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2,190 results on '"Wellcome"'

1. Population genomics of post-glacial western Eurasia

Author: Lundbeck Foundation, Novo Nordisk Foundation, Wellcome Trust, Carlsberg Foundation, Danish National Research Foundation, University of Copenhagen, Ferring Pharmaceuticals, Swedish Foundation for Humanities and Social Sciences, Villum Fonden, Independent Research Fund Denmark, Hanne and Torkel Weis-Fogh Fund, Wellcome, Swiss National Science Foundation, European Research Council, Aarhus University Research Foundation, Ministry of Education and Science (Kazakhstan), Ministerio de Economía y Competitividad (España), Ministero dell'Istruzione, dell'Università e della Ricerca, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat Valenciana, Nomis Foundation, European Commission, Ministry of Science and Higher Education of the Russian Federation, Ministry of Education, Science, Culture and Sports of the Republic of Armenia, National Institute of General Medical Sciences (US), Sikora, Martin [0000-0003-2818-8319], Lalueza-Fox, Carles [0000-0002-1730-5914], Allentoft, Morten, Sikora, Martin, Refoyo-Martínez, Alba, Irving-Pease, Evan K., Fischer, Anders, Barrie, William, Ingason, Andrés, Stenderup, Jesper, Sjögren, Karl-Göran, Pearson, Alice, Mota, Bárbara Sousa da, Schulz Paulsson, Bettina, Halgren, Alma, Macleod, Ruairidh, Jørkov, Marie Louise S., Demeter, Fabrice, Sørensen, Lasse, Nielsen, Poul Otto, Henriksen, Rasmus A., Vimala, Tharsika, McColl, Hugh, Margaryan, Ashot, Ilardo, Melissa, Vaughn, Andrew, Fischer Mortensen, Morten, Nielsen, Anne Birgitte, Ulfeldt Hede, Mikkel, Johannsen, Niels Nørkjær, Rasmussen, Peter, Vinner, Lasse, Renaud, Gabriel, Stern, Aaron, Trolle Jensen, Theis Zetner, Scorrano, Gabriele, Schroeder, Hannes, Lysdahl, Per, Ramsøe, Abigail Daisy, Skorobogatov, Andrei, Schork, Andrew Joseph, Rosengren, Anders, Ruter, Anthony, Outram, Alan, Timoshenko, Aleksey A., Buzhilova, Alexandra, Coppa, Alfredo, Zubova, Alisa, Silva, Ana María, Hansen, Anders J., Gromov, Andrey, Logvin, Andrey, Gotfredsen, Anne Birgitte, Nielsen, Bjarne Henning, González-Rabanal, Borja, Lalueza-Fox, Carles, McKenzie, Catriona J., Gaunitz, Charleen, Blasco, Concepción, Liesau, Corina, Martínez-Labarga, Cristina, Pozdnyakov, Dmitri V., Cuenca-Solana, David, Lordkipanidze, David O., En’shin, Dmitri, Salazar García, Domingo Carlos, Price, T. Douglas, Borić, Dušan, Kostyleva, Elena, Veselovskaya, Elizaveta V., Usmanova, Emma R., Cappellini, Enrico, Petersen, Erik Brinch, Kannegaard, Esben, Radina, Francesca, Yediay, Fulya Eylem, Duday, Henri, Gutiérrez-Zugasti, Igor, Merts, Ilya, Potekhina, Inna, Shevnina, Irina, Altinkaya, Isin, Guilaine, Jean, Hansen, Jesper, Aura Tortosa, Joan Emili, Zilhão, João, Vega, Jorge, Pedersen, Kristoffer Buck, Tunia, Krzysztof, Zhao, Lei, Mylnikova, Liudmila N., Larsson, Lars, Metz, Laure, Yepiskoposyan, Levon, Pedersen, Lisbeth, Sarti, Lucia, Orlando, Ludovic, Slimak, Ludovic, Klassen, Lutz, Blank, Malou, González-Morales, Manuel, Silvestrini, Mara, Vretemark, Maria, Nesterova, Marina S., Rykun, Marina, Rolfo, Mario Federico, Szmyt, Marzena, Przybyła, Marcin, Calattini, Mauro, Sablin, Mikhail, Dobisíková, Miluše, Meldgaard, Morten, Johansen, Morten, Berezina, Natalia, Card, Nick, Saveliev, Nikolai A., Poshekhonova, Olga, Rickards, Olga, Lozovskaya, Olga V., Gábor, Olivér, Uldum, Otto Christian, Aurino, Paola, Kosintsev, Pavel, Courtaud, Patrice, Ríos, Patricia, Mortensen, Peder, Lotz, Per, Persson, Per, Bangsgaard, Pernille, Barros Damgaard, Peter de, Petersen, Peter Vang, Prieto Martínez, Pilar, Włodarczak, Piotr, Smolyaninov, Roman V., Maring, Rikke, Menduiña, Roberto, Badalyan, Ruben, Iversen, Rune, Turin, Ruslan, Vasilyev, Sergey, Wåhlin, Sidsel, Borutskaya, Svetlana, Skochina, Svetlana, Sørensen, Søren Anker, Andersen, Søren H., Jørgensen, Thomas, Serikov, Yuri B., Molodin, Vyacheslav I., Smrcka, Vaclav, Merts, Victor, Appadurai, Vivek, Moiseyev, Vyacheslav, Magnusson, Yvonne, Kjær, Kurt H., Lynnerup, Niels, Lawson, Daniel J., Sudmant, Peter H., Rasmussen, Simon, Korneliussen, Thorfinn Sand, Durbin, Richard, Nielsen, Rasmus, Delaneau, Olivier, Werge, Thomas, Racimo, Fernando, Kristiansen, Kristian, Willerslev, Eske, Lundbeck Foundation, Novo Nordisk Foundation, Wellcome Trust, Carlsberg Foundation, Danish National Research Foundation, University of Copenhagen, Ferring Pharmaceuticals, Swedish Foundation for Humanities and Social Sciences, Villum Fonden, Independent Research Fund Denmark, Hanne and Torkel Weis-Fogh Fund, Wellcome, Swiss National Science Foundation, European Research Council, Aarhus University Research Foundation, Ministry of Education and Science (Kazakhstan), Ministerio de Economía y Competitividad (España), Ministero dell'Istruzione, dell'Università e della Ricerca, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat Valenciana, Nomis Foundation, European Commission, Ministry of Science and Higher Education of the Russian Federation, Ministry of Education, Science, Culture and Sports of the Republic of Armenia, National Institute of General Medical Sciences (US), Sikora, Martin [0000-0003-2818-8319], Lalueza-Fox, Carles [0000-0002-1730-5914], Allentoft, Morten, Sikora, Martin, Refoyo-Martínez, Alba, Irving-Pease, Evan K., Fischer, Anders, Barrie, William, Ingason, Andrés, Stenderup, Jesper, Sjögren, Karl-Göran, Pearson, Alice, Mota, Bárbara Sousa da, Schulz Paulsson, Bettina, Halgren, Alma, Macleod, Ruairidh, Jørkov, Marie Louise S., Demeter, Fabrice, Sørensen, Lasse, Nielsen, Poul Otto, Henriksen, Rasmus A., Vimala, Tharsika, McColl, Hugh, Margaryan, Ashot, Ilardo, Melissa, Vaughn, Andrew, Fischer Mortensen, Morten, Nielsen, Anne Birgitte, Ulfeldt Hede, Mikkel, Johannsen, Niels Nørkjær, Rasmussen, Peter, Vinner, Lasse, Renaud, Gabriel, Stern, Aaron, Trolle Jensen, Theis Zetner, Scorrano, Gabriele, Schroeder, Hannes, Lysdahl, Per, Ramsøe, Abigail Daisy, Skorobogatov, Andrei, Schork, Andrew Joseph, Rosengren, Anders, Ruter, Anthony, Outram, Alan, Timoshenko, Aleksey A., Buzhilova, Alexandra, Coppa, Alfredo, Zubova, Alisa, Silva, Ana María, Hansen, Anders J., Gromov, Andrey, Logvin, Andrey, Gotfredsen, Anne Birgitte, Nielsen, Bjarne Henning, González-Rabanal, Borja, Lalueza-Fox, Carles, McKenzie, Catriona J., Gaunitz, Charleen, Blasco, Concepción, Liesau, Corina, Martínez-Labarga, Cristina, Pozdnyakov, Dmitri V., Cuenca-Solana, David, Lordkipanidze, David O., En’shin, Dmitri, Salazar García, Domingo Carlos, Price, T. Douglas, Borić, Dušan, Kostyleva, Elena, Veselovskaya, Elizaveta V., Usmanova, Emma R., Cappellini, Enrico, Petersen, Erik Brinch, Kannegaard, Esben, Radina, Francesca, Yediay, Fulya Eylem, Duday, Henri, Gutiérrez-Zugasti, Igor, Merts, Ilya, Potekhina, Inna, Shevnina, Irina, Altinkaya, Isin, Guilaine, Jean, Hansen, Jesper, Aura Tortosa, Joan Emili, Zilhão, João, Vega, Jorge, Pedersen, Kristoffer Buck, Tunia, Krzysztof, Zhao, Lei, Mylnikova, Liudmila N., Larsson, Lars, Metz, Laure, Yepiskoposyan, Levon, Pedersen, Lisbeth, Sarti, Lucia, Orlando, Ludovic, Slimak, Ludovic, Klassen, Lutz, Blank, Malou, González-Morales, Manuel, Silvestrini, Mara, Vretemark, Maria, Nesterova, Marina S., Rykun, Marina, Rolfo, Mario Federico, Szmyt, Marzena, Przybyła, Marcin, Calattini, Mauro, Sablin, Mikhail, Dobisíková, Miluše, Meldgaard, Morten, Johansen, Morten, Berezina, Natalia, Card, Nick, Saveliev, Nikolai A., Poshekhonova, Olga, Rickards, Olga, Lozovskaya, Olga V., Gábor, Olivér, Uldum, Otto Christian, Aurino, Paola, Kosintsev, Pavel, Courtaud, Patrice, Ríos, Patricia, Mortensen, Peder, Lotz, Per, Persson, Per, Bangsgaard, Pernille, Barros Damgaard, Peter de, Petersen, Peter Vang, Prieto Martínez, Pilar, Włodarczak, Piotr, Smolyaninov, Roman V., Maring, Rikke, Menduiña, Roberto, Badalyan, Ruben, Iversen, Rune, Turin, Ruslan, Vasilyev, Sergey, Wåhlin, Sidsel, Borutskaya, Svetlana, Skochina, Svetlana, Sørensen, Søren Anker, Andersen, Søren H., Jørgensen, Thomas, Serikov, Yuri B., Molodin, Vyacheslav I., Smrcka, Vaclav, Merts, Victor, Appadurai, Vivek, Moiseyev, Vyacheslav, Magnusson, Yvonne, Kjær, Kurt H., Lynnerup, Niels, Lawson, Daniel J., Sudmant, Peter H., Rasmussen, Simon, Korneliussen, Thorfinn Sand, Durbin, Richard, Nielsen, Rasmus, Delaneau, Olivier, Werge, Thomas, Racimo, Fernando, Kristiansen, Kristian, and Willerslev, Eske
Abstract: Western Eurasia witnessed several large-scale human migrations during the Holocene1,2,3,4,5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
Published: 2024

2. Structural and functional insights into the delivery of a bacterial Rhs pore-forming toxin to the membrane

Author: Wellcome Trust, Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Fundación Biofísica Bizkaia, Ministerio de Ciencia e Innovación (España), European Commission, Agencia Estatal de Investigación (España), Eusko Jaurlaritza, Ikerbasque Basque Foundation for Science, Ministerio de Ciencia, Innovación y Universidades (España), Canadian HIV Trials Network Canadian Institutes of Health Research, Universidad Jaime I, Generalitat Valenciana, Burroughs Wellcome Fund, González-Magaña, Amaia [0000-0002-6007-8390], Tascón, Igor [0000-0003-2526-6238], Altuna, Jon [0000-0002-4993-7991], Albesa-Jové, David [0000-0003-2904-8203], González-Magaña, Amaia, Tascón, Igor, Altuna, Jon, Queralt, María, Colautti, Jake, Velázquez, Carmen, Zabala, Maialen, Rojas-Palomino, Jessica, Cárdenas, Marité, Alcaraz, Antonio, Whitney, John C., Ubarretxena, Iban, Albesa-Jové, David, Wellcome Trust, Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Fundación Biofísica Bizkaia, Ministerio de Ciencia e Innovación (España), European Commission, Agencia Estatal de Investigación (España), Eusko Jaurlaritza, Ikerbasque Basque Foundation for Science, Ministerio de Ciencia, Innovación y Universidades (España), Canadian HIV Trials Network Canadian Institutes of Health Research, Universidad Jaime I, Generalitat Valenciana, Burroughs Wellcome Fund, González-Magaña, Amaia [0000-0002-6007-8390], Tascón, Igor [0000-0003-2526-6238], Altuna, Jon [0000-0002-4993-7991], Albesa-Jové, David [0000-0003-2904-8203], González-Magaña, Amaia, Tascón, Igor, Altuna, Jon, Queralt, María, Colautti, Jake, Velázquez, Carmen, Zabala, Maialen, Rojas-Palomino, Jessica, Cárdenas, Marité, Alcaraz, Antonio, Whitney, John C., Ubarretxena, Iban, and Albesa-Jové, David
Abstract: Bacterial competition is a significant driver of toxin polymorphism, which allows continual compensatory evolution between toxins and the resistance developed to overcome their activity. Bacterial Rearrangement hot spot (Rhs) proteins represent a widespread example of toxin polymorphism. Here, we present the 2.45 Å cryo-electron microscopy structure of Tse5, an Rhs protein central to Pseudomonas aeruginosa type VI secretion system-mediated bacterial competition. This structural insight, coupled with an extensive array of biophysical and genetic investigations, unravels the multifaceted functional mechanisms of Tse5. The data suggest that interfacial Tse5-membrane binding delivers its encapsulated pore-forming toxin fragment to the target bacterial membrane, where it assembles pores that cause cell depolarisation and, ultimately, bacterial death.
Published: 2023

3. Cyclic di-AMP traps proton-coupled K+ transporters of the KUP family in an inward-occluded conformation

Author: Projekt DEAL, German Research Foundation, Wellcome, Biotechnology and Biological Sciences Research Council (UK), Engineering and Physical Sciences Research Council (UK), Fuss, Michael F. [0000-0002-8726-3131], Hellmich, Yvonne [0000-0002-5426-1551], Tascón, Igor [0000-0003-2526-6238], Stansfeld, Phillip J. [0000-0001-8800-7669], Vonck, Janet [0000-0001-5659-8863], Hänelt, Inga [0000-0003-1495-3163], Fuss, Michael F., Wieferig, Jan-Philip, Corey, Robin A., Hellmich, Yvonne, Tascón, Igor, Sousa, Joana S., Stansfeld, Phillip J., Vonck, Janet, Hänelt, Inga, Projekt DEAL, German Research Foundation, Wellcome, Biotechnology and Biological Sciences Research Council (UK), Engineering and Physical Sciences Research Council (UK), Fuss, Michael F. [0000-0002-8726-3131], Hellmich, Yvonne [0000-0002-5426-1551], Tascón, Igor [0000-0003-2526-6238], Stansfeld, Phillip J. [0000-0001-8800-7669], Vonck, Janet [0000-0001-5659-8863], Hänelt, Inga [0000-0003-1495-3163], Fuss, Michael F., Wieferig, Jan-Philip, Corey, Robin A., Hellmich, Yvonne, Tascón, Igor, Sousa, Joana S., Stansfeld, Phillip J., Vonck, Janet, and Hänelt, Inga
Abstract: Cyclic di-AMP is the only known essential second messenger in bacteria and archaea, regulating different proteins indispensable for numerous physiological processes. In particular, it controls various potassium and osmolyte transporters involved in osmoregulation. In Bacillus subtilis, the K+/H+ symporter KimA of the KUP family is inactivated by c-di-AMP. KimA sustains survival at potassium limitation at low external pH by mediating potassium ion uptake. However, at elevated intracellular K+ concentrations, further K+ accumulation would be toxic. In this study, we reveal the molecular basis of how c-di-AMP binding inhibits KimA. We report cryo-EM structures of KimA with bound c-di-AMP in detergent solution and reconstituted in amphipols. By combining structural data with functional assays and molecular dynamics simulations we reveal how c-di-AMP modulates transport. We show that an intracellular loop in the transmembrane domain interacts with c-di-AMP bound to the adjacent cytosolic domain. This reduces the mobility of transmembrane helices at the cytosolic side of the K+ binding site and therefore traps KimA in an inward-occluded conformation.
Published: 2023

4. Genetic insights into human cortical organization and development through genome-wide analyses of 2,347 neuroimaging phenotypes

Author: Wellcome Trust, UK Research and Innovation, National Institute for Health Research (UK), Cambridge Biomedical Research Centre, Autism Research Trust, Simons Foundation Autism Research Initiative, Templeton World Charity Foundation, National Institute of Mental Health (US), Junta de Andalucía, Max Planck Society, Helmholtz Association, Canada First Research Excellence Fund, Warrier, Varun, Stauffer, Eva-María, Huang, Qin Qin, Wigdor, Emilie M., Slob, Eric A. W., Seidlitz, Jakob, Ronan, Lisa, Valk, Sofie L., Mallard, Travis T., Grotzinger, Andrew D., Romero García, Rafael, Baron-Cohen, Simon, Geschwind, Daniel H., Lancaster, Madeline A., Murray, Graham K., Gandal, Michael J., Alexander-Bloch, Aaron, Won, Hyejung, Martin, Hilary C., Bullmore, Edward T., Bethlehem, Richard A. I., Wellcome Trust, UK Research and Innovation, National Institute for Health Research (UK), Cambridge Biomedical Research Centre, Autism Research Trust, Simons Foundation Autism Research Initiative, Templeton World Charity Foundation, National Institute of Mental Health (US), Junta de Andalucía, Max Planck Society, Helmholtz Association, Canada First Research Excellence Fund, Warrier, Varun, Stauffer, Eva-María, Huang, Qin Qin, Wigdor, Emilie M., Slob, Eric A. W., Seidlitz, Jakob, Ronan, Lisa, Valk, Sofie L., Mallard, Travis T., Grotzinger, Andrew D., Romero García, Rafael, Baron-Cohen, Simon, Geschwind, Daniel H., Lancaster, Madeline A., Murray, Graham K., Gandal, Michael J., Alexander-Bloch, Aaron, Won, Hyejung, Martin, Hilary C., Bullmore, Edward T., and Bethlehem, Richard A. I.
Abstract: Our understanding of the genetics of the human cerebral cortex is limited both in terms of the diversity and the anatomical granularity of brain structural phenotypes. Here we conducted a genome-wide association meta-analysis of 13 structural and diffusion magnetic resonance imaging-derived cortical phenotypes, measured globally and at 180 bilaterally averaged regions in 36,663 individuals and identified 4,349 experiment-wide significant loci. These phenotypes include cortical thickness, surface area, gray matter volume, measures of folding, neurite density and water diffusion. We identified four genetic latent structures and causal relationships between surface area and some measures of cortical folding. These latent structures partly relate to different underlying gene expression trajectories during development and are enriched for different cell types. We also identified differential enrichment for neurodevelopmental and constrained genes and demonstrate that common genetic variants associated with cortical expansion are associated with cephalic disorders. Finally, we identified complex interphenotype and inter-regional genetic relationships among the 13 phenotypes, reflecting the developmental differences among them. Together, these analyses identify distinct genetic organizational principles of the cortex and their correlates with neurodevelopment.
Published: 2023

