biology ,Gene Expression Regulation, Developmental ,Gene expression profiling ,medicine.anatomical_structure ,Body plan ,Regulatory sequence ,Sea Urchins ,embryonic structures - Abstract
Development of the body plan is controlled by large networks of regulatory genes. A gene regulatory network that controls the specification of endoderm and mesoderm in the sea urchin embryo is summarized here. The network was derived from large-scale perturbation analyses, in combination with computational methodologies, genomic data, cis-regulatory analysis, and molecular embryology. The network contains over 40 genes at present, and each node can be directly verified at the DNA sequence level by cis-regulatory analysis. Its architecture reveals specific and general aspects of development, such as how given cells generate their ordained fates in the embryo and why the process moves inexorably forward in developmental time.
- Published
- 2002
37. Comparative genomics of the human and mouse T cell receptor loci
- Author
-
Leroy Hood, Kai Wang, Cecilie Boysen, Inyoul Lee, Lee Rowen, Gustavo Glusman, Arian F.A. Smit, Jared C. Roach, and Ben F. Koop
- Subjects
Genetics ,Comparative genomics ,Immunology ,T-cell receptor ,Gene Conversion ,Receptors, Antigen, T-Cell ,Chromosome Mapping ,Locus (genetics) ,Genomics ,Computational biology ,Biology ,Mice ,Infectious Diseases ,Phylogenetics ,Terminology as Topic ,Immunology and Allergy ,Gene family ,Animals ,Humans ,Gene conversion ,Promoter Regions, Genetic ,Gene ,Phylogeny ,Repetitive Sequences, Nucleic Acid - Abstract
The availability of the complete genomic sequences of the human and mouse T cell receptor loci opens up new opportunities for understanding T cell receptors (TCRs) and their genes. The full complement of TCR gene segments is finally known and should prove a valuable resource for supporting functional studies. A rational nomenclature system has been implemented and is widely available through IMGT and other public databases. Systematic comparisons of the genomic sequences within each locus, between loci, and across species enable precise analyses of the various diversification mechanisms and some regulatory signals. The genomic landscape of the TCR loci provides fundamental insights into TCR evolution as highly localized and tightly regulated gene families.
- Published
- 2001
38. A physical map of human chromosome 14
- Author
-
Aye Mon Tin-Wollam, Gabor Gyapay, Asao Fujiyama, Eric Pelletier, Virginie Vico, William Saurin, Jean Weissenbach, Michael J. Levy, Delphine Muselet, Fumihiko Matsuda, Jean Louis Petit, Leroy Hood, Delphine Mavel, Corinne Da Silva, Thomas Brüls, François Artiguenave, Shizen Qin, Roland Heilig, Richard K. Wilson, and Lee Rowen
- Subjects
Genetics ,Chromosomes, Human, Pair 14 ,Chromosomes, Artificial, Bacterial ,Radiation Hybrid Mapping ,Multidisciplinary ,Computer science ,Physical Chromosome Mapping ,Computational biology ,Sequence-tagged site ,Gene mapping ,Clone (algebra) ,Path (graph theory) ,Redundancy (engineering) ,Escherichia coli ,Humans ,Radiation hybrid mapping ,Cloning, Molecular ,Sequence (medicine) ,Sequence Tagged Sites - Abstract
We report the construction of a tiling path of around 650 clones covering more than 99% of human chromosome 14. Clone overlap information to assemble the map was derived by comparing fully sequenced clones with a database of clone end sequences (sequence tag connector strategy). We selected homogeneously distributed seed points using an auxiliary high-resolution radiation hybrid map comprising 1,895 distinct positions. The high long-range continuity and low redundancy of the tiling path indicates that the sequence tag connector approach compares favourably with alternative mapping strategies.
