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1. AI and the democratization of knowledge

Author

Christophe Dessimoz and Paul D. Thomas

Subjects
Science
Abstract

The solution of the longstanding “protein folding problem” in 2021 showcased the transformative capabilities of AI in advancing the biomedical sciences. AI was characterized as successfully learning from protein structure data, which then spurred a more general call for AI-ready datasets to drive forward medical research. Here, we argue that it is the broad availability of knowledge, not just data, that is required to fuel further advances in AI in the scientific domain. This represents a quantum leap in a trend toward knowledge democratization that had already been developing in the biomedical sciences: knowledge is no longer primarily applied by specialists in a sub-field of biomedicine, but rather multidisciplinary teams, diverse biomedical research programs, and now machine learning. The development and application of explicit knowledge representations underpinning democratization is becoming a core scientific activity, and more investment in this activity is required if we are to achieve the promise of AI.

Published
2024
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2. Functional implications of glycans and their curation: insights from the workshop held at the 16th Annual International Biocuration Conference in Padua, Italy.

Author

Karina Martinez, Jon Agirre, Yukie Akune, Kiyoko F. Aoki-Kinoshita, Cecilia N. Arighi, Kristian B. Axelsen, Evan Bolton, Emily Bordeleau, Nathan J. Edwards, Elisa Fadda, Ten Feizi, Catherine A. Hayes, Callum M. Ives, Hiren J. Joshi, Khakurel Krishna Prasad, Sofia Kossida, Frédérique Lisacek, Yan Liu, Thomas Lütteke, Junfeng Ma, Adnan Malik, Maria Jesus Martin, Akul Y. Mehta, Sriram Neelamegham, Kalpana Panneerselvam, René Ranzinger, Sylvie Ricard-Blum, Gaoussou Sanou, Vijay Shanker, Paul D. Thomas, Michael Tiemeyer, James Urban, Randi Vita, Jeet Vora, Yasunori Yamamoto, and Raja Mazumder

Published
2024
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3. SARS-CoV-2 viral variants can rapidly be identified for clinical decision making and population surveillance using a high-throughput digital droplet PCR assay

Author

Olivier Pernet, Maia Weisenhaus, Chrysovalantis Stafylis, Christopher Williams, Mihaela Campan, Jonas Pettersson, Nicole Green, David M. Lee, Paul D. Thomas, Pamela Ward, Howard Hu, Jeffrey D. Klausner, Andrea A. Z. Kovacs, and the U. S. C. Variant Study Group

Subjects
Medicine, Science
Abstract

Abstract Epidemiologic surveillance of circulating SARS-CoV-2 variants is essential to assess impact on clinical outcomes and vaccine efficacy. Whole genome sequencing (WGS), the gold-standard to identify variants, requires significant infrastructure and expertise. We developed a digital droplet polymerase chain reaction (ddPCR) assay that can rapidly identify circulating variants of concern/interest (VOC/VOI) using variant-specific mutation combinations in the Spike gene. To validate the assay, 800 saliva samples known to be SARS-CoV-2 positive by RT-PCR were used. During the study (July 2020-March 2022) the assay was easily adaptable to identify not only existing circulating VAC/VOI, but all new variants as they evolved. The assay can discriminate nine variants (Alpha, Beta, Gamma, Delta, Eta, Epsilon, Lambda, Mu, and Omicron) and sub-lineages (Delta 417N, Omicron BA.1, BA.2). Sequence analyses confirmed variant type for 124/124 samples tested. This ddPCR assay is an inexpensive, sensitive, high-throughput assay that can easily be adapted as new variants are identified.

Published
2023
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4. InterPro in 2022.

Author

Typhaine Paysan-Lafosse, Matthias Blum, Sara Chuguransky, Tiago Grego, Beatriz Lázaro Pinto, Gustavo A. Salazar, Maxwell L. Bileschi, Peer Bork, Alan J. Bridge, Lucy J. Colwell, Julian Gough, Daniel H. Haft, Ivica Letunic, Aron Marchler-Bauer, Huaiyu Mi, Darren A. Natale, Christine A. Orengo, Arun Prasad Pandurangan, Catherine Rivoire, Christian J. A. Sigrist, Ian Sillitoe, Narmada Thanki, Paul D. Thomas, Silvio C. E. Tosatto, Cathy H. Wu, and Alex Bateman

Published
2023
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6. The Quest for Orthologs orthology benchmark service in 2022.