5. Release of Histone H3K4-reading transcription factors from chromosomes in mitosis is independent of adjacent H3 phosphorylation

Author: Wellcome Trust, Royal Society (UK), Bernice Barbour Foundation, Patterson Foundation, Harris, Rebecca J. [0000-0002-7884-9392], Higgins, Jonathan M. G. [0000-0001-6622-8268], Harris, Rebecca J., Heer, Maninder, Levasseur, Mark D., Cartwright, Tyrell N., Weston, Bethany, Mitchell, Jennifer L., Coxhead, Jonathan M., Gaughan, Luke, Prendergast, Lisa, Rico, Daniel, Higgins, Jonathan M. G., Wellcome Trust, Royal Society (UK), Bernice Barbour Foundation, Patterson Foundation, Harris, Rebecca J. [0000-0002-7884-9392], Higgins, Jonathan M. G. [0000-0001-6622-8268], Harris, Rebecca J., Heer, Maninder, Levasseur, Mark D., Cartwright, Tyrell N., Weston, Bethany, Mitchell, Jennifer L., Coxhead, Jonathan M., Gaughan, Luke, Prendergast, Lisa, Rico, Daniel, and Higgins, Jonathan M. G.
Abstract: Histone modifications influence the recruitment of reader proteins to chromosomes to regulate events including transcription and cell division. The idea of a histone code, where combinations of modifications specify unique downstream functions, is widely accepted and can be demonstrated in vitro. For example, on synthetic peptides, phosphorylation of Histone H3 at threonine-3 (H3T3ph) prevents the binding of reader proteins that recognize trimethylation of the adjacent lysine-4 (H3K4me3), including the TAF3 component of TFIID. To study these combinatorial effects in cells, we analyzed the genome-wide distribution of H3T3ph and H3K4me2/3 during mitosis. We find that H3T3ph anti-correlates with adjacent H3K4me2/3 in cells, and that the PHD domain of TAF3 can bind H3K4me2/3 in isolated mitotic chromatin despite the presence of H3T3ph. Unlike in vitro, H3K4 readers are still displaced from chromosomes in mitosis in Haspin-depleted cells lacking H3T3ph. H3T3ph is therefore unlikely to be responsible for transcriptional downregulation during cell division.
Published: 2023

6. Histone post-translational modifications — cause and consequence of genome function

Author: German Research Foundation, Helmholtz Association, Cancer Research UK, Wellcome Trust, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación la Caixa, European Commission, Millán-Zambrano, Gonzalo, Burton, Adam, Bannister, Andrew J., Schneider, Robert, German Research Foundation, Helmholtz Association, Cancer Research UK, Wellcome Trust, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación la Caixa, European Commission, Millán-Zambrano, Gonzalo, Burton, Adam, Bannister, Andrew J., and Schneider, Robert
Abstract: Much has been learned since the early 1960s about histone post-translational modifications (PTMs) and how they affect DNA-templated processes at the molecular level. This understanding has been bolstered in the past decade by the identification of new types of histone PTM, the advent of new genome-wide mapping approaches and methods to deposit or remove PTMs in a locally and temporally controlled manner. Now, with the availability of vast amounts of data across various biological systems, the functional role of PTMs in important processes (such as transcription, recombination, replication, DNA repair and the modulation of genomic architecture) is slowly emerging. This Review explores the contribution of histone PTMs to the regulation of genome function by discussing when these modifications play a causative (or instructive) role in DNA-templated processes and when they are deposited as a consequence of such processes, to reinforce and record the event. Important advances in the field showing that histone PTMs can exert both direct and indirect effects on genome function are also presented.
Published: 2022

7. ISARIC-COVID-19 dataset: A Prospective, Standardized, Global Dataset of Patients Hospitalized with COVID-19

Author: Bill & Melinda Gates Foundation, Minderoo Foundation, Commonwealth Foundation, Wellcome Trust, National Institute for Health Research (UK), Medical Research Council (UK), University of Liverpool, Imperial College London, Canadian Institutes of Health Research, Sunnybrook Research Institute, Health Research Board (Ireland), European Commission, All India Institute of Medical Sciences, University of Cape Town, University of Oxford, Research Council of Norway, Innovative Medicines Initiative, Governo Italiano, University of Queensland, Australian Research Council, Prince Charles Hospital Foundation, Instituto de Salud Carlos III, Institut National de la Santé et de la Recherche Médicale (France), Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), ISARIC Clinical Characterization Group, García-Gallo, Esteban, Merson, Laura, Kennon, Kalynn, Kelly, Sadie, Citarella, Barbara Wanjiru, Fryer, Daniel Vidali, Shrapnel, Sally, Lee, James, Duque, Sara, Fuentes, Yuli V., Balan, Valeria, Smith, Sue, Wei, Jia, Gonçalves, Bronner P., Russell, Clark D., Sigfrid, Louise, Dagens, Andrew, Olliaro, Piero L., Baruch, Joaquín, Kartsonaki, Christiana, Dunning, Jake, Rojek, Amanda, Rashan, Aasiyah, Beane, Abi, Murthy, Srinivas, Reyes, Luis Felipe, Bill & Melinda Gates Foundation, Minderoo Foundation, Commonwealth Foundation, Wellcome Trust, National Institute for Health Research (UK), Medical Research Council (UK), University of Liverpool, Imperial College London, Canadian Institutes of Health Research, Sunnybrook Research Institute, Health Research Board (Ireland), European Commission, All India Institute of Medical Sciences, University of Cape Town, University of Oxford, Research Council of Norway, Innovative Medicines Initiative, Governo Italiano, University of Queensland, Australian Research Council, Prince Charles Hospital Foundation, Instituto de Salud Carlos III, Institut National de la Santé et de la Recherche Médicale (France), Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), ISARIC Clinical Characterization Group, García-Gallo, Esteban, Merson, Laura, Kennon, Kalynn, Kelly, Sadie, Citarella, Barbara Wanjiru, Fryer, Daniel Vidali, Shrapnel, Sally, Lee, James, Duque, Sara, Fuentes, Yuli V., Balan, Valeria, Smith, Sue, Wei, Jia, Gonçalves, Bronner P., Russell, Clark D., Sigfrid, Louise, Dagens, Andrew, Olliaro, Piero L., Baruch, Joaquín, Kartsonaki, Christiana, Dunning, Jake, Rojek, Amanda, Rashan, Aasiyah, Beane, Abi, Murthy, Srinivas, and Reyes, Luis Felipe
Abstract: The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 dataset is one of the largest international databases of prospectively collected clinical data on people hospitalized with COVID-19. This dataset was compiled during the COVID-19 pandemic by a network of hospitals that collect data using the ISARIC-World Health Organization Clinical Characterization Protocol and data tools. The database includes data from more than 705,000 patients, collected in more than 60 countries and 1,500 centres worldwide. Patient data are available from acute hospital admissions with COVID-19 and outpatient follow-ups. The data include signs and symptoms, pre-existing comorbidities, vital signs, chronic and acute treatments, complications, dates of hospitalization and discharge, mortality, viral strains, vaccination status, and other data. Here, we present the dataset characteristics, explain its architecture and how to gain access, and provide tools to facilitate its use.
Published: 2022

8. Characterisation of a nucleo-adhesome

Author: Cancer Research UK, Wellcome Trust, Byron, Adam, Griffith, Billie G. C., Herrero, Ana, Loftus, Alexander E. P., Koeleman, Emma S., Kogerman, Linda, Dawson, John C., McGivern, Niamh, Culley, Jayne, Grimes, Graeme R., Serrels, Bryan, Kriegsheim, Alexvon, Brunton, Valerie G., Frame, Margaret C., Cancer Research UK, Wellcome Trust, Byron, Adam, Griffith, Billie G. C., Herrero, Ana, Loftus, Alexander E. P., Koeleman, Emma S., Kogerman, Linda, Dawson, John C., McGivern, Niamh, Culley, Jayne, Grimes, Graeme R., Serrels, Bryan, Kriegsheim, Alexvon, Brunton, Valerie G., and Frame, Margaret C.
Abstract: In addition to central functions in cell adhesion signalling, integrin-associated proteins have wider roles at sites distal to adhesion receptors. In experimentally defined adhesomes, we noticed that there is clear enrichment of proteins that localise to the nucleus, and conversely, we now report that nuclear proteomes contain a class of adhesome components that localise to the nucleus. We here define a nucleo-adhesome, providing experimental evidence for a remarkable scale of nuclear localisation of adhesion proteins, establishing a framework for interrogating nuclear adhesion protein functions. Adding to nuclear FAK’s known roles in regulating transcription, we now show that nuclear FAK regulates expression of many adhesion-related proteins that localise to the nucleus and that nuclear FAK binds to the adhesome component and nuclear protein Hic-5. FAK and Hic-5 work together in the nucleus, co-regulating a subset of genes transcriptionally. We demonstrate the principle that there are subcomplexes of nuclear adhesion proteins that cooperate to control transcription.
Published: 2022

9. MYC sensitises cells to apoptosis by driving energetic demand

Author: Wellcome Trust, Cancer Research UK, Barts Charity, Medical Research Council (UK), Edwards-Hicks, Joy, Su, Huizhong, Mangolini, Maurizio, Yoneten, Kubra K., Wills, Jimi, Rodriguez-Blanco, Giovanny, Young, Christine, Cho, Kevin, Barker, Heather, Muir, Morwenna, Guerrieri, Ania Naila, Li, Xue-Feng, White, Rachel, Manasterski, Piotr, Mandrou, Elena, Wills, Karen, Chen, Jingyu, Abraham, Emily, Sateri, Kianoosh, Qian, Bin-Zhi, Bankhead, Peter, Arends, Mark, Gammoh, Noor, Kriegsheim, Alexvon, Patti, Gary J., Sim, Andrew H., Acosta, Juan C., Brunton, Valerie G., Kranc, Kamil R., Christophorou, Maria, Pearce, Erika L., Ringshausen, Ingo, Finch, Andrew J., Wellcome Trust, Cancer Research UK, Barts Charity, Medical Research Council (UK), Edwards-Hicks, Joy, Su, Huizhong, Mangolini, Maurizio, Yoneten, Kubra K., Wills, Jimi, Rodriguez-Blanco, Giovanny, Young, Christine, Cho, Kevin, Barker, Heather, Muir, Morwenna, Guerrieri, Ania Naila, Li, Xue-Feng, White, Rachel, Manasterski, Piotr, Mandrou, Elena, Wills, Karen, Chen, Jingyu, Abraham, Emily, Sateri, Kianoosh, Qian, Bin-Zhi, Bankhead, Peter, Arends, Mark, Gammoh, Noor, Kriegsheim, Alexvon, Patti, Gary J., Sim, Andrew H., Acosta, Juan C., Brunton, Valerie G., Kranc, Kamil R., Christophorou, Maria, Pearce, Erika L., Ringshausen, Ingo, and Finch, Andrew J.
Abstract: The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.
Published: 2022

10. Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses.

Author: Generalitat de Catalunya, Fundación Josep Carreras, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Jeffrey Modell Foundation, Chan Zuckerberg Initiative, Wellcome Sanger Institute, European Commission, Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Rodríguez-Ubreva, Javier, Arutyunyan, Anna, Bonder, Marc J., Pino-Molina, Lucía del, Clark, Stephen J., Calle-Fabregat, Carlos de la, García-Alonso, Luz, Handfield, Louis-François, Ciudad, Laura, Andrés-León, Eduardo, Krueger, Felix, Català-Moll, Francesc, Rodríguez-Cortez, Virginia C., Polanski, Krzysztof, Mamanova, Lira, Dongen, Stijn van, Kiselev, Vladimir Yu, Martínez-Saavedra, María T., Heyn, Holger, Martin, Javier, Warnatz, Klaus, López-Granados, Eduardo, Rodriguez-Gallego, Carlos, Stegle, Oliver, Kelsey, Gavin, Vento-Tormo, Roser, Ballestar, Esteban, Generalitat de Catalunya, Fundación Josep Carreras, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Jeffrey Modell Foundation, Chan Zuckerberg Initiative, Wellcome Sanger Institute, European Commission, Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Rodríguez-Ubreva, Javier, Arutyunyan, Anna, Bonder, Marc J., Pino-Molina, Lucía del, Clark, Stephen J., Calle-Fabregat, Carlos de la, García-Alonso, Luz, Handfield, Louis-François, Ciudad, Laura, Andrés-León, Eduardo, Krueger, Felix, Català-Moll, Francesc, Rodríguez-Cortez, Virginia C., Polanski, Krzysztof, Mamanova, Lira, Dongen, Stijn van, Kiselev, Vladimir Yu, Martínez-Saavedra, María T., Heyn, Holger, Martin, Javier, Warnatz, Klaus, López-Granados, Eduardo, Rodriguez-Gallego, Carlos, Stegle, Oliver, Kelsey, Gavin, Vento-Tormo, Roser, and Ballestar, Esteban
Abstract: Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients.
Published: 2022

11. A CDK-regulated chromatin segregase promoting chromosome replication

Author: German Research Foundation, Wellcome Trust, Biotechnology and Biological Sciences Research Council (UK), Ministerio de Economía y Competitividad (España), Asociación Española Contra el Cáncer, Chacin, Erika, Bansal, Priyanka, Reusswig, Karl-Uwe, Diaz-Santin, Luis M., Ortega, Pedro, Vizjak, Petra, Gómez-González, Belén, Müller-Planitz, Felix, Aguilera, Andrés, Pfander, Boris, Cheung, Alan C. M., Kurat, Christoph F., German Research Foundation, Wellcome Trust, Biotechnology and Biological Sciences Research Council (UK), Ministerio de Economía y Competitividad (España), Asociación Española Contra el Cáncer, Chacin, Erika, Bansal, Priyanka, Reusswig, Karl-Uwe, Diaz-Santin, Luis M., Ortega, Pedro, Vizjak, Petra, Gómez-González, Belén, Müller-Planitz, Felix, Aguilera, Andrés, Pfander, Boris, Cheung, Alan C. M., and Kurat, Christoph F.
Abstract: The replication of chromosomes during S phase is critical for cellular and organismal function. Replicative stress can result in genome instability, which is a major driver of cancer. Yet how chromatin is made accessible during eukaryotic DNA synthesis is poorly understood. Here, we report the characterization of a chromatin remodeling enzyme—Yta7—entirely distinct from classical SNF2-ATPase family remodelers. Yta7 is a AAA -ATPase that assembles into ~1 MDa hexameric complexes capable of segregating histones from DNA. The Yta7 chromatin segregase promotes chromosome replication both in vivo and in vitro. Biochemical reconstitution experiments using purified proteins revealed that the enzymatic activity of Yta7 is regulated by S phase-forms of Cyclin-Dependent Kinase (S-CDK). S-CDK phosphorylation stimulates ATP hydrolysis by Yta7, promoting nucleosome disassembly and chromatin replication. Our results present a mechanism for how cells orchestrate chromatin dynamics in co-ordination with the cell cycle machinery to promote genome duplication during S phase.
Published: 2021

12. Spread of a SARS-CoV-2 variant through Europe in the summer of 2020

Author: Swiss National Science Foundation, European Commission, University of Basel, ETH Zurich, National Institute of General Medical Sciences (US), National Institute of Allergy and Infectious Diseases (US), Burroughs Wellcome Fund, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España), European Research Council, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Howard Hughes Medical Institute, Hodcroft, Emma B. [0000-0002-0078-2212], Zuber, Moira [0000-0002-4275-8739], Nadeau, Sarah [0000-0003-1008-8918], Vaughan, Timothy G. [0000-0001-6220-2239], Crawford, Katharine H. D. [0000-0002-6223-4019], Althaus, Christian L. [0000-0002-5230-6760], Reichmuth, Martina L. [0000-0001-9345-851X], Bowen, John E. [0000-0003-3590-9727], Walls, Alexandra C. [0000-0002-9636-8330], Corti, Davide [0000-0002-5797-1364], Bloom, Jesse D. [0000-0003-1267-3408], Veesler, David [0000-0002-6019-8675], Mateo, David [0000-0002-1590-4163], Hernando de Castro, Alberto [0000-0003-1180-1068], Comas, Iñaki [0000-0001-5504-9408], González-Candelas, Fernando [0000-0002-0879-5798], Stadler, Tanja [0000-0001-6431-535X], Neher, Richard A. [0000-0003-2525-1407], Hodcroft, Emma B., Zuber, Moira, Nadeau, Sarah, Vaughan, Timothy G., Crawford, Katharine H. D., Althaus, Christian L., Reichmuth, Martina L., Bowen, John E., Walls, Alexandra C., Corti, Davide, Bloom, Jesse D., Veesler, David, Mateo, David, Hernando de Castro, Alberto, Comas, Iñaki, González-Candelas, Fernando, Seqcovid-Spain Consortium, Stadler, Tanja, Neher, Richard A., Swiss National Science Foundation, European Commission, University of Basel, ETH Zurich, National Institute of General Medical Sciences (US), National Institute of Allergy and Infectious Diseases (US), Burroughs Wellcome Fund, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España), European Research Council, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Howard Hughes Medical Institute, Hodcroft, Emma B. [0000-0002-0078-2212], Zuber, Moira [0000-0002-4275-8739], Nadeau, Sarah [0000-0003-1008-8918], Vaughan, Timothy G. [0000-0001-6220-2239], Crawford, Katharine H. D. [0000-0002-6223-4019], Althaus, Christian L. [0000-0002-5230-6760], Reichmuth, Martina L. [0000-0001-9345-851X], Bowen, John E. [0000-0003-3590-9727], Walls, Alexandra C. [0000-0002-9636-8330], Corti, Davide [0000-0002-5797-1364], Bloom, Jesse D. [0000-0003-1267-3408], Veesler, David [0000-0002-6019-8675], Mateo, David [0000-0002-1590-4163], Hernando de Castro, Alberto [0000-0003-1180-1068], Comas, Iñaki [0000-0001-5504-9408], González-Candelas, Fernando [0000-0002-0879-5798], Stadler, Tanja [0000-0001-6431-535X], Neher, Richard A. [0000-0003-2525-1407], Hodcroft, Emma B., Zuber, Moira, Nadeau, Sarah, Vaughan, Timothy G., Crawford, Katharine H. D., Althaus, Christian L., Reichmuth, Martina L., Bowen, John E., Walls, Alexandra C., Corti, Davide, Bloom, Jesse D., Veesler, David, Mateo, David, Hernando de Castro, Alberto, Comas, Iñaki, González-Candelas, Fernando, Seqcovid-Spain Consortium, Stadler, Tanja, and Neher, Richard A.
Abstract: Following its emergence in late 2019, the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1,2 has been tracked via phylogenetic analysis of viral genome sequences in unprecedented detail3–5. While the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, within Europe travel resumed in the summer of 2020. Here we report on a novel SARS-CoV-2 variant, 20E (EU1), that emerged in Spain in early summer, and subsequently spread across Europe. We find no evidence of increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variant’s success. Despite travel restrictions, we estimate 20E (EU1) was introduced hundreds of times to European countries by summertime travelers, likely undermining local efforts to keep SARS-CoV-2 cases low. Our results demonstrate how a variant can rapidly become dominant even in absence of a substantial transmission advantage in favorable epidemiological settings. Genomic surveillance is critical to understanding how travel can impact SARS-CoV-2 transmission, and thus for informing future containment strategies as travel resumes.
Published: 2021