- Published
- 2001
39. Integration of cytogenetic landmarks into the draft sequence of the human genome
- Author
-
S. Narasimhan, W. L. Kuo, Ingrid Plajzer-Frick, Cynthia C. Morton, Thomas Ried, Jonghyeob Lee, Xiao Ning Chen, Terrence S. Furey, Jan Fang Cheng, Karl Sirotkin, W. D. Burrill, Ze Peng, Sheilla Sait, James R. Hudson, Vivian G. Cheung, A. A. Thorpe, S. Collins, Cynthia Friedman, Arek Kasprzyk, P. J. De Jong, M. Olvier, Kazutoyo Osoegawa, Ilan R. Kirsch, Lee Rowen, Daniel Pinkel, Barbara J. Trask, Joe W. Gray, S. M. Clegg, Steven R. Herrick, Ewan Birney, D. Scott, Alan Bruzel, David F. Callen, Carson C. Thoreen, S. Lowry, David R. Cox, P. Dhami, Shaying Zhao, Hillary Massa, Julie R. Korenberg, Donna G. Albertson, Robert L. Strausberg, Jeffrey M. Conroy, Raluca Yonescu, Gregory D. Schuler, Evan E. Eichler, Antoine M. Snijders, Norman A. Doggett, G. L. Shen-Ong, Cliff Han, Norma J. Nowak, M. Moriey, Emmanuelle Lemyre, Bradley J. Quade, Jeffrey A. Bailey, U. J. Kim, Azra H. Ligon, David Haussler, N. P. Carter, and Wonhee Jang
- Subjects
Genetics ,Chromosome Aberrations ,Genetic Markers ,Genome evolution ,Chromosomes, Artificial, Bacterial ,Radiation Hybrid Mapping ,Multidisciplinary ,Contig ,Genome, Human ,Sequence assembly ,Chromosome Mapping ,Computational biology ,Genome project ,Biology ,Genome ,Article ,Sequence-tagged site ,Cytogenetic Analysis ,Human Genome Project ,Humans ,Human genome ,In Situ Hybridization, Fluorescence ,Reference genome ,Sequence Tagged Sites - Abstract
We have placed 7,600 cytogenetically defined landmarks on the draft sequence of the human genome to help with the characterization of genes altered by gross chromosomal aberrations that cause human disease. The landmarks are large-insert clones mapped to chromosome bands by fluorescence in situ hybridization. Each clone contains a sequence tag that is positioned on the genomic sequence. This genome-wide set of sequence-anchored clones allows structural and functional analyses of the genome. This resource represents the first comprehensive integration of cytogenetic, radiation hybrid, linkage and sequence maps of the human genome; provides an independent validation of the sequence map1,2 and framework for contig order and orientation; surveys the genome for large-scale duplications, which are likely to require special attention during sequence assembly; and allows a stringent assessment of sequence differences between the dark and light bands of chromosomes. It also provides insight into large-scale chromatin structure and the evolution of chromosomes and gene families and will accelerate our understanding of the molecular bases of human disease and cancer. Supplementary information The online version of this article (doi:10.1038/35057192) contains supplementary material, which is available to authorized users.
- Published
- 2001
40. Differential Transcriptional Regulation of Individual TCR V Segments Before Gene Rearrangement
- Author
-
Fei Chen, Lee Hood, Ellen V. Rothenberg, and Lee Rowen
- Subjects
Transcription, Genetic ,Cellular differentiation ,Immunology ,Molecular Sequence Data ,Mice, SCID ,Regulatory Sequences, Nucleic Acid ,Mice ,RAG2 ,T-Lymphocyte Subsets ,MHC class I ,Transcriptional regulation ,Immunology and Allergy ,Animals ,Cloning, Molecular ,Gene Rearrangement, beta-Chain T-Cell Antigen Receptor ,Enhancer ,Promoter Regions, Genetic ,Mice, Knockout ,biology ,Gene Expression Regulation, Developmental ,Promoter ,Cell Differentiation ,Gene rearrangement ,Molecular biology ,Mice, Inbred C57BL ,Thymocyte ,Enhancer Elements, Genetic ,Genes, T-Cell Receptor beta ,biology.protein - Abstract
The promoter sequences of individual murine TCR Vβ segments are dissimilar, but any functional differences between them are masked after productive gene rearrangement by the dominance of the TCRβ 3′ enhancer. However, thymocytes of recombination-activating gene-2 (Rag2)-deficient mice allow the transcriptional activity of Vβ promoters to be studied before rearrangement. Here we report that many Vβ segments are detectably transcribed in Rag2−/− thymocytes and that there are significant differences in expression among different Vβ segments. Primer extension and characterization of cDNA clones from SCID thymocytes suggest that these germline Vβ transcripts generally use the same start sites as those previously determined in mature T cells. The strength of expression before rearrangement does not correlate with proximity to the known enhancer, because members of the most distal Vβ cluster (Vβ2.1, Vβ1.1, Vβ4.1) are relatively strongly expressed and more proximal Vβ segments (Vβ14.1, Vβ3.1, Vβ7.1, Vβ6.1) are only weakly expressed. Different Vβ segments also show different developmental programs of activation in different thymocyte subsets, with the Vβ5.1(L)-8.2(V) spliced transcript expressed earliest as well as most strongly overall. Comparison with Rag+ MHC class I−/− and class II−/− thymocytes confirms that many of these expression differences are leveled by rearrangement and/or by β selection, before MHC-dependent selection. However, the expression pattern of Vβ2.1 is highly distinctive and includes cell types apparently outside the T lineage, suggesting potential acquisition of specialized roles.