Author

Yannis Nevers, Tamsin E. M. Jones, Dushyanth Jyothi, Bethan Yates, Meritxell Ferret, Laura Portell-Silva, Laia Codó, Salvatore Cosentino, Marina Marcet-Houben, Anna Vlasova, Laetitia Poidevin, Arnaud Kress, Mark Hickman, Emma Persson, Ivana Pilizota, Cristina Guijarro-Clarke, Adrian M. Altenhoff, Elspeth A. Bruford, Christophe Dessimoz, Ingo Ebersberger, David M. Emms, Toni Gabaldón, Natasha M. Glover, Yanhui Hu, Wataru Iwasaki 0001, Odile Lecompte, Benjamin Linard, María J. Martín, David S. Roos, Erik Sonhammer, Paul D. Thomas, David Thybert, Klaas Vandepoele, Salvador Capella-Gutiérrez, Asier Gonzalez-Uriarte, Javier Garrayo-Ventas, Dmitry Repchevsky, Vicky Sundesha, and Erik L. L. Sonnhammer

Published
2022
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8. The Minimum Information about a Molecular Interaction CAusal STatement (MI2CAST).

Author

Vasundra Touré, Steven Vercruysse, Marcio Luis Acencio, Ruth C. Lovering, Sandra E. Orchard, Glyn Bradley, Cristina Casals-Casas, Claudine Chaouiya, Noemi del-Toro, åsmund Flobak, Pascale Gaudet, Henning Hermjakob, Charles Tapley Hoyt, Luana Licata, Astrid Lægreid, Christopher J. Mungall, Anne Niknejad, Simona Panni, Livia Perfetto, Pablo Porras, Dexter Pratt, Julio Saez-Rodriguez, Denis Thieffry, Paul D. Thomas, Dénes Türei, and Martin Kuiper

Published
2021
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9. The InterPro protein families and domains database: 20 years on.

Author

Matthias Blum, Hsin-Yu Chang, Sara Chuguransky, Tiago Grego, Swaathi Kandasamy, Alex L. Mitchell, Gift Nuka, Typhaine Paysan-Lafosse, Matloob Qureshi, Shriya Raj, Lorna J. Richardson, Gustavo A. Salazar, Lowri Williams, Peer Bork, Alan J. Bridge, Julian Gough, Daniel H. Haft, Ivica Letunic, Aron Marchler-Bauer, Huaiyu Mi, Darren A. Natale, Marco Necci, Christine A. Orengo, Arun Prasad Pandurangan, Catherine Rivoire, Christian J. A. Sigrist, Ian Sillitoe, Narmada Thanki, Paul D. Thomas, Silvio C. E. Tosatto, Cathy H. Wu, Alex Bateman, and Robert D. Finn

Published
2021
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10. The Gene Ontology resource: enriching a GOld mine.