13. Quantifying acquisition and transmission of Enterococcus faecium using genomic surveillance

Author: Wellcome Trust, Academy of Medical Sciences (UK), National Institute for Health Research (UK), Coll, Francesc [0000-0002-7882-2325], Gouliouris, Theodore, Coll, Francesc, Ludden, Catherine, Blane, Beth, Raven, Kathy E., Naydenova, Plamena, Crawley, Charles, Török, Mili Estée, Enoch, David A., Brown, Nicholas M., Harrison, Ewan M., Parkhill, Julian, Peacock, Sharon J., Wellcome Trust, Academy of Medical Sciences (UK), National Institute for Health Research (UK), Coll, Francesc [0000-0002-7882-2325], Gouliouris, Theodore, Coll, Francesc, Ludden, Catherine, Blane, Beth, Raven, Kathy E., Naydenova, Plamena, Crawley, Charles, Török, Mili Estée, Enoch, David A., Brown, Nicholas M., Harrison, Ewan M., Parkhill, Julian, and Peacock, Sharon J.
Abstract: Nosocomial acquisition and transmission of vancomycin-resistant Enterococcus faecium (VREfm) is the driver for E. faecium carriage in hospitalized patients, which, in turn, is a risk factor for invasive infection in immunocompromised patients. In the present study, we provide a comprehensive picture of E. faecium transmission in an entire sampled patient population using a sequence-driven approach. We prospectively identified and followed 149 haematology patients admitted to a hospital in England for 6 months. Patient stools (n = 376) and environmental swabs (n = 922) were taken at intervals and cultured for E. faecium. We sequenced 1,560 isolates (1,001 stool, 559 environment) and focused our genomic analyses on 1,477 isolates (95%) in the hospital-adapted clade A1. Of 101 patients who provided two or more stool samples, 40 (40%) developed E. faecium carriage after admission based on culture, compared with 64 patients (63%) based on genomic analysis (73% VREfm). Half of 922 environmental swabs (447, 48%) were positive for VREfm. Network analysis showed that, of 111 patients positive for the A1 clade, 67 had strong epidemiological and genomic links with at least one other patient and/or their direct environment, supporting nosocomial transmission. Six patients (3.4%) developed an invasive E. faecium infection from their own gut-colonizing strain, which was preceded by nosocomial acquisition of the infecting isolate in half of these. Two informatics approaches (subtype categorization to define phylogenetic clusters and the development of an SNP cut-off for transmission) were central to our analyses, both of which will inform the future translation of E. faecium sequencing into routine outbreak detection and investigation. In conclusion, we showed that carriage and environmental contamination by the hospital-adapted E. faecium lineage were hyperendemic in our study population and that improved infection control measures will be needed to reduce hospital acquisition ra
Published: 2021

14. Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis

Author: King Abdullah University of Science and Technology, Wellcome Trust, Burroughs Wellcome Fund, Fundação para a Ciência e a Tecnologia (Portugal), Fundação Calouste Gulbenkian, European Society of Clinical Microbiology and Infectious Diseases, Medical Research Council (UK), Biotechnology and Biological Sciences Research Council (UK), Japan Agency for Medical Research and Development, Coll, Francesc [0000-0002-7882-2325], Coll, Francesc, Phelan, Jody, Hill-Cawthorne, Grant A., Nair, Mridul B., Mallard, Kim, Ali, Shahjahan, Abdallah, Abdallah M., Alghamdi, Saad, Alsomali, Mona, Ahmed, Abdallah O., Portelli, Stephanie, Oppong, Yaa, Alves, Adriana, Barbosa Bessa, Theolis, Campino, Susana, Caws, Maxine, Chatterjee, Anirvan, Crampin, Amelia C., Dheda, Keertan, Furnham, Nicholas, Glynn, Judith R., Grandjean, Louis Louis, Ha, Dang Minh, Hasan, Rumina, Hasan, Zahra, Hibberd, Martin L., Joloba, Moses, Jones-López, Edward C., Matsumoto, Tomoshige, Miranda, Anabela, Moore, David J., Mocillo, Nora, Panaiotov, Stefan, Parkhill, Julian, Penha, Carlos, Perdigão, João, Portugal, Isabel, Rchiad, Zineb, Robledo, Jaime, Sheen, Patricia, Shesha, Nashwa Talaat, Sirgel, Frik A., Sola, Christophe, Oliveira Sousa, Erivelton, Streicher, Elizabeth M., Helden, Paul Van, Viveiros, Miguel, Warren, Robert M., McNerney, Ruth, Pain, Arnab, Clark, Taane G., King Abdullah University of Science and Technology, Wellcome Trust, Burroughs Wellcome Fund, Fundação para a Ciência e a Tecnologia (Portugal), Fundação Calouste Gulbenkian, European Society of Clinical Microbiology and Infectious Diseases, Medical Research Council (UK), Biotechnology and Biological Sciences Research Council (UK), Japan Agency for Medical Research and Development, Coll, Francesc [0000-0002-7882-2325], Coll, Francesc, Phelan, Jody, Hill-Cawthorne, Grant A., Nair, Mridul B., Mallard, Kim, Ali, Shahjahan, Abdallah, Abdallah M., Alghamdi, Saad, Alsomali, Mona, Ahmed, Abdallah O., Portelli, Stephanie, Oppong, Yaa, Alves, Adriana, Barbosa Bessa, Theolis, Campino, Susana, Caws, Maxine, Chatterjee, Anirvan, Crampin, Amelia C., Dheda, Keertan, Furnham, Nicholas, Glynn, Judith R., Grandjean, Louis Louis, Ha, Dang Minh, Hasan, Rumina, Hasan, Zahra, Hibberd, Martin L., Joloba, Moses, Jones-López, Edward C., Matsumoto, Tomoshige, Miranda, Anabela, Moore, David J., Mocillo, Nora, Panaiotov, Stefan, Parkhill, Julian, Penha, Carlos, Perdigão, João, Portugal, Isabel, Rchiad, Zineb, Robledo, Jaime, Sheen, Patricia, Shesha, Nashwa Talaat, Sirgel, Frik A., Sola, Christophe, Oliveira Sousa, Erivelton, Streicher, Elizabeth M., Helden, Paul Van, Viveiros, Miguel, Warren, Robert M., McNerney, Ruth, Pain, Arnab, and Clark, Taane G.
Abstract: To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 Mycobacterium tuberculosis clinical isolates from more than 30 countries. A GWAS approach within a mixed-regression framework was followed by a phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes, novel mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to ethionamide, pyrazinamide, capreomycin, cycloserine and para-aminosalicylic acid was enhanced by inclusion of insertions and deletions. Odds ratios for mutations within candidate genes were found to reflect levels of resistance. New epistatic relationships between candidate drug-resistance-associated genes were identified. Findings also suggest the involvement of efflux pumps (drrA and Rv2688c) in the emergence of resistance. This study will inform the design of new diagnostic tests and expedite the investigation of resistance and compensatory epistatic mechanisms.
Published: 2018

15. Structural basis of proton-coupled potassium transport in the KUP family

Author: Max Planck Society, German Research Foundation, Wellcome, Medical Research Council (UK), Biotechnology and Biological Sciences Research Council (UK), Engineering and Physical Sciences Research Council (UK), University of Warwick, Tascón, Igor [0000-0003-2526-6238], Griwatz, David [0000-0002-3564-897X], Stansfeld, Phillip J. [0000-0001-8800-7669], Hänelt, Inga [0000-0003-1495-3163], Tascón, Igor, Sousa, Joana S., Corey, Robin A., Mills, Deryck J., Griwatz, David, Aumüller, Nadine, Mikusevic, Vedrana, Stansfeld, Phillip J., Vonck, Janet, Hänelt, Inga, Max Planck Society, German Research Foundation, Wellcome, Medical Research Council (UK), Biotechnology and Biological Sciences Research Council (UK), Engineering and Physical Sciences Research Council (UK), University of Warwick, Tascón, Igor [0000-0003-2526-6238], Griwatz, David [0000-0002-3564-897X], Stansfeld, Phillip J. [0000-0001-8800-7669], Hänelt, Inga [0000-0003-1495-3163], Tascón, Igor, Sousa, Joana S., Corey, Robin A., Mills, Deryck J., Griwatz, David, Aumüller, Nadine, Mikusevic, Vedrana, Stansfeld, Phillip J., Vonck, Janet, and Hänelt, Inga
Abstract: Potassium homeostasis is vital for all organisms, but is challenging in single-celled organisms like bacteria and yeast and immobile organisms like plants that constantly need to adapt to changing external conditions. KUP transporters facilitate potassium uptake by the co-transport of protons. Here, we uncover the molecular basis for transport in this widely distributed family. We identify the potassium importer KimA from Bacillus subtilis as a member of the KUP family, demonstrate that it functions as a K+/H+ symporter and report a 3.7 Å cryo-EM structure of the KimA homodimer in an inward-occluded, trans-inhibited conformation. By introducing point mutations, we identify key residues for potassium and proton binding, which are conserved among other KUP proteins.
Published: 2020

16. Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

Author: Medical Research Council (UK), Wellcome Trust, NIHR Biomedical Research Centre (UK), NHS Foundation Trust, University College London, National Institute for Health Research (UK), European Research Council, European Commission, Instituto de Salud Carlos III, Fundació Seny, Fundación Ramón Areces, Fundación Marques de Valdecilla, Thygesen, Johan H., Presman, Amelia, Harju-Seppänen, Jasmine, Irizar, Haritz, Jones, Rebecca, Kuchenbaecker, Karoline B., Lin, Kuang, Alizadeh, Behrooz Z., Austin-Zimmerman, Isabelle, Bartels-Velthuis, Agna, Bhat, Anjali, Bruggeman, Richard, Cahn, Wiepke, Calafato, Stella, Crespo-Facorro, Benedicto, de Haan, Lieuwe, Zwarte, Sonja M. C., Di Forti, Marta, Díez-Revuelta, Álvaro, Hall, Jeremy, Hall, Mei-Hua, Iyegbe, Conrad, Jablensky, Assen V., Kahn, René S., Kalaydjieva, Luba, Kravariti, Eugenia, Lawrie, Stephen M., Luykx, Jurjen J., Mata, Ignacio F., McDonald, Colm, McIntosh, Andrew M., McQuillin, Andrew, Muir, Rebecca, Ophoff, Roel A., Picchioni, Marco, Prata, Diana P., Ranlund, Siri, Rujescu, Dan, Rutten, Bart P. F., Schulze, Katja, Shaikh, Madiha, Schirmbeck, Frederike, Simons, Claudia J. P., Toulopoulou, Timothea, van Amelsvoort, Therese, van Haren, Neeltje E. M., Os, Jim van, Winkel, Ruud van, Vassos, Evangelos, Walshe, Muriel, Weisbrod, Matthias, Zartaloudi, Eirini, Bell, Vaughan, Powell, John, Lewis, Cathryn M., Murray, Robin M., Bramon, Elvira, Medical Research Council (UK), Wellcome Trust, NIHR Biomedical Research Centre (UK), NHS Foundation Trust, University College London, National Institute for Health Research (UK), European Research Council, European Commission, Instituto de Salud Carlos III, Fundació Seny, Fundación Ramón Areces, Fundación Marques de Valdecilla, Thygesen, Johan H., Presman, Amelia, Harju-Seppänen, Jasmine, Irizar, Haritz, Jones, Rebecca, Kuchenbaecker, Karoline B., Lin, Kuang, Alizadeh, Behrooz Z., Austin-Zimmerman, Isabelle, Bartels-Velthuis, Agna, Bhat, Anjali, Bruggeman, Richard, Cahn, Wiepke, Calafato, Stella, Crespo-Facorro, Benedicto, de Haan, Lieuwe, Zwarte, Sonja M. C., Di Forti, Marta, Díez-Revuelta, Álvaro, Hall, Jeremy, Hall, Mei-Hua, Iyegbe, Conrad, Jablensky, Assen V., Kahn, René S., Kalaydjieva, Luba, Kravariti, Eugenia, Lawrie, Stephen M., Luykx, Jurjen J., Mata, Ignacio F., McDonald, Colm, McIntosh, Andrew M., McQuillin, Andrew, Muir, Rebecca, Ophoff, Roel A., Picchioni, Marco, Prata, Diana P., Ranlund, Siri, Rujescu, Dan, Rutten, Bart P. F., Schulze, Katja, Shaikh, Madiha, Schirmbeck, Frederike, Simons, Claudia J. P., Toulopoulou, Timothea, van Amelsvoort, Therese, van Haren, Neeltje E. M., Os, Jim van, Winkel, Ruud van, Vassos, Evangelos, Walshe, Muriel, Weisbrod, Matthias, Zartaloudi, Eirini, Bell, Vaughan, Powell, John, Lewis, Cathryn M., Murray, Robin M., and Bramon, Elvira
Abstract: The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.
Published: 2020

17. The dental proteome of Homo antecessor

Author: European Commission, Lundbeck Foundation, Danish National Research Foundation, Novo Nordisk Foundation, Carlsberg Foundation, Wellcome Trust, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Junta de Castilla y León, Fundación Atapuerca, Leakey Foundation, Howard Hughes Medical Institute, Fundación la Caixa, Generalitat de Catalunya, Instituto de Salud Carlos III, John Templeton Foundation, Shota Rustaveli National Science Foundation, Welker, Frido, Ramos-Madrigal, Jazmín, Gutenbrunner, Petra, Mackie, Meaghan, Tiwary, Shivani, Rakownikow Jersie-Christensen, Rosa, Chiva, Cristina, Dickinson, Mark R., Kuhlwilm, Martin, Manuel, Marc de, Gelabert, Pere, Martinón-Torres, María, Margvelashvili, Ann, Arsuaga, Juan Luis, Carbonell, Eudald, Marqués-Bonet, Tomàs, Penkman, Kirsty, Sabidó, Eduard, Cox, Jürgen, Olsen, Jesper V., Lordkipanidze, David, Racimo, Fernando, Lalueza-Fox, Carles, Bermúdez de Castro, José María, Willerslev, Eske, Cappellini, Enrico, European Commission, Lundbeck Foundation, Danish National Research Foundation, Novo Nordisk Foundation, Carlsberg Foundation, Wellcome Trust, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Junta de Castilla y León, Fundación Atapuerca, Leakey Foundation, Howard Hughes Medical Institute, Fundación la Caixa, Generalitat de Catalunya, Instituto de Salud Carlos III, John Templeton Foundation, Shota Rustaveli National Science Foundation, Welker, Frido, Ramos-Madrigal, Jazmín, Gutenbrunner, Petra, Mackie, Meaghan, Tiwary, Shivani, Rakownikow Jersie-Christensen, Rosa, Chiva, Cristina, Dickinson, Mark R., Kuhlwilm, Martin, Manuel, Marc de, Gelabert, Pere, Martinón-Torres, María, Margvelashvili, Ann, Arsuaga, Juan Luis, Carbonell, Eudald, Marqués-Bonet, Tomàs, Penkman, Kirsty, Sabidó, Eduard, Cox, Jürgen, Olsen, Jesper V., Lordkipanidze, David, Racimo, Fernando, Lalueza-Fox, Carles, Bermúdez de Castro, José María, Willerslev, Eske, and Cappellini, Enrico
Abstract: The phylogenetic relationships between hominins of the Early Pleistocene epoch in Eurasia, such as Homo antecessor, and hominins that appear later in the fossil record during the Middle Pleistocene epoch, such as Homo sapiens, are highly debated. For the oldest remains, the molecular study of these relationships is hindered by the degradation of ancient DNA. However, recent research has demonstrated that the analysis of ancient proteins can address this challenge. Here we present the dental enamel proteomes of H. antecessor from Atapuerca (Spain) and Homo erectus from Dmanisi (Georgia), two key fossil assemblages that have a central role in models of Pleistocene hominin morphology, dispersal and divergence. We provide evidence that H. antecessor is a close sister lineage to subsequent Middle and Late Pleistocene hominins, including modern humans, Neanderthals and Denisovans. This placement implies that the modern-like face of H. antecessor—that is, similar to that of modern humans—may have a considerably deep ancestry in the genus Homo, and that the cranial morphology of Neanderthals represents a derived form. By recovering AMELY-specific peptide sequences, we also conclude that the H. antecessor molar fragment from Atapuerca that we analysed belonged to a male individual. Finally, these H. antecessor and H. erectus fossils preserve evidence of enamel proteome phosphorylation and proteolytic digestion that occurred in vivo during tooth formation. Our results provide important insights into the evolutionary relationships between H. antecessor and other hominin groups, and pave the way for future studies using enamel proteomes to investigate hominin biology across the existence of the genus Homo.
Published: 2020