- Published
- 2001
41. Genomic Landscapes and Strategies for Sequencing the Human Genome
- Author
-
Lee Rowen
- Subjects
Comparative genomics ,Cancer genome sequencing ,Whole genome sequencing ,Evolutionary biology ,Human genome ,Genome project ,Biology ,ENCODE ,Genome ,Personal genomics - Abstract
This is an exciting and bewildering time for those of us engaged in sequencing the human genome. It is clear that the big push to get the job done is now upon us, but it is not clear how best to accomplish the task. It is also unclear what “sequencing the genome” really means. One could idealize an end product consisting of 24 very long contiguous stretches of sequence, one for each of the 22 autosomal chromosomes, X, and Y. But no one thinks this will happen. At the other extreme, the sequence could consist of short, say, 10 kb stretches of nucleotides that collectively cover about 90% of the genome but that are not mapped with regard to chromosomal location or gene content. As far as I know, no one would consider this a reasonable end point either. Therefore, the sequence will be something in between. But what?
- Published
- 2000
42. Deciphering Genomes Through Automated Large-scale Sequencing
- Author
-
Stephen R. Lasky, Lee Rowen, and Leroy Hood
- Subjects
Computational biology ,Biology ,Bioinformatics ,Genome ,Large-Scale Sequencing - Published
- 1999
43. Cloning, characterization, and the complete 56.8-kilobase DNA sequence of the human NOTCH4 gene
- Author
-
Thomas Spies, Leroy Hood, Barbara J. Trask, Yu Deng, Amy B. Banta, Penny Dong, Guyang M. Huang, Lei Chen, Linheng Li, Todd M. Smith, Cynthia Friedman, and Lee Rowen
- Subjects
Gene isoform ,Adult ,DNA, Complementary ,Sequence analysis ,Molecular Sequence Data ,Gene Expression ,Receptors, Cell Surface ,Biology ,Major Histocompatibility Complex ,Notch Family ,Proto-Oncogene Proteins ,Genetics ,Gene family ,Coding region ,Humans ,Tissue Distribution ,Amino Acid Sequence ,Cloning, Molecular ,Promoter Regions, Genetic ,Receptor, Notch4 ,Peptide sequence ,Polymorphism, Genetic ,Base Sequence ,Receptors, Notch ,Genome, Human ,Alternative splicing ,Nucleic acid sequence ,Chromosome Mapping ,Exons ,Sequence Analysis, DNA ,Molecular biology ,Alternative Splicing ,Chromosomes, Human, Pair 6 ,Sequence Alignment - Abstract
The first complete mammalian genomic sequence reported thus far in the Notch gene family, including a putative promoter region and 30 exons of the human NOTCH4 gene spanning 56.8 kb of DNA, were sequenced. The NOTCH4 locus contains a TATA-less promoter with two putative transcription initiation sites (Inr), three RBP-Jkappa sites, and two GATA recognition sites. Two cDNA isoforms, NOTCH4(L) and NOTCH4(S),were identified. Whereas the NOTCH4(S) isoform contains the entire coding sequence, the NOTCH4(L) isoform has two unspliced intronic sequences between exons 11 and 12 and exons 20 and 21 and a misspliced exon 6. Consistent with these results, two alternatively spliced isoforms of transcripts of approximately 9.3 and 6.7 kb were detected by Northern blot analysis. The predicted amino acid sequence of the NOTCH4 protein based on the NOTCH4(S) cDNA sequence contains 2003 amino acids and includes the predominant motifs of the Notch family: 29 epidermal growth factor (EGF)-like repeats, 3 Notch/lin-12 repeats, a transmembrane region, 6 cdc10/Ankyrin repeats, and a PEST domain.