Author

Seth Carbon, Eric Douglass, Benjamin M. Good, Deepak R. Unni, Nomi L. Harris, Christopher J. Mungall, Siddartha Basu, Rex L. Chisholm, Robert J. Dodson, Eric Hartline, Petra Fey, Paul D. Thomas, Laurent-Philippe Albou, Dustin Ebert, Michael J. Kesling, Huaiyu Mi, Anushya Muruganujan, Xiaosong Huang, Tremayne Mushayahama, Sandra A. LaBonte, Deborah A. Siegele, Giulia Antonazzo, Helen Attrill, Nick H. Brown, Phani V. Garapati, Steven J. Marygold, Vitor Trovisco, Gilberto dos Santos, Kathleen Falls, Christopher J. Tabone, Pinglei Zhou, Joshua L. Goodman, Victor B. Strelets, Jim Thurmond, Penelope Garmiri, Rizwan Ishtiaq, Milagros Rodríguez-López, Marcio Luis Acencio, Martin Kuiper, Astrid Lægreid, Colin Logie, Ruth C. Lovering, Barbara Kramarz, Shirin C. C. Saverimuttu, Sandra M. Pinheiro, Heather Gunn, Renzhi Su, Katherine E. Thurlow, Marcus C. Chibucos, Michelle G. Giglio, Suvarna Nadendla, James B. Munro, Rebecca C. Jackson, Margaret J. Duesbury, Noemi del-Toro, Birgit H. M. Meldal, Kalpana Paneerselvam, Livia Perfetto, Pablo Porras, Sandra E. Orchard, Anjali Shrivastava, Hsin-Yu Chang, Robert D. Finn, Alex L. Mitchell, Neil D. Rawlings, Lorna J. Richardson, Amaia Sangrador-Vegas, Judith A. Blake, Karen R. Christie, Mary E. Dolan, Harold J. Drabkin, David P. Hill, Li Ni, Dmitry M. Sitnikov, Midori A. Harris, Stephen G. Oliver, Kim Rutherford, Valerie Wood, Jaqueline Hayles, Jürg Bähler, Elizabeth R. Bolton, Jeffrey DePons, Melinda R. Dwinell, G. Thomas Hayman, Mary L. Kaldunski, Anne E. Kwitek, Stanley J. F. Laulederkind, Cody Plasterer, Marek Tutaj, Mahima Vedi, Shur-Jen Wang, Peter D'Eustachio, Lisa Matthews, James P. Balhoff, Suzi A. Aleksander, Michael J. Alexander, J. Michael Cherry, Stacia R. Engel, Felix Gondwe, Kalpana Karra, Stuart R. Miyasato, Robert S. Nash, Matt Simison, Marek S. Skrzypek, Shuai Weng, Edith D. Wong, Marc Feuermann, Pascale Gaudet, Anne Morgat, Erica Bakker, Tanya Z. Berardini, Leonore Reiser, Shabari Subramaniam, Eva Huala, Cecilia N. Arighi, Andrea H. Auchincloss, Kristian B. Axelsen, Ghislaine Argoud-Puy, Alex Bateman, Marie-Claude Blatter, Emmanuel Boutet, Emily Bowler, Lionel Breuza, Alan J. Bridge, Ramona Britto, Hema Bye-A-Jee, Cristina Casals-Casas, Elisabeth Coudert, Paul Denny 0002, Anne Estreicher, Maria Livia Famiglietti, George E. Georghiou, Arnaud Gos, Nadine Gruaz-Gumowski, Emma Hatton-Ellis, Chantal Hulo, Alexandr Ignatchenko, Florence Jungo, Kati Laiho, Philippe Le Mercier, Damien Lieberherr, Antonia Lock, Yvonne Lussi, Alistair MacDougall, Michele Magrane, Maria Jesus Martin, Patrick Masson, Darren A. Natale, Nevila Hyka-Nouspikel, Ivo Pedruzzi, Lucille Pourcel, Sylvain Poux, Sangya Pundir, Catherine Rivoire, Elena Speretta, Shyamala Sundaram, Nidhi Tyagi, Kate Warner, Rossana Zaru, Cathy H. Wu, Alexander D. Diehl, Juancarlos Chan, Christian A. Grove, Raymond Y. N. Lee, Hans-Michael Müller, Daniela Raciti, Kimberly Van Auken, Paul W. Sternberg, Matthew Berriman, Michael Paulini, Kevin L. Howe, Sibyl Gao, Adam Wright, Lincoln Stein, Douglas G. Howe, Sabrina Toro, Monte Westerfield, Pankaj Jaiswal, Laurel Cooper, and Justin Elser

Published
2021
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12. Setting the basis of best practices and standards for curation and annotation of logical models in biology - highlights of the [BC]2 2019 CoLoMoTo/SysMod Workshop.

Author

Anna Niarakis, Martin Kuiper, Marek Ostaszewski, Rahuman S. Malik-Sheriff, Cristina Casals-Casas, Denis Thieffry, Tom C. Freeman, Paul D. Thomas, Vasundra Touré, Vincent Noël, Gautier Stoll, Julio Saez-Rodriguez, Aurélien Naldi, Eugenia Oshurko, Ioannis Xenarios, Sylvain Soliman, Claudine Chaouiya, Tomás Helikar, and Laurence Calzone

Published
2021
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13. The Quest for Orthologs benchmark service and consensus calls in 2020.

Author

Adrian M. Altenhoff, Javier Garrayo-Ventas, Salvatore Cosentino, David Emms, Natasha M. Glover, Ana Hernández-Plaza, Yannis Nevers, Vicky Sundesha, Damian Szklarczyk, José María Fernández 0001, Laia Codó, The Quest for Orthologs Consortium, Josep Lluis Gelpí, Jaime Huerta-Cepas, Wataru Iwasaki 0001, Steven Kelly 0003, Odile Lecompte, Matthieu Muffato, Maria Jesus Martin, Salvador Capella-Gutiérrez, Paul D. Thomas, Erik L. L. Sonnhammer, and Christophe Dessimoz

Published
2020
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14. Alliance of Genome Resources Portal: unified model organism research platform.