18. A comparative genomics multitool for scientific discovery and conservation

Author: National Institutes of Health (US), Swedish Research Council, Knut and Alice Wallenberg Foundation, Uppsala University, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Howard Hughes Medical Institute, European Research Council, Fundación la Caixa, Wellcome Trust, Royal Society (UK), Ministerio de Economía y Competitividad (España), Fondation Prince Albert II de Monaco, Smithsonian Institution, Irish Research Council, Medical Research Council (UK), National Science Foundation (US), Academy of Finland, Genereux, Diane P., Serres-Armero, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita D., Murén, Eva, Juan, David, Bejerano, Gill, Casewell, Nicholas R., Chemnick, Leona G., Damas, Joana, Di Palma, Federica, Diekhans, Mark, Fiddes, Ian T., Garber, Manuel, Gladyshev, Vadim N., Goodman, Linda, Haerty, Wilfried, Houck, Marlys L., Hubley, Robert, Kivioja, Teemu, Koepfli, Klaus-Peter, Kuderna, Lukas F. K., Lander, Eric S., Meadows, Jennifer R.S., Murphy, William J., Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R., Pollard, Katherine S., Ray, David A., Shapiro, Beth, Smit, Arian F. A., Springer, Mark S., Steiner, Cynthia C., Swofford, Ross, Taipale, Jussi, Teeling, Emma C., Turner-Maier, Jason, Alfoldi, Jessica, Birren, Bruce, Ryder, Oliver A., Lewin, Harris A., Paten, Benedict, Marqués-Bonet, Tomàs, Lindblad-Toh, Kerstin, Karlsson, Elinor K., National Institutes of Health (US), Swedish Research Council, Knut and Alice Wallenberg Foundation, Uppsala University, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Howard Hughes Medical Institute, European Research Council, Fundación la Caixa, Wellcome Trust, Royal Society (UK), Ministerio de Economía y Competitividad (España), Fondation Prince Albert II de Monaco, Smithsonian Institution, Irish Research Council, Medical Research Council (UK), National Science Foundation (US), Academy of Finland, Genereux, Diane P., Serres-Armero, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita D., Murén, Eva, Juan, David, Bejerano, Gill, Casewell, Nicholas R., Chemnick, Leona G., Damas, Joana, Di Palma, Federica, Diekhans, Mark, Fiddes, Ian T., Garber, Manuel, Gladyshev, Vadim N., Goodman, Linda, Haerty, Wilfried, Houck, Marlys L., Hubley, Robert, Kivioja, Teemu, Koepfli, Klaus-Peter, Kuderna, Lukas F. K., Lander, Eric S., Meadows, Jennifer R.S., Murphy, William J., Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R., Pollard, Katherine S., Ray, David A., Shapiro, Beth, Smit, Arian F. A., Springer, Mark S., Steiner, Cynthia C., Swofford, Ross, Taipale, Jussi, Teeling, Emma C., Turner-Maier, Jason, Alfoldi, Jessica, Birren, Bruce, Ryder, Oliver A., Lewin, Harris A., Paten, Benedict, Marqués-Bonet, Tomàs, Lindblad-Toh, Kerstin, and Karlsson, Elinor K.
Abstract: The Zoonomia Project is investigating the genomics of shared and specialized traits in eutherian mammals. Here we provide genome assemblies for 131 species, of which all but 9 are previously uncharacterized, and describe a whole-genome alignment of 240 species of considerable phylogenetic diversity, comprising representatives from more than 80% of mammalian families. We find that regions of reduced genetic diversity are more abundant in species at a high risk of extinction, discern signals of evolutionary selection at high resolution and provide insights from individual reference genomes. By prioritizing phylogenetic diversity and making data available quickly and without restriction, the Zoonomia Project aims to support biological discovery, medical research and the conservation of biodiversity.
Published: 2020

19. WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion

Author: Cancer Research UK, Royal Society (UK), European Commission, Helmsley Charitable Trust, Wellcome Trust, NHS Foundation Trust, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Cáncer (España), Rodriguez-Hernandez, Irene, Maiques, Óscar, Kohlhammer, Leonie, Cantelli, Gaia, Perdrix-Rosell, Anna, Monge, Joanne, Fanshawe, Bruce, Bridgeman, Victoria L., Karagiannis, Sophia N., Penin, Rosa M., Marcolval, Joaquim, Marti, Rosa M., Matías-Guiu, Xavier, Fruhwirth, Gilbert O., Orgaz, José L., Malanchi, Ilaria, Sanz-Moreno, Victoria, Cancer Research UK, Royal Society (UK), European Commission, Helmsley Charitable Trust, Wellcome Trust, NHS Foundation Trust, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Cáncer (España), Rodriguez-Hernandez, Irene, Maiques, Óscar, Kohlhammer, Leonie, Cantelli, Gaia, Perdrix-Rosell, Anna, Monge, Joanne, Fanshawe, Bruce, Bridgeman, Victoria L., Karagiannis, Sophia N., Penin, Rosa M., Marcolval, Joaquim, Marti, Rosa M., Matías-Guiu, Xavier, Fruhwirth, Gilbert O., Orgaz, José L., Malanchi, Ilaria, and Sanz-Moreno, Victoria
Abstract: Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. Notably, melanoma can disseminate using amoeboid invasive strategies. We show here that high Myosin II activity, high levels of ki-67 and high tumour-initiating abilities are characteristic of invasive amoeboid melanoma cells. Mechanistically, we find that WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II and plays a crucial role in regulating tumour-initiating potential, local invasion and distant metastasis formation. Importantly, amoeboid melanoma cells express both proliferative and invasive gene signatures. As such, invasive fronts of human and mouse melanomas are enriched in amoeboid cells that are also ki-67 positive. This pattern is further enhanced in metastatic lesions. We propose eradication of amoeboid melanoma cells after surgical removal as a therapeutic strategy.
Published: 2020

20. A high-stringency blueprint of the human proteome

Author: Instituto de Salud Carlos III, Comunidad de Madrid, National Institutes of Health (US), Canada Research Chairs, Wellcome Trust, Knut and Alice Wallenberg Foundation, Fundaçao Capes (Brasil), Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), Cancer Council NSW (Australia), Cancer Institute NSW (Australia), Stanford University, Adhikari, Subash, Nice, Edouard C., Deutsch, Eric W., Lane, Lydie, Omenn, Gilbert S., Pennington, Stephen R., Paik, Young-Ki, Overall, Christopher M., Corrales, Fernando J., Cristea, Ileana M., Van Eyk, Jennifer E., Uhlén, Mathias, Lindskog, Cecilia, Chan, Daniel W., Bairoch, Amos, Waddington, James C., Justice, Joshua L., LaBaer, Joshua, Rodriguez, Henry, He, Fuchu, Kostrzewa, Markus, Ping, Peipei, Gundry, Rebekah L., Stewart, Peter, Srivastava, Sanjeeva, Srivastava, Sudhir, Nogueira, Fabio C. S., Domont, Gilberto B., Vandenbrouck, Yves, Lam, Maggie P. Y., Wennersten, Sara, Vizcaíno, Juan Antonio, Wilkins, Marc, Schwenk, Jochen M., Lundberg, Emma, Bandeira, Nuno, Marko-Varga, György, Weintraub, Susan T., Pineau, Charles, Kusebauch, Ulrike, Moritz, Robert L., Beom Ahn, Seong, Palmblad, Magnus, Snyder, Michael P., Aebersold, Ruedi, Baker, Mark S., Instituto de Salud Carlos III, Comunidad de Madrid, National Institutes of Health (US), Canada Research Chairs, Wellcome Trust, Knut and Alice Wallenberg Foundation, Fundaçao Capes (Brasil), Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), Cancer Council NSW (Australia), Cancer Institute NSW (Australia), Stanford University, Adhikari, Subash, Nice, Edouard C., Deutsch, Eric W., Lane, Lydie, Omenn, Gilbert S., Pennington, Stephen R., Paik, Young-Ki, Overall, Christopher M., Corrales, Fernando J., Cristea, Ileana M., Van Eyk, Jennifer E., Uhlén, Mathias, Lindskog, Cecilia, Chan, Daniel W., Bairoch, Amos, Waddington, James C., Justice, Joshua L., LaBaer, Joshua, Rodriguez, Henry, He, Fuchu, Kostrzewa, Markus, Ping, Peipei, Gundry, Rebekah L., Stewart, Peter, Srivastava, Sanjeeva, Srivastava, Sudhir, Nogueira, Fabio C. S., Domont, Gilberto B., Vandenbrouck, Yves, Lam, Maggie P. Y., Wennersten, Sara, Vizcaíno, Juan Antonio, Wilkins, Marc, Schwenk, Jochen M., Lundberg, Emma, Bandeira, Nuno, Marko-Varga, György, Weintraub, Susan T., Pineau, Charles, Kusebauch, Ulrike, Moritz, Robert L., Beom Ahn, Seong, Palmblad, Magnus, Snyder, Michael P., Aebersold, Ruedi, and Baker, Mark S.
Abstract: The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP’s tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases.
Published: 2020

21. Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders

Author: Wellcome, Fundació La Marató de TV3, Gerrard, Dave T., Berry, Andrew A., Jennings, Rachel E., Birket, Matthew J., Zarrineh, Peyman, Garstang, Myles G., Withey, Sarah L., Short, Patrick, Jiménez-Gancedo, Sandra, Firbas, Panos, Donaldson, Ian J., Sharrocks, Andrew D., Piper Hanley, Karen, Hurles, Matthew E., Gómez-Skarmeta, José Luis, Bobola, Nicoletta, Hanley, Neil A., Wellcome, Fundació La Marató de TV3, Gerrard, Dave T., Berry, Andrew A., Jennings, Rachel E., Birket, Matthew J., Zarrineh, Peyman, Garstang, Myles G., Withey, Sarah L., Short, Patrick, Jiménez-Gancedo, Sandra, Firbas, Panos, Donaldson, Ian J., Sharrocks, Andrew D., Piper Hanley, Karen, Hurles, Matthew E., Gómez-Skarmeta, José Luis, Bobola, Nicoletta, and Hanley, Neil A.
Abstract: How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark the fidelity of stem cell differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we study histone modifications across thirteen tissues during human organogenesis. We integrate the data with transcription to build an overview of how the human genome differentially regulates alternative organ fates including by repression. Promoters from nearly 20,000 genes partition into discrete states. Key developmental gene sets are actively repressed outside of the appropriate organ without obvious bivalency. Candidate enhancers, functional in zebrafish, allow imputation of tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 noncoding mutations from patients with developmental disorders allows correlation to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for investigating normal and abnormal human development.
Published: 2020

22. A fraction of barrier-to-autointegration factor (BAF) associates with centromeres and controls mitosis progression

Author: Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Hungarian Academy of Sciences, Wellcome Trust, Generalitat de Catalunya, Torras-Llort, Mònica, Medina-Giró, Sònia, Escudero-Ferruz, Paula, Lipinszki, Zoltan, Moreno-Moreno, Olga, Karman, Zoltan, Przewloka, Marcin R., Azorin, Fernando, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Hungarian Academy of Sciences, Wellcome Trust, Generalitat de Catalunya, Torras-Llort, Mònica, Medina-Giró, Sònia, Escudero-Ferruz, Paula, Lipinszki, Zoltan, Moreno-Moreno, Olga, Karman, Zoltan, Przewloka, Marcin R., and Azorin, Fernando
Abstract: Barrier-to-Autointegration Factor (BAF) is a conserved nuclear envelope (NE) component that binds chromatin and helps its anchoring to the NE. Cycles of phosphorylation and dephosphorylation control BAF function. Entering mitosis, phosphorylation releases BAF from chromatin and facilitates NE-disassembly. At mitotic exit, PP2A-mediated dephosphorylation restores chromatin binding and nucleates NE-reassembly. Here, we show that in Drosophila a small fraction of BAF (cenBAF) associates with centromeres. We also find that PP4 phosphatase, which is recruited to centromeres by CENP-C, prevents phosphorylation and release of cenBAF during mitosis. cenBAF is necessary for proper centromere assembly and accurate chromosome segregation, being critical for mitosis progression. Disrupting cenBAF localization prevents PP2A inactivation in mitosis compromising global BAF phosphorylation, which in turn leads to its persistent association with chromatin, delays anaphase onset and causes NE defects. These results suggest that, together with PP4 and CENP-C, cenBAF forms a centromere-based mechanism that controls chromosome segregation and mitosis progression.
Published: 2020

23. Complement genes contribute sex-biased vulnerability in diverse disorders

Author: Onderzoek, Brain, Onderzoeksgroep 11, Beeldverwerking ISI, Hersenen-Medisch 1, Hersenen-Bedrijfsvoering, Infectieziekten onderzoek1 (Bont), Infection & Immunity, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium 2, Psychosis Endophenotype International Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Onderzoek, Brain, Onderzoeksgroep 11, Beeldverwerking ISI, Hersenen-Medisch 1, Hersenen-Bedrijfsvoering, Infectieziekten onderzoek1 (Bont), Infection & Immunity, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium 2, Psychosis Endophenotype International Consortium, and Schizophrenia Working Group of the Psychiatric Genomics Consortium
Published: 2020

24. FACT mediates cohesin function on chromatin

Author: Wellcome Trust, Medical Research Council (UK), European Commission, European Research Council, Agence Nationale de la Recherche (France), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), García-Luis, Jonay, Lazar-Stefanita, Luciana, Gutiérrez-Escribano, Pilar, Thierry, Agnes, Cournac, Axel, García, Alicia, González-Arranz, Sara, Sánchez, Mar, Jarmuz, Adam, Montoya, Alex, Dore, Marian, Kramer, Holger, Karimi, Mohammad M., Antequera, Francisco, Koszul, Romain, Aragón, Luis, Wellcome Trust, Medical Research Council (UK), European Commission, European Research Council, Agence Nationale de la Recherche (France), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), García-Luis, Jonay, Lazar-Stefanita, Luciana, Gutiérrez-Escribano, Pilar, Thierry, Agnes, Cournac, Axel, García, Alicia, González-Arranz, Sara, Sánchez, Mar, Jarmuz, Adam, Montoya, Alex, Dore, Marian, Kramer, Holger, Karimi, Mohammad M., Antequera, Francisco, Koszul, Romain, and Aragón, Luis
Abstract: Cohesin is a regulator of genome architecture with roles in sister chromatid cohesion and chromosome compaction. The recruitment and mobility of cohesin complexes on DNA is restricted by nucleosomes. Here, we show that the role of cohesin in chromosome organization requires the histone chaperone FACT (‘facilitates chromatin transcription’) in Saccharomyces cerevisiae. We find that FACT interacts directly with cohesin, and is dynamically required for its localization on chromatin. Depletion of FACT in metaphase cells prevents cohesin accumulation at pericentric regions and causes reduced binding on chromosome arms. Using the Hi-C technique, we show that cohesin-dependent TAD (topological associated domain)-like structures in G1 and metaphase chromosomes are reduced in the absence of FACT. Sister chromatid cohesion is intact in FACT-depleted cells, although chromosome segregation failure is observed. Our data show that FACT contributes to the formation of cohesin-dependent TADs, thus uncovering a new role for this complex in nuclear organization during interphase and mitotic chromosome folding.
Published: 2019

25. The structure of a polygamous repressor reveals how phage-inducible chromosomal islands spread in nature

Author: Ministerio de Economía y Competitividad (España), Generalitat Valenciana, Medical Research Council (UK), Biotechnology and Biological Sciences Research Council (UK), Wellcome Trust, Royal Society (UK), Wolfson Foundation, European Research Council, Marina, Alberto [0000-0002-1334-5273], Ciges-Tomas, J. Rafael, Alite, Christian, Humphrey, Suzanne, Donderis, Jorge, Bowring, Janine, Salvatella, Xavier, Penadés, José R., Marina, Alberto, Ministerio de Economía y Competitividad (España), Generalitat Valenciana, Medical Research Council (UK), Biotechnology and Biological Sciences Research Council (UK), Wellcome Trust, Royal Society (UK), Wolfson Foundation, European Research Council, Marina, Alberto [0000-0002-1334-5273], Ciges-Tomas, J. Rafael, Alite, Christian, Humphrey, Suzanne, Donderis, Jorge, Bowring, Janine, Salvatella, Xavier, Penadés, José R., and Marina, Alberto
Abstract: Stl is a master repressor encoded by Staphylococcus aureus pathogenicity islands (SaPIs) that maintains integration of these elements in the bacterial chromosome. After infection or induction of a resident helper phage, SaPIs are de-repressed by specific interactions of phage proteins with Stl. SaPIs have evolved a fascinating mechanism to ensure their promiscuous transfer by targeting structurally unrelated proteins performing identically conserved functions for the phage. Here we decipher the molecular mechanism of this elegant strategy by determining the structure of SaPIbov1 Stl alone and in complex with two structurally unrelated dUTPases from different S. aureus phages. Remarkably, SaPIbov1 Stl has evolved different domains implicated in DNA and partner recognition specificity. This work presents the solved structure of a SaPI repressor protein and the discovery of a modular repressor that acquires multispecificity through domain recruiting. Our results establish the mechanism that allows widespread dissemination of SaPIs in nature.
Published: 2019

26. Biological insights from 108 schizophrenia-associated genetic loci

Author: Ripke, Stephan, Neale, Benjamin M., Corvin, Aiden, Walters, James T. R., Farh, Kai-How, Holmans, Peter A., Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A., Huang, Hailiang, Pers, Tune H., Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., Begemann, Martin, Belliveau Jr, Richard A., Bene, Judit, Bergen, Sarah E., Bevilacqua, Elizabeth, Bigdeli, Tim B., Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberly D., Chan, Raymond C. K., Chen, Ronald Y. L., Chen, Eric Y. H., Cheng, Wei, Cheung, Eric F. C., Ann Chong, Siow, Robert Cloninger, C., Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J., Curtis, David, Davidson, Michael, Davis, Kenneth L., Degenhardt, Franziska, Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H., Farrell, Martilias S., Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Friedman, Joseph I., Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodriguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M., Henskens, Frans A., Herms, Stefan, Hirschhorn, Joel N., Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V., Hougaard, David M., Ikeda, Masashi, Joa, Inge, Julia, Antonio, Kahn, Rene S., Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C., Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Ausrele Kucinskiene, Zita, Kuzelova-Ptackova, Hana, Kahler, Anna K., Laurent, Claudine, Lee Chee Keong, Jimmy, Hong Lee, S., Legge, Sophie E., Lerer, Bernard, Li, Miaoxin, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lonnqvist, Jouko, Macek Jr, Milan, Magnusson, Patrik K. E., Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Mors, Ole, Murphy, Kieran C., Murray, Robin M., Myin-Germeys, Inez, Muller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Endophenotypes International Consortium, Psychosis, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O., Pietilainen, Olli, Pimm, Jonathan, Pocklington, Andrew J., Powell, John, Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Roffman, Joshua L., Roussos, Panos, Ruderfer, Douglas M., Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schulze, Thomas G., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon-Cheong, Spencer, ChrisC. A., Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Strohmaier, Jana, Scott Stroup, T., Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Soderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Witt, Stephanie H., Wolen, Aaron R., Wong, Emily H. M., Wormley, Brandon K., Simon Xi, Hualin, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Trust Case-Control Consortium, Wellcome, Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H. R., Bramon, Elvira, Buxbaum, Joseph D., Borglum, Anders D., Cichon, Sven, Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tonu, Gejman, Pablo V., Gill, Michael, Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jonsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mortensen, Preben B., Mowry, Bryan J., Nothen, Markus M., Ophoff, Roel A., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P., Rujescu, Dan, Sham, Pak C., Sklar, Pamela, St Clair, David, Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., and Sullivan, Patrick F.
Subjects: Genetic research -- Analysis, Schizophrenia -- Research -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia., Author(s): Schizophrenia Working Group of the Psychiatric Genomics Consortium; Stephan Ripke [1, 2]; Benjamin M. Neale [1, 2, 3, 4]; Aiden Corvin [5]; James T. R. Walters [6]; Kai-How Farh [...]
Published: 2014
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27. RNA metabolism is the primary target of formamide in vivo