- Published
- 1998
44. Members of the olfactory receptor gene family are contained in large blocks of DNA duplicated polymorphically near the ends of human chromosomes
- Author
-
F Johnson, Dominique Giorgi, Hillary Massa, Janey Youngblom, David J. Wong, S. Naylor, Barbara J. Trask, Oanh T H Nguyen, Wen Lin Kuo, Antonia Martin-Gallardo, Shawn P. Iadonato, Cynthia Friedman, Ger van den Engh, John W. Blankenship, Sylvie Rouquier, Carolyn Akinbami, Lee Rowen, Todd M. Smith, Tammy Morrish, and Colin Collins
- Subjects
Population ,Molecular Sequence Data ,Biology ,Receptors, Odorant ,Gene duplication ,Genetics ,medicine ,Gene family ,Humans ,Amino Acid Sequence ,education ,Molecular Biology ,Gene ,Genetics (clinical) ,Genomic organization ,Repetitive Sequences, Nucleic Acid ,education.field_of_study ,Olfactory receptor ,Polymorphism, Genetic ,Chromosome Mapping ,General Medicine ,DNA ,Telomere ,Subtelomere ,medicine.anatomical_structure ,Human genome ,Chromosomes, Human, Pair 19 ,Sequence Alignment - Abstract
We have identified three new members of the olfactory receptor (OR) gene family within a large segment of DNA that is duplicated with high similarity near many human telomeres. This segment is present at 3q, 15q, and 19p in each of 45 unrelated humans sampled from various populations. Additional copies are present polymorphically at 11 other subtelomeric locations. The frequency with which the block is present at some locations varies among populations. While humans carry seven to 11 copies of the OR-containing block, it is located in chimpanzee and gorilla predominantly at a single site, which is not orthologous to any of the locations in the human genome. The observation that sequences flanking the OR-containing segment are duplicated on larger and different sets of chromosomes than the OR block itself demonstrates that the segment is part of a much larger, complex patchwork of subtelomeric duplications. The population analyses and structural results suggest the types of processes that have shaped these regions during evolution. From its sequence, one of the OR genes in this duplicated block appears to be potentially functional. Our findings raise the possibility that functional diversity in the OR family is generated in part through duplications and inter-chromosomal rearrangements of the DNA near human telomeres.
- Published
- 1998
45. Sequencing the human genome
- Author
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Gregory G. Mahairas, Lee Rowen, and Leroy Hood
- Subjects
Genetics ,Multidisciplinary ,Genome ,Databases, Factual ,Genome, Human ,Chromosome Mapping ,Sequence Analysis, DNA ,Biology ,medicine.disease_cause ,Yeast ,Computer Communication Networks ,Genetic Techniques ,Human Genome Project ,medicine ,Animals ,Chromosomes, Human ,Humans ,Human genome ,Cloning, Molecular ,Diffusion of Innovation ,Escherichia coli ,Gene Library ,Sequence Tagged Sites - Abstract
The human genome project is at the halfway point. The genomes of 11 microbes, Escherichia coli , and yeast are finished, yet the human genome is only 2 percent finished. The scale-up to finish by 2005 presents a significant challenge.
- Published
- 1998
46. T Cell Receptor, Evolution of
- Author
-
Lee Rowen
- Subjects
T-cell receptor ,Biology ,Cell biology - Published
- 1998
47. Identification of Organ-Enriched Protein Biomarkers of Acute Liver Injury by Targeted Quantitative Proteomics of Blood in Acetaminophen- and Carbon-Tetrachloride-Treated Mouse Models and Acetaminophen Overdose Patients.