Author: Wellcome Trust, Ministerio de Economía y Competitividad (España), Universidad Pablo de Olavide, Hoyos-Manchado, Rafael, Reyes-Martín, Félix, Rallis, Charalampos, Gamero-Estévez, Enrique, Rodríguez-Gómez, Pablo, Quintero-Blanco, Juan, Bähler, Jürg, Jiménez-Martínez, Juan, Tallada, Víctor A., Wellcome Trust, Ministerio de Economía y Competitividad (España), Universidad Pablo de Olavide, Hoyos-Manchado, Rafael, Reyes-Martín, Félix, Rallis, Charalampos, Gamero-Estévez, Enrique, Rodríguez-Gómez, Pablo, Quintero-Blanco, Juan, Bähler, Jürg, Jiménez-Martínez, Juan, and Tallada, Víctor A.
Abstract: The synthesis, processing and function of coding and non-coding RNA molecules and their interacting proteins has been the focus of a great deal of research that has boosted our understanding of key molecular pathways that underlie higher order events such as cell cycle control, development, innate immune response and the occurrence of genetic diseases. In this study, we have found that formamide preferentially weakens RNA related processes in vivo. Using a non-essential Schizosaccharomyces pombe gene deletion collection, we identify deleted loci that make cells sensitive to formamide. Sensitive deletions are significantly enriched in genes involved in RNA metabolism. Accordingly, we find that previously known temperature-sensitive splicing mutants become lethal in the presence of the drug under permissive temperature. Furthermore, in a wild type background, splicing efficiency is decreased and R-loop formation is increased in the presence of formamide. In addition, we have also isolated 35 formamide-sensitive mutants, many of which display remarkable morphology and cell cycle defects potentially unveiling new players in the regulation of these processes. We conclude that formamide preferentially targets RNA related processes in vivo, probably by relaxing RNA secondary structures and/or RNA-protein interactions, and can be used as an effective tool to characterize these processes.
Published: 2017

28. Metabolic gatekeeper function of B-lymphoid transcription factors

Author: Wellcome Trust, Melanoma Research Alliance (US), Howard Hughes Medical Institute, Josep Carreras Leukemia Foundation, American Cancer Society, National Institutes of Health (US), Federal Ministry of Education and Research (Germany), Chan, Lai N., Chen, Zhengshan, Braas, Daniel, Lee, Jae-Woong, Xiao, Gang, Huimin, Geng, Cosgun, Kadriye Nehir, Hurtz, Christian, Shojaee, Seyedmehdi, Cazzaniga, Valeria, Schjerven, Hilde, Ernst, Thomas, Hochhaus, Andreas, Kornblau, Steven M., Konopleva, Marina, Pufall, Miles A., Cazzaniga, Giovanni, Liu, Grace J., Milne, Thomas A., Koeffler, H. Philip, Ross, Theodora S., Sánchez García, Isidro, Borkhardt, Arndt, Yamamoto, Keith R., Dickins, Ross A., Graeber, Thomas G., Müschen, Markus, Wellcome Trust, Melanoma Research Alliance (US), Howard Hughes Medical Institute, Josep Carreras Leukemia Foundation, American Cancer Society, National Institutes of Health (US), Federal Ministry of Education and Research (Germany), Chan, Lai N., Chen, Zhengshan, Braas, Daniel, Lee, Jae-Woong, Xiao, Gang, Huimin, Geng, Cosgun, Kadriye Nehir, Hurtz, Christian, Shojaee, Seyedmehdi, Cazzaniga, Valeria, Schjerven, Hilde, Ernst, Thomas, Hochhaus, Andreas, Kornblau, Steven M., Konopleva, Marina, Pufall, Miles A., Cazzaniga, Giovanni, Liu, Grace J., Milne, Thomas A., Koeffler, H. Philip, Ross, Theodora S., Sánchez García, Isidro, Borkhardt, Arndt, Yamamoto, Keith R., Dickins, Ross A., Graeber, Thomas G., and Müschen, Markus
Abstract: B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors fun
Published: 2017

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

Author: Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA, Univ Oxford, Dept Stat, Oxford OX1 3TG, England, Scripps Res Inst, La Jolla, CA 92037 USA, Perlegen Sci Inc, Mountain View, CA 94043 USA, Baylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USA, Affymetrix Inc, Santa Clara, CA 95051 USA, Pacific Biosci, Menlo Pk, CA 94025 USA, Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA, Harvard Univ, Broad Inst, Cambridge, MA 02139 USA, MIT, Cambridge, MA 02139 USA, Chinese Acad Sci, Beijing Genom Inst, Beijing 100300, Peoples R China, Massachusetts Gen Hosp, Boston, MA 02114 USA, Harvard Univ, Sch Med, Simches Res Ctr, Boston, MA 02114 USA, Chinese Natl Human Genome Ctr, Beijing Econ Technol Dev Area, Beijing 100176, Peoples R China, Chinese Natl Human Genome Ctr, Shanghai 201203, Peoples R China, Fudan Univ, Shanghai 201203, Peoples R China, CAS, SIBS, Sch Life Sci, MPG Partner Inst Computat Biol, Shanghai 201203, Peoples R China, Chinese Univ Hong Kong, Dept Biochem, Croucher Lab Human Genet, Shatin, Hong Kong, Peoples R China, Hong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R China, Hong Kong Univ Sci & Technol, Appl Genom Ctr, Kowloon, Hong Kong, Peoples R China, Illumina, San Diego, CA 92121 USA, Complete Genom Inc, Sunnyvale, CA 94085 USA, Prognosys Biosci Inc, San Diego, CA 92121 USA, McGill Univ, Montreal, PQ H3A 1A4, Canada, Genome Quebec Innovat Ctr, Montreal, PQ H3A 1A4, Canada, Univ Montreal, Publ Law Res Ctr, Downtown Stn, Montreal, PQ H3C 3J7, Canada, Ontario Inst Canc Res, MaRS Ctr, Toronto, ON M5G 1L7, Canada, Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA, Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA, Univ Hong Kong, Genome Res Ctr, Hong Kong, Hong Kong, Peoples R China, Univ Tokyo, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan, RIKEN SNP Res Ctr, Tsurumi Ku, Kanagawa 2300045, Japan, Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England, Univ Cambridge, Dept Oncol, Cambridge CB1 8RN, England, Solexa Ltd, Saffron Walden CB10 1XL, Essex, England, Columbia Univ, New York, NY 10027 USA, Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England, Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA, Int Epidemiol Inst, Rockville, MD 20850 USA, Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA, Univ Chicago, Dept Stat, Chicago, IL 60637 USA, Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA, Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England, Univ Washington, Dept Biostat, Seattle, WA 98195 USA, NHGRI, US NIH, Bethesda, MD 20892 USA, Natl Lib Med, US NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA, Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA, Beijing Normal Univ, Beijing 100875, Peoples R China, Hlth Sci Univ Hokkaido, Ishikari, Hokkaido 0610293, Japan, Shinshu Univ, Sch Med, Dept Med Genet, Matsumoto, Nagano 3908621, Japan, UNESCO Bangkok, Bangkok 10110, Thailand, Univ Tsukuba, Eubios Eth Inst, Tsukuba, Ibaraki 3058691, Japan, Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA, Univ Ibadan, Coll Med, Ibadan, Oyo State, Nigeria, Case Western Reserve Univ, Sch Med, Dept Bioeth, Cleveland, OH 44106 USA, Univ Utah, Dept Human Genet, Eccles Inst Human Genet, Salt Lake City, UT 84112 USA, Chinese Acad Social Sci, Inst Philosophy, Ctr Appl Eth, Beijing 100067, Peoples R China, Genet Interest Grp, London N13 0P, England, Kyoto Univ, Inst Res Humanities, Kyoto 6068501, Japan, Grad Sch Biostudies, Sakyo Ku, Kyoto 6068501, Japan, Nagasaki Univ, Grad Sch Biomed Sci, Dept Human Genet, Nagasaki 8528523, Japan, Univ Oklahoma, Dept Anthropol, Norman, OK 73019 USA, Vanderbilt Univ, Ctr Genet & Hlth Policy, Nashville, TN 37232 USA, Wellcome Trust Res Labs, London NW1 2BE, England, Washington Univ, Sch Med, Genome Sequencing Ctr, St Louis, MO 63108 USA, Chinese Acad Sci, Beijing 100864, Peoples R China, Genome Canada, Ottawa, ON K2P 1P1, Canada, McGill Univ, Off Technol Transfer, Montreal, PQ H3A 2A7, Canada, Genome Quebec, Montreal, PQ H3B 1S6, Canada, Minist Educ Culture Sports Sci & Technol, Chiyoda Ku, Tokyo 1008959, Japan, Minist Sci & Technol, Beijing 100862, Peoples R China, Human Genet Resource Adm China, Beijing 100081, Peoples R China, US NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA, Novartis Pharmaceut Corp, Biomarker Dev, E Hanover, NJ 07936 USA, US NIH, Off Technol Transfer, Rockville, MD 20852 USA, Univ Maryland, Sch Law, Baltimore, MD 21201 USA, Mjdaly@chgr.mgh.harvard.edu; mcvean@stats.ox.ac.uk, Frazer, Kelly A., Ballinger, Dennis G., Cox, David R., Hinds, David A., Stuve, Laura L., Gibbs, Richard A., Belmont, John W., Boudreau, Andrew, Hardenbol, Paul, Leal, Suzanne M., Pasternak, Shiran, Tanaka, Toshihiro, Tsunoda, Tatsuhiko, Deloukas, Panos, Bird, Christine P., Delgado, Marcos, Dermitzakis, Emmanouil T., Gwilliam, Rhian, Hunt, Sarah, Morrison, Jonathan, Powell, Don, Wheeler, David A., Stranger, Barbara E., Whittaker, Pamela, Bentley, David R., Daly, Mark J., De Bakker, Paul I.W., Barrett, Jeff, Chretien, Yves R., Maller, Julian, McCarroll, Steve, Patterson, Nick, Willis, Thomas D., Pe'er, Itsik, Price, Alkes, Purcell, Shaun, Richter, Daniel J., Sabeti, Pardis, Saxena, Richa, Schaffner, Stephen F., Sham, Pak C., Varilly, Patrick, Altshuler, David, Yu, Fuli, Stein, Lincoln D., Krishnan, Lalitha, Smith, Albert Vernon, Tello-Ruiz, Marcela K., Thorisson, Gudmundur A., Chakravarti, Aravinda, Chen, Peter E., Cutler, David J., Kashuk, Carl S., Lin, Shin, Yang, Huanming, Abecasis, Gon??alo R., Guan, Weihua, Li, Yun, Munro, Heather M., Qin, Zhaohui Steve, Thomas, Daryl J., McVean, Gilean, Auton, Adam, Bottolo, Leonardo, Cardin, Niall, Zeng, Changqing, Eyheramendy, Susana, Freeman, Colin, Marchini, Jonathan, Myers, Simon, Spencer, Chris, Stephens, Matthew, Donnelly, Peter, Cardon, Lon R., Clarke, Geraldine, Evans, David M., Gao, Yang, Morris, Andrew P., Weir, Bruce S., Johnson, Todd A., Mullikin, James C., Sherry, Stephen T., Feolo, Michael, Skol, Andrew, Hu, Haoran, Hu, Weitao, Li, Chaohua, Lin, Wei, Liu, Siqi, Pan, Hao, Tang, Xiaoli, Wang, Jian, Wang, Wei, Yu, Jun, Zhang, Bo, Zhang, Qingrun, Zhao, Hongbin, Zhao, Hui, Zhou, Jun, Gabriel, Stacey B., Barry, Rachel, Blumenstiel, Brendan, Camargo, Amy, Defelice, Matthew, Faggart, Maura, Goyette, Mary, Gupta, Supriya, Moore, Jamie, Nguyen, Huy, Onofrio, Robert C., Parkin, Melissa, Roy, Jessica, Stahl, Erich, Winchester, Ellen, Ziaugra, Liuda, Shen, Yan, Yao, Zhijian, Huang, Wei, Chu, Xun, He, Yungang, Jin, Li, Liu, Yangfan, Shen, Yayun, Sun, Weiwei, Wang, Haifeng, Wang, Yi, Wang, Ying, Xiong, Xiaoyan, Xu, Liang, Waye, Mary M.Y., Tsui, Stephen K.W., Wong, J. Tze-Fei, Galver, Luana M., Fan, Jian-Bing, Gunderson, Kevin, Murray, Sarah S., Oliphant, Arnold R., Chee, Mark S., Montpetit, Alexandre, Chagnon, Fanny, Ferretti, Vincent, Leboeuf, Martin, Olivier, Jean-Franccois, Phillips, Michael S., Roumy, Stephanie, Sallee, Clementine, Verner, Andrei, Hudson, Thomas J., Kwok, Pui-Yan, Cai, Dongmei, Koboldt, Daniel C., Miller, Raymond D., Pawlikowska, Ludmila, Taillon-Miller, Patricia, Xiao, Ming, Tsui, Lap-Chee, Mak, William, Song, You Qiang, Tam, Paul K.H., Nakamura, Yusuke, Kawaguchi, Takahisa, Kitamoto, Takuya, Morizono, Takashi, Nagashima, Atsushi, Ohnishi, Yozo, Sekine, Akihiro, Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA, Univ Oxford, Dept Stat, Oxford OX1 3TG, England, Scripps Res Inst, La Jolla, CA 92037 USA, Perlegen Sci Inc, Mountain View, CA 94043 USA, Baylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USA, Affymetrix Inc, Santa Clara, CA 95051 USA, Pacific Biosci, Menlo Pk, CA 94025 USA, Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA, Harvard Univ, Broad Inst, Cambridge, MA 02139 USA, MIT, Cambridge, MA 02139 USA, Chinese Acad Sci, Beijing Genom Inst, Beijing 100300, Peoples R China, Massachusetts Gen Hosp, Boston, MA 02114 USA, Harvard Univ, Sch Med, Simches Res Ctr, Boston, MA 02114 USA, Chinese Natl Human Genome Ctr, Beijing Econ Technol Dev Area, Beijing 100176, Peoples R China, Chinese Natl Human Genome Ctr, Shanghai 201203, Peoples R China, Fudan Univ, Shanghai 201203, Peoples R China, CAS, SIBS, Sch Life Sci, MPG Partner Inst Computat Biol, Shanghai 201203, Peoples R China, Chinese Univ Hong Kong, Dept Biochem, Croucher Lab Human Genet, Shatin, Hong Kong, Peoples R China, Hong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R China, Hong Kong Univ Sci & Technol, Appl Genom Ctr, Kowloon, Hong Kong, Peoples R China, Illumina, San Diego, CA 92121 USA, Complete Genom Inc, Sunnyvale, CA 94085 USA, Prognosys Biosci Inc, San Diego, CA 92121 USA, McGill Univ, Montreal, PQ H3A 1A4, Canada, Genome Quebec Innovat Ctr, Montreal, PQ H3A 1A4, Canada, Univ Montreal, Publ Law Res Ctr, Downtown Stn, Montreal, PQ H3C 3J7, Canada, Ontario Inst Canc Res, MaRS Ctr, Toronto, ON M5G 1L7, Canada, Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA, Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA, Univ Hong Kong, Genome Res Ctr, Hong Kong, Hong Kong, Peoples R China, Univ Tokyo, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan, RIKEN SNP Res Ctr, Tsurumi Ku, Kanagawa 2300045, Japan, Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England, Univ Cambridge, Dept Oncol, Cambridge CB1 8RN, England, Solexa Ltd, Saffron Walden CB10 1XL, Essex, England, Columbia Univ, New York, NY 10027 USA, Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England, Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA, Int Epidemiol Inst, Rockville, MD 20850 USA, Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA, Univ Chicago, Dept Stat, Chicago, IL 60637 USA, Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA, Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England, Univ Washington, Dept Biostat, Seattle, WA 98195 USA, NHGRI, US NIH, Bethesda, MD 20892 USA, Natl Lib Med, US NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA, Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA, Beijing Normal Univ, Beijing 100875, Peoples R China, Hlth Sci Univ Hokkaido, Ishikari, Hokkaido 0610293, Japan, Shinshu Univ, Sch Med, Dept Med Genet, Matsumoto, Nagano 3908621, Japan, UNESCO Bangkok, Bangkok 10110, Thailand, Univ Tsukuba, Eubios Eth Inst, Tsukuba, Ibaraki 3058691, Japan, Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA, Univ Ibadan, Coll Med, Ibadan, Oyo State, Nigeria, Case Western Reserve Univ, Sch Med, Dept Bioeth, Cleveland, OH 44106 USA, Univ Utah, Dept Human Genet, Eccles Inst Human Genet, Salt Lake City, UT 84112 USA, Chinese Acad Social Sci, Inst Philosophy, Ctr Appl Eth, Beijing 100067, Peoples R China, Genet Interest Grp, London N13 0P, England, Kyoto Univ, Inst Res Humanities, Kyoto 6068501, Japan, Grad Sch Biostudies, Sakyo Ku, Kyoto 6068501, Japan, Nagasaki Univ, Grad Sch Biomed Sci, Dept Human Genet, Nagasaki 8528523, Japan, Univ Oklahoma, Dept Anthropol, Norman, OK 73019 USA, Vanderbilt Univ, Ctr Genet & Hlth Policy, Nashville, TN 37232 USA, Wellcome Trust Res Labs, London NW1 2BE, England, Washington Univ, Sch Med, Genome Sequencing Ctr, St Louis, MO 63108 USA, Chinese Acad Sci, Beijing 100864, Peoples R China, Genome Canada, Ottawa, ON K2P 1P1, Canada, McGill Univ, Off Technol Transfer, Montreal, PQ H3A 2A7, Canada, Genome Quebec, Montreal, PQ H3B 1S6, Canada, Minist Educ Culture Sports Sci & Technol, Chiyoda Ku, Tokyo 1008959, Japan, Minist Sci & Technol, Beijing 100862, Peoples R China, Human Genet Resource Adm China, Beijing 100081, Peoples R China, US NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA, Novartis Pharmaceut Corp, Biomarker Dev, E Hanover, NJ 07936 USA, US NIH, Off Technol Transfer, Rockville, MD 20852 USA, Univ Maryland, Sch Law, Baltimore, MD 21201 USA, Mjdaly@chgr.mgh.harvard.edu; mcvean@stats.ox.ac.uk, Frazer, Kelly A., Ballinger, Dennis G., Cox, David R., Hinds, David A., Stuve, Laura L., Gibbs, Richard A., Belmont, John W., Boudreau, Andrew, Hardenbol, Paul, Leal, Suzanne M., Pasternak, Shiran, Tanaka, Toshihiro, Tsunoda, Tatsuhiko, Deloukas, Panos, Bird, Christine P., Delgado, Marcos, Dermitzakis, Emmanouil T., Gwilliam, Rhian, Hunt, Sarah, Morrison, Jonathan, Powell, Don, Wheeler, David A., Stranger, Barbara E., Whittaker, Pamela, Bentley, David R., Daly, Mark J., De Bakker, Paul I.W., Barrett, Jeff, Chretien, Yves R., Maller, Julian, McCarroll, Steve, Patterson, Nick, Willis, Thomas D., Pe'er, Itsik, Price, Alkes, Purcell, Shaun, Richter, Daniel J., Sabeti, Pardis, Saxena, Richa, Schaffner, Stephen F., Sham, Pak C., Varilly, Patrick, Altshuler, David, Yu, Fuli, Stein, Lincoln D., Krishnan, Lalitha, Smith, Albert Vernon, Tello-Ruiz, Marcela K., Thorisson, Gudmundur A., Chakravarti, Aravinda, Chen, Peter E., Cutler, David J., Kashuk, Carl S., Lin, Shin, Yang, Huanming, Abecasis, Gon??alo R., Guan, Weihua, Li, Yun, Munro, Heather M., Qin, Zhaohui Steve, Thomas, Daryl J., McVean, Gilean, Auton, Adam, Bottolo, Leonardo, Cardin, Niall, Zeng, Changqing, Eyheramendy, Susana, Freeman, Colin, Marchini, Jonathan, Myers, Simon, Spencer, Chris, Stephens, Matthew, Donnelly, Peter, Cardon, Lon R., Clarke, Geraldine, Evans, David M., Gao, Yang, Morris, Andrew P., Weir, Bruce S., Johnson, Todd A., Mullikin, James C., Sherry, Stephen T., Feolo, Michael, Skol, Andrew, Hu, Haoran, Hu, Weitao, Li, Chaohua, Lin, Wei, Liu, Siqi, Pan, Hao, Tang, Xiaoli, Wang, Jian, Wang, Wei, Yu, Jun, Zhang, Bo, Zhang, Qingrun, Zhao, Hongbin, Zhao, Hui, Zhou, Jun, Gabriel, Stacey B., Barry, Rachel, Blumenstiel, Brendan, Camargo, Amy, Defelice, Matthew, Faggart, Maura, Goyette, Mary, Gupta, Supriya, Moore, Jamie, Nguyen, Huy, Onofrio, Robert C., Parkin, Melissa, Roy, Jessica, Stahl, Erich, Winchester, Ellen, Ziaugra, Liuda, Shen, Yan, Yao, Zhijian, Huang, Wei, Chu, Xun, He, Yungang, Jin, Li, Liu, Yangfan, Shen, Yayun, Sun, Weiwei, Wang, Haifeng, Wang, Yi, Wang, Ying, Xiong, Xiaoyan, Xu, Liang, Waye, Mary M.Y., Tsui, Stephen K.W., Wong, J. Tze-Fei, Galver, Luana M., Fan, Jian-Bing, Gunderson, Kevin, Murray, Sarah S., Oliphant, Arnold R., Chee, Mark S., Montpetit, Alexandre, Chagnon, Fanny, Ferretti, Vincent, Leboeuf, Martin, Olivier, Jean-Franccois, Phillips, Michael S., Roumy, Stephanie, Sallee, Clementine, Verner, Andrei, Hudson, Thomas J., Kwok, Pui-Yan, Cai, Dongmei, Koboldt, Daniel C., Miller, Raymond D., Pawlikowska, Ludmila, Taillon-Miller, Patricia, Xiao, Ming, Tsui, Lap-Chee, Mak, William, Song, You Qiang, Tam, Paul K.H., Nakamura, Yusuke, Kawaguchi, Takahisa, Kitamoto, Takuya, Morizono, Takashi, Nagashima, Atsushi, Ohnishi, Yozo, and Sekine, Akihiro
Abstract: We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r(2) of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r(2) of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.
Published: 2009