- Author
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Shizhen Qin, Yong Zhou, Li Gray, Kusebauch, Ulrike, McEvoy, Laurence, Antoine, Daniel J., Hampson, Lucy, Park, Kevin B., Campbell, David, Caballero, Juan, Glusman, Gustavo, Xiaowei Yan, Taek-Kyun Kim, Yue Yuan, Kai Wang, Lee Rowen, Moritz, Robert L., Omenn, Gilbert S., Pirmohamed, Munir, and Hood, Leroy
- Published
- 2016
- Full Text
- View/download PDF
48. Human immunodeficiency virus type 1 infection despite prior immunization with a recombinant envelope vaccine regimen
- Author
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M J McElrath, Lee Rowen, Philip D. Greenberg, David C. Montefiori, T J Matthews, James I. Mullins, Lawrence Corey, and Leroy Hood
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Male ,Time Factors ,T-Lymphocytes ,Molecular Sequence Data ,Context (language use) ,HIV Infections ,Biology ,CD8-Positive T-Lymphocytes ,HIV Antibodies ,HIV Envelope Protein gp160 ,Immune system ,Risk-Taking ,Immunity ,HIV Seropositivity ,medicine ,Humans ,Amino Acid Sequence ,Homosexuality, Male ,Protein Precursors ,Smallpox vaccine ,Neutralizing antibody ,Immunodeficiency ,AIDS Vaccines ,B-Lymphocytes ,Vaccines, Synthetic ,Multidisciplinary ,Gene Products, env ,medicine.disease ,Virology ,Vaccination ,Immunization ,Immunology ,biology.protein ,HIV-1 ,Smallpox Vaccine ,Research Article - Abstract
With efforts underway to develop a preventive human immunodeficiency virus type 1 (HIV-1) vaccine, it remains unclear which immune responses are sufficient to protect against infection and whether prior HIV-1 immunity can alter the subsequent course of HIV-1 infection. We investigated these issues in the context of a volunteer who received six HIV-1LAI envelope immunizations and 10 weeks thereafter acquired HIV-1 infection through a high-risk sexual exposure. In contrast to nonvaccinated acutely infected individuals, anamnestic HIV-1-specific B- and T-cell responses appeared within 3 weeks in this individual, and neutralizing antibody preceded CD8+ cytotoxic responses. Despite an asymptomatic course and an initial low level of detectable infectious virus, a progressive CD4+ cell decline and dysfunction occurred within 2 years. Although vaccination elicited immunity to HIV-1 envelope, which was recalled upon HIV-1 exposure, it was insufficient to prevent infection and subsequent immunodeficiency.
- Published
- 1996
49. Frequency and polymorphism of simple sequence repeats in a contiguous 685-kb DNA sequence containing the human T-cell receptor beta-chain gene complex
- Author
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Patrick Concannon, Leroy Hood, Patrick Charmley, and Lee Rowen
- Subjects
Linkage disequilibrium ,Receptors, Antigen, T-Cell, alpha-beta ,Molecular Sequence Data ,Restriction Mapping ,Gene mutation ,Biology ,DNA, Satellite ,Polymerase Chain Reaction ,DNA sequencing ,Tandem repeat ,Genetics ,Direct repeat ,Humans ,Alleles ,DNA Primers ,Repetitive Sequences, Nucleic Acid ,Polymorphism, Genetic ,Contig ,Base Sequence ,Chromosome Mapping ,DNA ,Molecular biology ,Genetic marker ,Microsatellite ,Chromosomes, Human, Pair 7 - Abstract
The human T-cell receptor beta-chain (TCRB) gene complex spans 575 kb in chromosome region 7q35 and has been the subject of a large-scale DNA sequencing effort. A contiguous 685-kb DNA sequence from this region was searched by computer analysis for the occurrence of simple sequence repeats (microsatellites) with core sequence lengths of 2-5 nucleotides. Twenty-nine such microsatellites of repeat number n > or = 9 were found, with the majority being dinucleotide repeats. By PCR analysis, 19 were found to be polymorphic in repeat number, thus averaging one per 36 kb. These polymorphic di-, tri-, and tetranucleotide repeats had between 3 and 15 differently sized alleles each. The potential usefulness of these TCRB microsatellites for detecting disease susceptibility alleles was examined by measuring the linkage disequilibrium between these markers and flanking biallelic mutations. All but 4 microsatellites (79%) demonstrated significant linkage disequilibrium (P < 0.0001). This present study highlights the utility and potential outcomes of large-scale DNA sequencing for the identification of polymorphic simple sequence repeats.
- Published
- 1995
50. Human and mouse T-cell receptor loci: genomics, evolution, diversity, and serendipity
- Author
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Leroy Hood, Lee Rowen, and Ben F. Koop
- Subjects
Serendipity ,General Neuroscience ,media_common.quotation_subject ,T-cell receptor ,Receptors, Antigen, T-Cell ,Genetic Variation ,Genomics ,Biology ,Biological Evolution ,General Biochemistry, Genetics and Molecular Biology ,Mice ,History and Philosophy of Science ,Evolutionary biology ,Animals ,Humans ,Diversity (politics) ,media_common - Published
- 1995
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