30. Genetic evidence for an origin of the Armenians from Bronze Age mixing of multiple populations

Author: Wellcome Trust, Haber, Marc, Mezzavilla, Massimo, Xue, Yali, Comas, David, Gasparini, Paolo, Zalloua, Pierre, Tyler-Smith, Chris, Wellcome Trust, Haber, Marc, Mezzavilla, Massimo, Xue, Yali, Comas, David, Gasparini, Paolo, Zalloua, Pierre, and Tyler-Smith, Chris
Abstract: The Armenians are a culturally isolated population who historically inhabited a region in the Near East bounded by the Mediterranean and Black seas and the Caucasus, but remain under-represented in genetic studies and have a complex history including a major geographic displacement during World War I. Here, we analyse genome-wide variation in 173 Armenians and compare them with 78 other worldwide populations. We find that Armenians form a distinctive cluster linking the Near East, Europe, and the Caucasus. We show that Armenian diversity can be explained by several mixtures of Eurasian populations that occurred between ~3000 and ~2000 bce, a period characterized by major population migrations after the domestication of the horse, appearance of chariots, and the rise of advanced civilizations in the Near East. However, genetic signals of population mixture cease after ~1200 bce when Bronze Age civilizations in the Eastern Mediterranean world suddenly and violently collapsed. Armenians have since remained isolated and genetic structure within the population developed ~500 years ago when Armenia was divided between the Ottomans and the Safavid Empire in Iran. Finally, we show that Armenians have higher genetic affinity to Neolithic Europeans than other present-day Near Easterners, and that 29% of Armenian ancestry may originate from an ancestral population that is best represented by Neolithic Europeans.
Published: 2016

31. C14ORF39/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility

Author: Ministerio de Economía y Competitividad (España), German Research Foundation, European Commission, Wellcome Trust, Royal Society (UK), Gómez Hernández, Laura, Felipe-Medina, Natalia, Sánchez-Martín, M., Davies, Owen R., Ramos, Isabel, García-Tuñón, Ignacio, Rooij, Dirk G. de, Dereli, Ihsan, Tóth, Attila, Barbero, José Luis, Benavente, Ricardo, Llano, Elena, Pendás, Alberto M., Ministerio de Economía y Competitividad (España), German Research Foundation, European Commission, Wellcome Trust, Royal Society (UK), Gómez Hernández, Laura, Felipe-Medina, Natalia, Sánchez-Martín, M., Davies, Owen R., Ramos, Isabel, García-Tuñón, Ignacio, Rooij, Dirk G. de, Dereli, Ihsan, Tóth, Attila, Barbero, José Luis, Benavente, Ricardo, Llano, Elena, and Pendás, Alberto M.
Abstract: Meiotic recombination generates crossovers between homologous chromosomes that are essential for genome haploidization. The synaptonemal complex is a ‘zipper’-like protein assembly that synapses homologue pairs together and provides the structural framework for processing recombination sites into crossovers. Humans show individual differences in the number of crossovers generated across the genome. Recently, an anonymous gene variant in C14ORF39/SIX6OS1 was identified that influences the recombination rate in humans. Here we show that C14ORF39/SIX6OS1 encodes a component of the central element of the synaptonemal complex. Yeast two-hybrid analysis reveals that SIX6OS1 interacts with the well-established protein synaptonemal complex central element 1 (SYCE1). Mice lacking SIX6OS1 are defective in chromosome synapsis at meiotic prophase I, which provokes an arrest at the pachytene-like stage and results in infertility. In accordance with its role as a modifier of the human recombination rate, SIX6OS1 is essential for the appropriate processing of intermediate recombination nodules before crossover formation.
Published: 2016

32. Discovery and characterization of smORF-encoded bioactive polypeptides

Author: National Institutes of Health (US), Wellcome Trust, Saghatelian, Alan, Couso, Juan Pablo, National Institutes of Health (US), Wellcome Trust, Saghatelian, Alan, and Couso, Juan Pablo
Abstract: Analysis of genomes, transcriptomes and proteomes reveals the existence of hundreds to thousands of translated, yet non-annotated, short open reading frames (small ORFs or smORFs). The discovery of smORFs and their protein products, smORF-encoded polypeptides (SEPs), points to a fundamental gap in our knowledge of protein-coding genes. Various studies have identified central roles for smORFs in metabolism, apoptosis and development. The discovery of these bioactive SEPs emphasizes the functional potential of this unexplored class of biomolecules. Here, we provide an overview of this emerging field and highlight the opportunities for chemical biology to answer fundamental questions about these novel genes. Such studies will provide new insights into the protein-coding potential of genomes and identify functional genes with roles in biology and disease.
Published: 2015

33. TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors

Author: Medical Research Council (UK), Vanderbilt University, Purdue University, Kumamoto University, National Health Service (UK), Cambridge University Hospitals (UK), University of Manchester, Junta de Andalucía, Ministerio de Economía y Competitividad (España), National Institute for Health Research (UK), Wellcome Trust, Bessa, José, Luengo, Mario, Hanley, Neil A., Gómez-Skarmeta, José Luis, Vallier, Ludovic, Ferrer, Jorge, Medical Research Council (UK), Vanderbilt University, Purdue University, Kumamoto University, National Health Service (UK), Cambridge University Hospitals (UK), University of Manchester, Junta de Andalucía, Ministerio de Economía y Competitividad (España), National Institute for Health Research (UK), Wellcome Trust, Bessa, José, Luengo, Mario, Hanley, Neil A., Gómez-Skarmeta, José Luis, Vallier, Ludovic, and Ferrer, Jorge
Abstract: The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas.
Published: 2015

34. Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

Author: Eusko Jaurlaritza, Fundación Científica Asociación Española Contra el Cáncer, Wellcome Trust, Fundación Mutua Madrileña, European Research Council, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Ministerio de Educación y Ciencia (España), Comunidad de Madrid, European Commission, Salazar, María, Pérez-Gómez, Eduardo, Flores, Juana María, Quintanilla, Miguel, Sánchez, Cristina, Carracedo, Ángel, Velasco, Guillermo, Eusko Jaurlaritza, Fundación Científica Asociación Española Contra el Cáncer, Wellcome Trust, Fundación Mutua Madrileña, European Research Council, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Ministerio de Educación y Ciencia (España), Comunidad de Madrid, European Commission, Salazar, María, Pérez-Gómez, Eduardo, Flores, Juana María, Quintanilla, Miguel, Sánchez, Cristina, Carracedo, Ángel, and Velasco, Guillermo
Abstract: Tribbles pseudokinase-3 (TRIB3) has been proposed to act as an inhibitor of AKT although the precise molecular basis of this activity and whether the loss of TRIB3 contributes to cancer initiation and progression remain to be clarified. In this study, by using a wide array of in vitro and in vivo approaches, including a Trib3 knockout mouse, we demonstrate that TRIB3 has a tumor-suppressing role. We also find that the mechanism by which TRIB3 loss enhances tumorigenesis relies on the dysregulation of the phosphorylation of AKT by the mTORC2 complex, which leads to an enhanced phosphorylation of AKT on Ser473 and the subsequent hyperphosphorylation and inactivation of the transcription factor FOXO3. These observations support the notion that loss of TRIB3 is associated with a more aggressive phenotype in various types of tumors by enhancing the activity of the mTORC2/AKT/FOXO axis.
Published: 2015

35. Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Author: Cancer Research UK, National Cancer Institute (US), Wellcome Trust, European Commission, Kuchenbaecker, Karoline B., Ramus, Susan J., Tyrer, Jonathan, Hoya, Miguel de la, Díez, Orland, Blanco, Ignacio, Durán, Mercedes, Tejada, María Isabel, Cancer Research UK, National Cancer Institute (US), Wellcome Trust, European Commission, Kuchenbaecker, Karoline B., Ramus, Susan J., Tyrer, Jonathan, Hoya, Miguel de la, Díez, Orland, Blanco, Ignacio, Durán, Mercedes, and Tejada, María Isabel
Abstract: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high EOC risk. After imputation to the 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,397 cases unselected for family history and 30,816 controls, 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) specifically with the serous EOC subtype, at p<5×10−8. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1/2 mutation carriers.
Published: 2015

36. The European Genome-phenome Archive of human data consented for biomedical research

Author: EMBO, Wellcome Trust, Medical Research Council (UK), Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Fundación la Caixa, Centro Nacional de Supercomputación (España), European Commission, Lappalainen, Ilkka, Navarro, Arcadi, Flicek, Paul, EMBO, Wellcome Trust, Medical Research Council (UK), Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Fundación la Caixa, Centro Nacional de Supercomputación (España), European Commission, Lappalainen, Ilkka, Navarro, Arcadi, and Flicek, Paul
Abstract: The European Genome-phenome Archive (EGA) is a permanent archive that promotes the distribution and sharing of genetic and phenotypic data consented for specific approved uses but not fully open, public distribution. The EGA follows strict protocols for information management, data storage, security and dissemination. Authorized access to the data is managed in partnership with the data-providing organizations. The EGA includes major reference data collections for human genetics research.
Published: 2015

37. Genome-wide association study identifies five loci associated with lung function

Author: E, Repapi, I, Sayers, LV, Wain, RB, Burton, T, Johnson, M, Obeidat, JH, Zhao, A, Ramasamy, G, Zhai, V, Vitart, JE, Huffman, W, Igl, E, Albrecht, P, Deloukas, J, Henderson, J, Granell, WL, McArdle, AR, Rudnicka, Consortium, Wellcome Trust Case Control, I, Barroso, RJF, Loos, NJ, Wareham, L, Mustelin, Rantanen, Taina, I, Surakka, M, Imboden, HE, Wichmann, I, Grkovic, S, Jankovic, L, Zgaga, A, Hartikainen, L, Peltonen, U, Gyllensten, Å, Johansson, G, Zaboli, H, Campbell, SH, Wild, JF, Wilson, S, Gläser, G, Homuth, H, Völzke, M, Mangino, N, Soranzo, TD, Spector, O, Polašek, I, Rudan, AF, Wright, M, Heliövaara, S, Ripatti, A, Pouta, Å, Torinsson Naluai, A, Olin, K, Torén, MN, Cooper, AL, James, LJ, Palmer, AD, Hingorani, SG, Wannamethee, PH, Whincup, GD, Smith, S, Ebrahim, TM, McKeever, ID, Pavord, AK, MacLeod, AD, Morris, DJ, Porteous, C, Cooper, E, Dennison, S, Shaheen, S, Karrasch, E, Schnabel, H, Schulz, H, Grallert, N, Bouatia-Naji, J, Delplanque, P, Froguel, JD, Blakey, Team, The NSHD Respiratory Study, JR, Britton, RW, Morris, JW, Holloway, DA, Lawlor, J, Hui, F, Nyberg, M, Jarvelin, C, Jackson, M, Kähönen, J, Kaprio, NM, Probst-Hensch, B, Koch, C, Hayward, DE, Evans, P, Elliott, DP, Strachan, IP, Hall, and MD, Tobin
Subjects: geenit, keuhkotoiminnot, respiratory system, genetic, Lung function
Abstract: Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n ≤ 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV1 or FEV1/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 × 10−12), 4q24 in GSTCD (2.18 × 10−23), 5q33 in HTR4 (P = 4.29 × 10−9), 6p21 in AGER (P = 3.07 × 10−15) and 15q23 in THSD4 (P = 7.24 × 10−15). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease. peerReviewed
Published: 2010

38. A genome-wide association study of anorexia nervosa

Author: Experimental psychopathology, Sub Physical and Colloid Chemistry, Sub General Pharmaceutics, Leerstoel Ridder, LS Dierenwelzijn & Proefdierkunde, Leerstoel Elburg, Stress and self-regulation, Boraska, V, Franklin, C S, Floyd, J A B, Thornton, L M, Huckins, L M, Southam, L, Rayner, N W, Tachmazidou, I, Klump, K L, Treasure, J, Lewis, C M, Schmidt, U, Tozzi, F, Kiezebrink, K, Hebebrand, J, Gorwood, P, Adan, R A H, Kas, M J H, Favaro, A, Santonastaso, P, Fernández-Aranda, F, Gratacos, M, Rybakowski, F, Dmitrzak-Weglarz, M, Kaprio, J, Keski-Rahkonen, A, Raevuori, A, Van Furth, E F, Slof-Op 't Landt, M C T, Hudson, J I, Reichborn-Kjennerud, T, Knudsen, G P S, Monteleone, P, Kaplan, A S, Karwautz, A, Hakonarson, H, Berrettini, W H, Guo, Y, Li, D, Schork, N J, Komaki, G, Ando, T, Inoko, H, Esko, T, Fischer, K, Männik, K, Danner, U N, Hendriks, J, van Elburg, Annemarie, Kennedy, J L, Wellcome Trust Case Control Consortium 3, Experimental psychopathology, Sub Physical and Colloid Chemistry, Sub General Pharmaceutics, Leerstoel Ridder, LS Dierenwelzijn & Proefdierkunde, Leerstoel Elburg, Stress and self-regulation, Boraska, V, Franklin, C S, Floyd, J A B, Thornton, L M, Huckins, L M, Southam, L, Rayner, N W, Tachmazidou, I, Klump, K L, Treasure, J, Lewis, C M, Schmidt, U, Tozzi, F, Kiezebrink, K, Hebebrand, J, Gorwood, P, Adan, R A H, Kas, M J H, Favaro, A, Santonastaso, P, Fernández-Aranda, F, Gratacos, M, Rybakowski, F, Dmitrzak-Weglarz, M, Kaprio, J, Keski-Rahkonen, A, Raevuori, A, Van Furth, E F, Slof-Op 't Landt, M C T, Hudson, J I, Reichborn-Kjennerud, T, Knudsen, G P S, Monteleone, P, Kaplan, A S, Karwautz, A, Hakonarson, H, Berrettini, W H, Guo, Y, Li, D, Schork, N J, Komaki, G, Ando, T, Inoko, H, Esko, T, Fischer, K, Männik, K, Danner, U N, Hendriks, J, van Elburg, Annemarie, Kennedy, J L, and Wellcome Trust Case Control Consortium 3
Published: 2014

39. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants

Author: National Research Foundation Singapore, Agency for Science, Technology and Research A*STAR (Singapore), Centro Esther Koplowitz, European Foundation for the Study of Diabetes, Fundación Lilly, National University of Singapore, Junta de Andalucía, Wellcome Trust, Juvenile Diabetes Research Foundation International, European Commission, Ministerio de Economía y Competitividad (España), Tena, Juan J., Gómez-Marín, Carlos, Gómez-Skarmeta, José Luis, Ferrer, Jorge, National Research Foundation Singapore, Agency for Science, Technology and Research A*STAR (Singapore), Centro Esther Koplowitz, European Foundation for the Study of Diabetes, Fundación Lilly, National University of Singapore, Junta de Andalucía, Wellcome Trust, Juvenile Diabetes Research Foundation International, European Commission, Ministerio de Economía y Competitividad (España), Tena, Juan J., Gómez-Marín, Carlos, Gómez-Skarmeta, José Luis, and Ferrer, Jorge
Abstract: Type 2 diabetes affects over 300 million people, causing severe complications and premature death, yet the underlying molecular mechanisms are largely unknown. Pancreatic islet dysfunction is central in type 2 diabetes pathogenesis, and understanding islet genome regulation could therefore provide valuable mechanistic insights. We have now mapped and examined the function of human islet cis-regulatory networks. We identify genomic sequences that are targeted by islet transcription factors to drive islet-specific gene activity and show that most such sequences reside in clusters of enhancers that form physical three-dimensional chromatin domains. We find that sequence variants associated with type 2 diabetes and fasting glycemia are enriched in these clustered islet enhancers and identify trait-associated variants that disrupt DNA binding and islet enhancer activity. Our studies illustrate how islet transcription factors interact functionally with the epigenome and provide systematic evidence that the dysregulation of islet enhancers is relevant to the mechanisms underlying type 2 diabetes.
Published: 2014

40. Using ancestry-informative markers to identify fine structure across 15 populations of European origin

Author: Gambaro, Giovanni, Wellcome Trust Case Control Consortium, 3, Gambaro, Giovanni (ORCID:0000-0001-5733-2370), Gambaro, Giovanni, Wellcome Trust Case Control Consortium, 3, and Gambaro, Giovanni (ORCID:0000-0001-5733-2370)
Abstract: The Wellcome Trust Case Control Consortium 3 anorexia nervosa genome-wide association scan includes 2907 cases from 15 different populations of European origin genotyped on the Illumina 670K chip. We compared methods for identifying population stratification, and suggest list of markers that may help to counter this problem. It is usual to identify population structure in such studies using only common variants with minor allele frequency (MAF) >5%; we find that this may result in highly informative SNPs being discarded, and suggest that instead all SNPs with MAF >1% may be used. We established informative axes of variation identified via principal component analysis and highlight important features of the genetic structure of diverse European-descent populations, some studied for the first time at this scale. Finally, we investigated the substructure within each of these 15 populations and identified SNPs that help capture hidden stratification. This work can provide information regarding the designing and interpretation of association results in the International Consortia.European Journal of Human Genetics advance online publication, 19 February 2014; doi:10.1038/ejhg.2014.1.
Published: 2014

41. A robust SNP barcode for typing Mycobacterium tuberculosis complex strains

Author: Bloomsbury Research Foundation, Fundação para a Ciência e a Tecnologia (Portugal), King Abdullah University of Science and Technology, Wellcome Sanger Institute, Coll, Francesc [0000-0002-7882-2325], Coll, Francesc, McNerney, Ruth, Guerra-Assunção, José Afonso, Glynn, Judith R., Perdigão, João, Viveiros, Miguel, Portugal, Isabel, Pain, Arnab, Martin, Nigel, Clark, Taane G., Bloomsbury Research Foundation, Fundação para a Ciência e a Tecnologia (Portugal), King Abdullah University of Science and Technology, Wellcome Sanger Institute, Coll, Francesc [0000-0002-7882-2325], Coll, Francesc, McNerney, Ruth, Guerra-Assunção, José Afonso, Glynn, Judith R., Perdigão, João, Viveiros, Miguel, Portugal, Isabel, Pain, Arnab, Martin, Nigel, and Clark, Taane G.
Abstract: Strain-specific genomic diversity in the Mycobacterium tuberculosis complex (MTBC) is an important factor in pathogenesis that may affect virulence, transmissibility, host response and emergence of drug resistance. Several systems have been proposed to classify MTBC strains into distinct lineages and families. Here, we investigate single-nucleotide polymorphisms (SNPs) as robust (stable) markers of genetic variation for phylogenetic analysis. We identify ~92 k SNP across a global collection of 1,601 genomes. The SNP-based phylogeny is consistent with the gold-standard regions of difference (RD) classification system. Of the ~7 k strain-specific SNPs identified, 62 markers are proposed to discriminate known circulating strains. This SNP-based barcode is the first to cover all main lineages, and classifies a greater number of sublineages than current alternatives. It may be used to classify clinical isolates to evaluate tools to control the disease, including therapeutics and vaccines whose effectiveness may vary by strain type.
Published: 2014

42. Genome-wide association study identifies eight loci associated with blood pressure

Author: Newton-Cheh, C, Johnson, T, Gateva, V, Tobin, MD, Bochud, M, Coin, L, Najjar, SS, Zhao, JH, Heath, SC, Eyheramendy, S, Papadakis, K, Voight, BF, Scott, LJ, Zhang, F, Farrall, M, Tanaka, T, Wallace, C, Chambers, JC, Khaw, KT, Nilsson, P, van der Harst, P, Polidoro, S, Grobbee, DE, Onland-Moret, NC, Bots, ML, Wain, LV, Elliott, KS, Teumer, A, Luan, J, Lucas, G, Kuusisto, J, Burton, PR, Hadley, D, McArdle, WL, Wellcome Trust Case Control Consortium, Brown, M, Dominiczak, A, Newhouse, SJ, Samani, NJ, Webster, J, Zeggini, E, Beckmann, JS, Bergmann, S, Lim, N, Song, K, Vollenweider, P, Waeber, G, Waterworth, DM, Yuan, X, Groop, L, Orho-Melander, M, Allione, A, Di Gregorio, A, Guarrera, S, Panico, S, Ricceri, F, Romanazzi, V, Sacerdote, C, Vineis, P, Barroso, I, Sandhu, MS, Luben, RN, Crawford, GJ, Jousilahti, P, Perola, M, Boehnke, M, Bonnycastle, LL, Collins, FS, Jackson, AU, Mohlke, KL, Stringham, HM, Valle, TT, Willer, CJ, Bergman, RN, Morken, MA, Döring, A, Gieger, C, Illig, T, Meitinger, T, Org, E, Pfeufer, A, Wichmann, HE, Kathiresan, S, Marrugat, J, O'Donnell, CJ, Schwartz, SM, Siscovick, DS, Subirana, I, Freimer, NB, Hartikainen, AL, McCarthy, MI, O'Reilly, PF, Peltonen, L, Pouta, A, de Jong, PE, Snieder, H, van Gilst, WH, Clarke, R, Goel, A, Hamsten, A, Peden, JF, Seedorf, U, Syvänen, AC, Tognoni, G, Lakatta, EG, Sanna, S, Scheet, P, Schlessinger, D, Scuteri, A, Dörr, M, Ernst, F, Felix, SB, Homuth, G, Lorbeer, R, Reffelmann, T, Rettig, R, Völker, U, Galan, P, Gut, IG, Hercberg, S, Lathrop, GM, Zelenika, D, Deloukas, P, Soranzo, N, Williams, FM, Zhai, G, Salomaa, V, Laakso, M, Elosua, R, Forouhi, NG, Völzke, H, Uiterwaal, CS, van der Schouw, YT, Numans, ME, Matullo, G, Navis, G, Berglund, G, Bingham, SA, Kooner, JS, Connell, JM, Bandinelli, S, Ferrucci, L, Watkins, H, Spector, TD, Tuomilehto, J, Altshuler, D, Strachan, DP, Laan, M, Meneton, P, Wareham, NJ, Uda, M, Jarvelin, MR, Mooser, V, Melander, O, Loos, RJ, Elliott, P, Abecasis, GR, Caulfield, M, and Munroe, PB
Published: 2009

43. Detailed molecular characterisation of acute myeloid leukaemia with a normal karyotype using targeted DNA capture

Author: Leukaemia & Lymphoma Research (UK), Leukaemia Foundation, Wellcome Trust, University of Cambridge, National Institute for Health Research (UK), Varela, Ignacio, Moreno, Teresa, Rad, Roland, Vassiliou, George S., Leukaemia & Lymphoma Research (UK), Leukaemia Foundation, Wellcome Trust, University of Cambridge, National Institute for Health Research (UK), Varela, Ignacio, Moreno, Teresa, Rad, Roland, and Vassiliou, George S.
Abstract: Advances in sequencing technologies are giving unprecedented insights into the spectrum of somatic mutations underlying acute myeloid leukaemia with a normal karyotype (AML-NK). It is clear that the prognosis of individual patients is strongly influenced by the combination of mutations in their leukaemia and that many leukaemias are composed of multiple subclones, with differential susceptibilities to treatment. Here, we describe a method, employing targeted capture coupled with next-generation sequencing and tailored bioinformatic analysis, for the simultaneous study of 24 genes recurrently mutated in AML-NK. Mutational analysis was performed using open source software and an in-house script (Mutation Identification and Analysis Software), which identified dominant clone mutations with 100% specificity. In each of seven cases of AML-NK studied, we identified and verified mutations in 2-4 genes in the main leukaemic clone. Additionally, high sequencing depth enabled us to identify putative subclonal mutations and detect leukaemia-specific mutations in DNA from remission marrow. Finally, we used normalised read depths to detect copy number changes and identified and subsequently verified a tandem duplication of exons 2-9 of MLL and at least one deletion involving PTEN. This methodology reliably detects sequence and copy number mutations, and can thus greatly facilitate the classification, clinical research, diagnosis and management of AML-NK.
Published: 2013

44. Noncanonical G recognition mediates KSRP regulation of let-7 biogenesis

Author: Medical Research Council (UK), Wellcome Trust, Association for International Cancer Research, Associazione Italiana per la Ricerca sul Cancro, Nicastro, Giuseppe, García-Mayoral, M.F., Hollingworth, David, Kelly, Geoff, Martin, Stephen R., Briata, Paola, Gherzi, Roberto, Ramos, Andrés, Medical Research Council (UK), Wellcome Trust, Association for International Cancer Research, Associazione Italiana per la Ricerca sul Cancro, Nicastro, Giuseppe, García-Mayoral, M.F., Hollingworth, David, Kelly, Geoff, Martin, Stephen R., Briata, Paola, Gherzi, Roberto, and Ramos, Andrés
Abstract: Let-7 is an important tumor-suppressive microRNA (miRNA) that acts as an on-off switch for cellular differentiation and regulates the expression of a set of human oncogenes. Binding of the human KSRP protein to let-7 miRNA precursors positively regulates their processing to mature let-7, thereby contributing to control of cell proliferation, apoptosis and differentiation. Here we analyze the molecular basis for KSRP–let-7 precursor selectivity and show how the third KH domain of the protein recognizes a G-rich sequence in the pre–let-7 terminal loop and dominates the interaction. The structure of the KH3–RNA complex explains the protein recognition of this noncanonical KH target sequence, and we demonstrate that the specificity of this binding is crucial for the functional interaction between the protein and the miRNA precursor
Published: 2012

45. Insights into hominid evolution from the gorilla genome sequence

Author: Wellcome Trust, European Molecular Biology Laboratory, University of Cambridge, Lundbeck Foundation, Academy of Finland, Emil Aaltonen Foundation, European Commission, European Research Council, Ministerio de Educación (España), Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), National Human Genome Research Institute (US), Danish Council for Independent Research, Swiss National Science Foundation, Louis Jeantet Foundation, EMBO, BIOBASE, National Science Foundation (US), Howard Hughes Medical Institute, Scally, Aylwyn, Marqués-Bonet, Tomàs, Prado-Martinez, Javier, Durbin, Richard, Wellcome Trust, European Molecular Biology Laboratory, University of Cambridge, Lundbeck Foundation, Academy of Finland, Emil Aaltonen Foundation, European Commission, European Research Council, Ministerio de Educación (España), Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), National Human Genome Research Institute (US), Danish Council for Independent Research, Swiss National Science Foundation, Louis Jeantet Foundation, EMBO, BIOBASE, National Science Foundation (US), Howard Hughes Medical Institute, Scally, Aylwyn, Marqués-Bonet, Tomàs, Prado-Martinez, Javier, and Durbin, Richard
Abstract: Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution. © 2012 Macmillan Publishers Limited. All rights reserved.
Published: 2012

46. The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm.

Author: Wellcome Trust, German Research Foundation, Ministerio de Educación y Ciencia (España), Fundación Ramón Areces, Weavers, Helen, Prieto-Sánchez, Silvia, Grawe, Ferdinand, García-López, Amparo, Artero, Rubén, Wilsch-Braeuninger, Michaela, Ruiz-Gómez, Mar, Skaer, Helen, Denholm, Barry, Wellcome Trust, German Research Foundation, Ministerio de Educación y Ciencia (España), Fundación Ramón Areces, Weavers, Helen, Prieto-Sánchez, Silvia, Grawe, Ferdinand, García-López, Amparo, Artero, Rubén, Wilsch-Braeuninger, Michaela, Ruiz-Gómez, Mar, Skaer, Helen, and Denholm, Barry
Abstract: The nephron is the basic structural and functional unit of the vertebrate kidney. It is composed of a glomerulus, the site of ultrafiltration, and a renal tubule, along which the filtrate is modified. Although widely regarded as a vertebrate adaptation, 'nephron-like' features can be found in the excretory systems of many invertebrates, raising the possibility that components of the vertebrate excretory system were inherited from their invertebrate ancestors. Here we show that the insect nephrocyte has remarkable anatomical, molecular and functional similarity to the glomerular podocyte, a cell in the vertebrate kidney that forms the main size-selective barrier as blood is ultrafiltered to make urine. In particular, both cell types possess a specialized filtration diaphragm, known as the slit diaphragm in podocytes or the nephrocyte diaphragm in nephrocytes. We find that fly (Drosophila melanogaster) orthologues of the major constituents of the slit diaphragm, including nephrin, NEPH1 (also known as KIRREL), CD2AP, ZO-1 (TJP1) and podocin, are expressed in the nephrocyte and form a complex of interacting proteins that closely mirrors the vertebrate slit diaphragm complex. Furthermore, we find that the nephrocyte diaphragm is completely lost in flies lacking the orthologues of nephrin or NEPH1-a phenotype resembling loss of the slit diaphragm in the absence of either nephrin (as in human congenital nephrotic syndrome of the Finnish type, NPHS1) or NEPH1. These changes markedly impair filtration function in the nephrocyte. The similarities we describe between invertebrate nephrocytes and vertebrate podocytes provide evidence suggesting that the two cell types are evolutionarily related, and establish the nephrocyte as a simple model in which to study podocyte biology and podocyte-associated diseases.
Published: 2009

47. Assessment of transcript reconstruction methods for RNA-seq.

Author: Head of Medical Sequencing ; Head of Medical Sequencing, Institut de Génétique et Développement de Rennes (IGDR) ; CNRS - IFR140 - Université de Rennes 1, Centro de Regulación Genómica (CRG) ; Pompeu Fabra University, Department of Statistics ; University of California, Berkeley, Oncogenetics Team ; The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sanger Institute ; Wellcome Trust, Laboratoire d'Informatique de Nantes Atlantique (LINA) ; CNRS - Université de Nantes - École Nationale Supérieure des Mines - Nantes, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM) ; CNRS - INSERM - Université Pierre et Marie Curie (UPMC) - Paris VI, Protéines de défense des réponses immune et inflammatoire : identification, régulation et rôles physiopathologiques ; INSERM - Université de Rouen, Université de Lausanne (UNIL) ; Université de Lausanne, Centre Georges Chevrier. Ordre et desordre dans l'histoire des societes (CGCODDHS) ; CNRS - Université de Bourgogne, School of Life Sciences [Lausanne] ; École Polytechnique Fédérale de Lausanne, Swiss Institute of Bioinformatics (SIB) ; Swiss Institute of Bioinformatics, Centro Nacional de Análisi Genómico (CNAG) ; Centro Nacional de Análisis Genómico, Department of Computer Science [Royal Holloway] ; Royal Holloway, University of London, University of California Santa Cruz (UCSC) ; University of California Santa Cruz, Swiss Institute of Bioinformatics - Lausanne (SIB) ; Swiss Institute of Bioinformatics, Analyse ; Institut Élie Cartan de Lorraine (IECL) ; CNRS - Université de Lorraine - CNRS - Université de Lorraine, Steijger, Tamara, Abril, Josep F, Engström, Pär G, Kokocinski, Felix, Akerman, Martin, Alioto, Tyler, Ambrosini, Giovanna, Antonarakis, Stylianos E, Behr, Jonas, Bertone, Paul, Bohnert, Regina, Bucher, Philipp, Cloonan, Nicole, Derrien, Thomas, Djebali, Sarah, Du, Jiang, Dudoit, Sandrine, Gerstein, Mark, Gingeras, Thomas R, Gonzalez, David, Grimmond, Sean M, Guigó, Roderic, Habegger, Lukas, Harrow, Jennifer, Hubbard, Tim J, Iseli, Christian, Jean, Géraldine, Kahles, André, Lagarde, Julien, Leng, Jing, Lefebvre, Gregory, Lewis, Suzanna, Mortazavi, Ali, Niermann, Peter, Rätsch, Gunnar, Reymond, Alexandre, Ribeca, Paolo, Richard, Hugues, Rougemont, Jacques, Rozowsky, Joel, Sammeth, Michael, Sboner, Andrea, Schulz, Marcel H, Searle, Steven M J, Solorzano, Naryttza Diaz, Solovyev, Victor, Stanke, Mario, Stevenson, Brian J, Stockinger, Heinz, Valsesia, Armand, Weese, David, White, Simon, Wold, Barbara J, Wu, Jie, Wu, Thomas D, Zeller, Georg, Zerbino, Daniel, Zhang, Michael Q, Head of Medical Sequencing ; Head of Medical Sequencing, Institut de Génétique et Développement de Rennes (IGDR) ; CNRS - IFR140 - Université de Rennes 1, Centro de Regulación Genómica (CRG) ; Pompeu Fabra University, Department of Statistics ; University of California, Berkeley, Oncogenetics Team ; The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sanger Institute ; Wellcome Trust, Laboratoire d'Informatique de Nantes Atlantique (LINA) ; CNRS - Université de Nantes - École Nationale Supérieure des Mines - Nantes, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM) ; CNRS - INSERM - Université Pierre et Marie Curie (UPMC) - Paris VI, Protéines de défense des réponses immune et inflammatoire : identification, régulation et rôles physiopathologiques ; INSERM - Université de Rouen, Université de Lausanne (UNIL) ; Université de Lausanne, Centre Georges Chevrier. Ordre et desordre dans l'histoire des societes (CGCODDHS) ; CNRS - Université de Bourgogne, School of Life Sciences [Lausanne] ; École Polytechnique Fédérale de Lausanne, Swiss Institute of Bioinformatics (SIB) ; Swiss Institute of Bioinformatics, Centro Nacional de Análisi Genómico (CNAG) ; Centro Nacional de Análisis Genómico, Department of Computer Science [Royal Holloway] ; Royal Holloway, University of London, University of California Santa Cruz (UCSC) ; University of California Santa Cruz, Swiss Institute of Bioinformatics - Lausanne (SIB) ; Swiss Institute of Bioinformatics, Analyse ; Institut Élie Cartan de Lorraine (IECL) ; CNRS - Université de Lorraine - CNRS - Université de Lorraine, Steijger, Tamara, Abril, Josep F, Engström, Pär G, Kokocinski, Felix, Akerman, Martin, Alioto, Tyler, Ambrosini, Giovanna, Antonarakis, Stylianos E, Behr, Jonas, Bertone, Paul, Bohnert, Regina, Bucher, Philipp, Cloonan, Nicole, Derrien, Thomas, Djebali, Sarah, Du, Jiang, Dudoit, Sandrine, Gerstein, Mark, Gingeras, Thomas R, Gonzalez, David, Grimmond, Sean M, Guigó, Roderic, Habegger, Lukas, Harrow, Jennifer, Hubbard, Tim J, Iseli, Christian, Jean, Géraldine, Kahles, André, Lagarde, Julien, Leng, Jing, Lefebvre, Gregory, Lewis, Suzanna, Mortazavi, Ali, Niermann, Peter, Rätsch, Gunnar, Reymond, Alexandre, Ribeca, Paolo, Richard, Hugues, Rougemont, Jacques, Rozowsky, Joel, Sammeth, Michael, Sboner, Andrea, Schulz, Marcel H, Searle, Steven M J, Solorzano, Naryttza Diaz, Solovyev, Victor, Stanke, Mario, Stevenson, Brian J, Stockinger, Heinz, Valsesia, Armand, Weese, David, White, Simon, Wold, Barbara J, Wu, Jie, Wu, Thomas D, Zeller, Georg, Zerbino, Daniel, and Zhang, Michael Q
Abstract: LINA-COMBI, International audience, We evaluated 25 protocol variants of 14 independent computational methods for exon identification, transcript reconstruction and expression-level quantification from RNA-seq data. Our results show that most algorithms are able to identify discrete transcript components with high success rates but that assembly of complete isoform structures poses a major challenge even when all constituent elements are identified. Expression-level estimates also varied widely across methods, even when based on similar transcript models. Consequently, the complexity of higher eukaryotic genomes imposes severe limitations on transcript recall and splice product discrimination that are likely to remain limiting factors for the analysis of current-generation RNA-seq data.

48. Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Author: Ashley N. Sigafoos, Salima El Chehadeh, Marcia C. Willing, Ela Akay, Florian Cherik, Anne-Marie E. Goyette, Vinodh Narayanan, Diane Masser-Frye, Catherine Karimov, Rhonda E. Schnur, Rebekah Bressi, Rhys H. Thomas, Gary D. Clark, Tina Barbaro-Dieber, Jill A. Rosenfeld, Carlos A. Bacino, Maria J. Guillen Sacoto, Laura Russell, Kristin Lindstrom, Caroline Schluth-Bolard, Xia Wang, Yvonne Hilhorst-Hofstee, Marcelo Vargas, Zehua Zhu, Ash Zawerton, Boris Keren, Mariëtte J.V. Hoffer, Isabelle Marey, Alice Poisson, Daphné Lehalle, Maries Joseph, Gaetan Lesca, Simon Zwolinski, Laurence Perrin, Rhoda Akilapa, Emilia K. Bijlsma, Christel Depienne, Amélie Piton, Claire G. Salter, Lucie Dupuis, Daryl A. Scott, Jolien S. Klein Wassink-Ruiter, Benjamin Cogné, Mathilde Nizon, Richard Chang, Kirsty McWalter, Myriam Srour, Perrine Charles, Anne-Claude Tabet, Natalie Canham, Sylvie Odent, Caroline Nava, Karl J. Clark, Elizabeth J. Bhoj, Jonathan Levy, Keri Ramsey, Yves Alembik, Lucia Ortega, Sophie Dupuis-Girod, Shoji Ichikawa, Christine Francannet, Marta Bertoli, Christèle Dubourg, Eric W. Klee, Ange-Line Bruel, Sebastien Moutton, Emily Fassi, Anthony Vandersteen, Abdul Haseeb, Antonina Wojcik, Patrick R. Blackburn, Lynne M. Bird, Patrick Rump, Véronique Lefebvre, Alma Kuechler, Sophie Nambot, Keren Machol, Cyril Mignot, Andreas Hartmann, Rossana Sanchez Russo, Erica H. Gerkes, Sylvie Jaillard, Roberto Mendoza-Londono, Trevor Cole, Pauline Monin, Cleveland Clinic, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, This research was funded in part by the Agence Nationale de la Recherche and European High-Functioning Autism Network (ANR EUHFAUTISM), the Assistance Publique–Hôpitaux de Paris (AP-HP), the Institut National de la Santé et de la Recherche Médicale (INSERM), the BioPsy labex (to Christel Depienne and C.N.) and the Association Française du Syndrome Gilles de la Tourette (AFSGT) to Christel Depienne. It was also funded by the Cleveland Clinic Lerner Research Institute (LRI Chair’s Innovative Research Award to V.L.), and by Harper’s Quest and the LAMSHF Syndrome Research Fund (donations to V.L.) and the Center for Individualized Medicine, Mayo Clinic. This study makes use of data generated by the DECIPHER community and the Deciphering Developmental Disorders (DDD) Study, which is funded by the Wellcome Trust. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network., We thank the patients and their families for their participation in this study, and the C4RCD Research Group (Newell Belnap, Amanda Courtright, Ana Claasen, David Craig, Matt Huentelman, Madison LaFleur, Sampathkumar Rangasamy, Ryan Richholt, Isabelle Schrauwen, Ashley L. Siniard, and Szabolics Szelinger) for providing clinical information on patient P18., Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Centre d'Exploration et de Recherche Médicales par Émission de Positons (CERMEP), Université Joseph Fourier - Grenoble 1 (UJF)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Medizin, Haploinsufficiency, L-SOX5, VARIANTS, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Missense mutation, 2.1 Biological and endogenous factors, Aetiology, Child, Genetics (clinical), Genetics, Pediatric, Genetics & Heredity, 0303 health sciences, Pedigree, FAMILY, DNA-Binding Proteins, developmental delay, TRANSCRIPTION FACTORS, Phenotype, intellectual disability, Child, Preschool, missense variants, Female, SOXD Transcription Factors, Adult, EXPRESSION, Adolescent, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Mutation, Missense, autism, Cell fate determination, Biology, LONG FORM, SEQUENCE, Article, 03 medical and health sciences, Young Adult, Rare Diseases, Clinical Research, CARTILAGE, Intellectual Disability, medicine, Animals, Humans, Language Development Disorders, Genetic Predisposition to Disease, Preschool, Transcription factor, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MUTATIONS, Human Genome, Infant, medicine.disease, Brain Disorders, Neurodevelopmental Disorders, Deciphering Developmental Disorder Study, Mutation, Autism, epilepsy, Missense, 030217 neurology & neurosurgery, GENERATION
Abstract: International audience; PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types of SOX5 alterations. Functional consequences of selected substitutions were investigated.RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.CONCLUSIONS:This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.
Published: 2020

49. Monoallelic expression and epigenetic inheritance sustained by a Trypanosoma brucei variant surface glycoprotein exclusion complex

Author: Faria, Joana, Glover, Lucy, Hutchinson, Sebastian, Boehm, Cordula, Field, Mark C., Horn, David, University of Dundee, The work was funded by Wellcome Trust Investigator Awards to D.H. [100320/Z/12/Z] and M.C.F. [204697/Z/16/Z] with additional support from a Wellcome Trust Centre Award [203134/Z/16/Z]. The University of Dundee Flow Cytometry and Imaging Facilities are supported by a Wellcome Trust award [097418/Z/11/Z], and the MRC Next Generation Optical Microscopy award [MR/K015869/1], respectively, and while both the Proteomics and Imaging Facilities are supported by a Wellcome Trust Technology Platform award [097945/B/11/Z].
Subjects: DNA Replication, Transcription, Genetic, Science, [SDV]Life Sciences [q-bio], Trypanosoma brucei brucei, Protozoan Proteins, MESH: DNA Replication, MESH: Host-Parasite Interactions, Article, Cell Line, Epigenesis, Genetic, Host-Parasite Interactions, parasitic diseases, Parasite genetics, Animals, MESH: Animals, MESH: Epigenesis, Genetic, MESH: Immune Evasion, lcsh:Science, MESH: Protozoan Proteins, Alleles, Immune Evasion, MESH: Alleles, MESH: Transcription, Genetic, MESH: Trypanosoma brucei brucei, Gene silencing, MESH: Gene Expression Regulation, Antigenic Variation, MESH: Cell Line, Parasite biology, Chromatin Assembly Factor-1, MESH: Trypanosomiasis, African, Trypanosomiasis, African, Gene Expression Regulation, MESH: Antigenic Variation, MESH: Variant Surface Glycoproteins, Trypanosoma, lcsh:Q, Epigenetics analysis, MESH: Chromatin Assembly Factor-1, Variant Surface Glycoproteins, Trypanosoma
Abstract: The largest gene families in eukaryotes are subject to allelic exclusion, but mechanisms underpinning single allele selection and inheritance remain unclear. Here, we describe a protein complex sustaining variant surface glycoprotein (VSG) allelic exclusion and antigenic variation in Trypanosoma brucei parasites. The VSG-exclusion-1 (VEX1) protein binds both telomeric VSG-associated chromatin and VEX2, an ortholog of nonsense-mediated-decay helicase, UPF1. VEX1 and VEX2 assemble in an RNA polymerase-I transcription-dependent manner and sustain the active, subtelomeric VSG-associated transcription compartment. VSG transcripts and VSG coats become highly heterogeneous when VEX proteins are depleted. Further, the DNA replication-associated chromatin assembly factor, CAF-1, binds to and specifically maintains VEX1 compartmentalisation following DNA replication. Thus, the VEX-complex controls VSG-exclusion, while CAF-1 sustains VEX-complex inheritance in association with the active-VSG. Notably, the VEX2-orthologue and CAF-1 in mammals are also implicated in exclusion and inheritance functions. In trypanosomes, these factors sustain a highly effective and paradigmatic immune evasion strategy., Monoallelic expression of variant surface glycoprotein genes (VSGs) is essential for immune evasion by Trypanosoma brucei. Here, Faria et al. show that the VEX protein complex controls VSG allelic exclusion, and that CAF‐1 sustains inheritance of the VEX‐complex in association with the active VSG.
Published: 2019

50. Past and future spread of the arbovirus vectors Aedes aegypti and Aedes albopictus

Author: Donal Bisanzio, Thomas W. Scott, G. R. William Wint, T. Alex Perkins, Nicole Davis Weaver, Lucas Earl, Laurie B. Marczak, Erik Wetter, Hongjie Yu, Shengjie Lai, Dingdong Yi, Simon I. Hay, Wim Van Bortel, Cedric Marsboom, Francis Schaffner, Giovanini E. Coelho, David M. Pigott, Jane P. Messina, Xin Lu, Robert C. Reiner, Linus Bengtsson, Andrew J. Tatem, David L. Smith, Chester G. Moore, Shreya Shirude, Qiyong Liu, Peter A. Jones, Kimberly J. Johnson, Roberta G. Carvalho, John S. Brownstein, Moritz U. G. Kraemer, Oliver J. Brady, Nuno R. Faria, Louis Lambrechts, Nick Golding, Marius Gilbert, Heinrich H. Nax, Guy Hendrickx, Oliver G. Pybus, Simon Cauchemez, Catherine Linard, University of Oxford [Oxford], Boston Children's Hospital, Harvard Medical School [Boston] (HMS), University of Washington [Seattle], London School of Hygiene and Tropical Medicine (LSHTM), Université libre de Bruxelles (ULB), Fonds National de la Recherche Scientifique [Bruxelles] (FNRS), Harvard University [Cambridge], University of Nottingham, UK (UON), Eck Institute for Global Health, University of Notre Dame [Indiana] (UND), Fudan University [Shanghai], University of Southampton, Flowminder Foundation, Central South University [Changsha], National University of Defense Technology [China], Southwestern University of Finance and Economics [Chengdu, China], Waen Associates Ltd, Pan American Health Organization [Washington] (PAHO), Ministry of Health [Brasília, Brazil], European Centre for Disease Prevention and Control (ECDC), Institute of Tropical Medicine [Antwerp] (ITM), Egis Avia (FRANCE), Francis Schaffner Consultancy, Colorado State University [Fort Collins] (CSU), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Karolinska Institutet [Stockholm], Stockholm School of Economics (SSE), Interactions Virus-Insectes - Insect-Virus Interactions (IVI), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Modélisation mathématique des maladies infectieuses - Mathematical modelling of Infectious Diseases, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université de Namur [Namur] (UNamur), University of California [Davis] (UC Davis), University of California, Chinese Center for Disease Control and Prevention, Shandong University, University of Melbourne, The authors thank S. Ray for providing comments during the revision process. M.U.G.K. acknowledges funding from the Society in Science, The Branco Weiss Fellowship, administered by the ETH Zurich. M.U.G.K. also acknowledges funding from the Training Grant from the National Institute of Child Health and Human Development (T32HD040128). M.U.G.K., S.I.H., J.P.M., N.G., O.J.B. and G.R.W.W. acknowledge funding from the International Research Consortium on Dengue Risk Assessment Management and Surveillance (IDAMS, European Commission 7th Framework Programme no. 21893). O.B.J. was funded by a Sir Henry Wellcome Fellowship funded by the Wellcome Trust (grant number 206471/Z/17/Z) and a grant from the Bill and Melinda Gates Foundation (OP1183567). S.I.H. received a grant from the Research for Health in Humanitarian Crises (R2HC) Programme, managed by Enhancing Learning and Research for Humanitarian Assistance (ELRHA, no. 13468), which also supported M.U.G.K. and N.G. The R2HC programme aims to improve health outcomes by strengthening the evidence base for public health interventions in humanitarian crises. The £8 million R2HC programme is funded equally by the Wellcome Trust and Department of International Development (DFiD), with ELRHA overseeing the programme’s execution and management. S.I.H. was also funded by a Senior Research Fellowship from the Wellcome Trust (no. 95066) and grants from the Bill & Melinda Gates Foundation (OPP1106023, OPP1093011, OPP1132415 and OPP1159934). This study was made possible by the support of the American people through the US Agency for International Development Emerging Pandemic Threats Program-2 PREDICT-2 (Cooperative Agreement number AID-OAA-A-14-00102), which also supported M.U.G.K. J.S.B. is supported by the National Library of Medicine of the National Institutes of Health (R01LM010812 and R01LM011965), which also supports M.U.G.K. D.L.S. is funded by the National Institutes of Health and National Institute of Allergy and Infectious Diseases (no. U10AI089674). H.H.N. was funded by the European Commission through the European Research Council Advanced Investigator Grant ‘Momentum’ 324247. L.L. received funding from the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (grant ANR-10-LABX-62-IBEID), the French Agence Nationale de la Recherche (grant ANR-16-CE35-0004), the City of Paris Emergence(s) programme in Biomedical Research, and the European Union’s Horizon 2020 research and innovation programme under ZikaPLAN grant agreement No. 734584. S.C. received funding from the AXA Research Fund, the Investissement d’Avenir program, the Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases program (Grant ANR-10-LABX-62-IBEID), the Models of Infectious Disease Agent Study of the National Institute of General Medical Sciences, the INCEPTION project (PIA/ANR-16-CONV-0005), and the European Union’s Horizon 2020 research and innovation programme under ZIKAlliance grant agreement No 734548. N.G. is supported by a University of Melbourne McKenzie fellowship. W.V.B., G.H. and F.S. acknowledge funding from VBORNET and VectorNet, an ECDC and EFSA-funded project (no. ECDC/09/018 and OC/EFSA/AHAW/2013/02), and thank all contributing VBORNET and VectorNet experts for data sharing. T.W.S., R.C.R. and L.L. received funding from the National Institutes of Health Program Project grant (no. P01 AI098670). X.L. is supported by the Natural Science Foundation of China (71771213, 71522014, 71725001, 91846301 and 71790615). This work was also partially supported by the European Union’s Horizon 2020 Research and Innovation Programme under ZIKAlliance Grant Agreement no. 734548., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CE35-0004,MOSQUIBIOTA,Contribution de la diversité bactérienne intestinale à la capacité vectorielle d'Aedes aegypti(2016), European Project: 734548,ZIKAlliance(2016), European Project: 324247,EC:FP7:ERC,ERC-2012-ADG_20120411,MOMENTUM(2013), European Project: 281803,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,IDAMS(2011), University of Oxford, Harvard University, European Centre for Disease Prevention and Control [Stockholm, Sweden] (ECDC), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and University of California (UC)
Subjects: Microbiology (medical), Microbiologie et protistologie [parasitologie hum. et anim.], Aedes albopictus, Arbovirus Infections, Immunology, Aedes aegypti, medicine.disease_cause, Applied Microbiology and Biotechnology, Arbovirus, Microbiology, Article, Dengue fever, Zika virus, 03 medical and health sciences, Genetics, medicine, Chikungunya, 030304 developmental biology, Aedes, 0303 health sciences, biology, 030306 microbiology, Ecology, virus diseases, Cell Biology, biology.organism_classification, medicine.disease, 3. Good health, Microbiologie et protistologie [entomologie,phytoparasitolog.], Geography, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Infectious diseases
Abstract: The global population at risk from mosquito-borne diseases—including dengue, yellow fever, chikungunya and Zika—is expanding in concert with changes in the distribution of two key vectors: Aedes aegypti and Aedes albopictus. The distribution of these species is largely driven by both human movement and the presence of suitable climate. Using statistical mapping techniques, we show that human movement patterns explain the spread of both species in Europe and the United States following their introduction. We find that the spread of Ae. aegypti is characterized by long distance importations, while Ae. albopictus has expanded more along the fringes of its distribution. We describe these processes and predict the future distributions of both species in response to accelerating urbanization, connectivity and climate change. Global surveillance and control efforts that aim to mitigate the spread of chikungunya, dengue, yellow fever and Zika viruses must consider the so far unabated spread of these mosquitos. Our maps and predictions offer an opportunity to strategically target surveillance and control programmes and thereby augment efforts to reduce arbovirus burden in human populations globally., 0, SCOPUS: ar.j, SCOPUS: er.j, info:eu-repo/semantics/published
Published: 2019

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