Author

Julie Agapite, Laurent-Philippe Albou, Suzi A. Aleksander, Joanna Argasinska, Valerio Arnaboldi, Helen Attrill, Susan M. Bello, Judith A. Blake, Olin Blodgett, Yvonne M. Bradford, Carol J. Bult, Scott Cain, Brian R. Calvi, Seth Carbon, Juancarlos Chan, Wen J. Chen, J. Michael Cherry, Jae-Hyoung Cho, Karen R. Christie, Madeline A. Crosby, Jeff de Pons, Mary E. Dolan, Gilberto dos Santos, Barbara Dunn, Nathan A. Dunn, Anne E. Eagle, Dustin Ebert, Stacia R. Engel, David Fashena, Ken Frazer, Sibyl Gao, Felix Gondwe, Joshua L. Goodman, L. Sian Gramates, Christian A. Grove, Todd W. Harris, Marie-Claire Harrison, Douglas G. Howe, Kevin L. Howe, Sagar Jha, James A. Kadin, Thomas C. Kaufman, Patrick Kalita, Kalpana Karra, Ranjana Kishore, Stanley J. F. Laulederkind, Raymond Y. N. Lee, Kevin A. MacPherson, Steven J. Marygold, Beverley Matthews, Gillian H. Millburn, Stuart R. Miyasato, Sierra A. T. Moxon, Hans-Michael Müller, Christopher J. Mungall, Anushya Muruganujan, Tremayne Mushayahama, Robert S. Nash, Patrick Ng, Michael Paulini, Norbert Perrimon, Christian Pich 0002, Daniela Raciti, Joel E. Richardson, Matthew Russell, Susan Russo Gelbart, Leyla Ruzicka, Kevin Schaper, Mary Shimoyama, Matt Simison, Cynthia L. Smith, David R. Shaw, Ajay Shrivatsav, Marek S. Skrzypek, Jennifer R. Smith, Paul W. Sternberg, Christopher J. Tabone, Paul D. Thomas, Jyothi Thota, Sabrina Toro, Monika Tomczuk, Marek Tutaj, Monika Tutaj, Jose-Maria Urbano, Kimberly Van Auken, Ceri E. Van Slyke, Shur-Jen Wang, Shuai Weng, Monte Westerfield, Gary Williams, Edith D. Wong, Adam Wright, and Karen Yook

Published
2020
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15. A roadmap for the functional annotation of protein families: a community perspective.

Author

Valérie de Crécy-Lagard, Rocio Amorin de Hegedus, Cecilia N. Arighi, Jill Babor, Alex Bateman, Ian Blaby, Crysten Blaby-Haas, Alan J. Bridge, Stephen K. Burley, Stacey Cleveland, Lucy J. Colwell, Ana Conesa, Christian Dallago, Antoine Danchin, Anita de Waard, Adam Deutschbauer, Raquel Dias, Yousong Ding, Gang Fang, Iddo Friedberg, John Gerlt, Joshua Goldford, Mark Gorelik, Benjamin M. Gyori, Christopher S. Henry, Geoffrey Hutinet, Marshall Jaroch, Peter D. Karp, Liudmyla Kondratova, Zhiyong Lu, Aron Marchler-Bauer, Maria Jesus Martin, Claire D. McWhite, Gaurav D. Moghe, Paul Monaghan, Anne Morgat, Christopher J. Mungall, Darren A. Natale, William C. Nelson, Seán I. O'Donoghue, Christine A. Orengo, Katherine H. O'Toole, Predrag Radivojac, Colbie Reed, Richard J. Roberts, Dmitri Rodionov, Irina A. Rodionova, Jeffrey DePons, Lana Saleh, Gloria M. Sheynkman, Françoise Thibaud-Nissen, Paul D. Thomas, Peter Uetz, David Vallenet, Erica Watson Carter, Peter Weigele, Valerie Wood, Elisha M. Wood-Charlson, and Jin Xu

Published
2022
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17. InterPro in 2019: improving coverage, classification and access to protein sequence annotations.

Author

Alex L. Mitchell, Teresa K. Attwood, Patricia C. Babbitt, Matthias Blum, Peer Bork, Alan J. Bridge, Shoshana D. Brown, Hsin-Yu Chang, Sara El-Gebali, Matthew Fraser, Julian Gough, David Haft, Hongzhan Huang, Ivica Letunic, Rodrigo Lopez, Aurelien Luciani, Fábio Madeira, Aron Marchler-Bauer, Huaiyu Mi, Darren A. Natale, Marco Necci, Gift Nuka, Christine A. Orengo, Arun Prasad Pandurangan, Typhaine Paysan-Lafosse, Sebastien Pesseat, Simon C. Potter, Matloob Qureshi, Neil D. Rawlings, Nicole Redaschi, Lorna J. Richardson, Catherine Rivoire, Gustavo A. Salazar, Amaia Sangrador-Vegas, Christian J. A. Sigrist, Ian Sillitoe, Granger G. Sutton, Narmada Thanki, Paul D. Thomas, Silvio C. E. Tosatto, Siew-Yit Yong, and Robert D. Finn

Published
2019
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24. PEREGRINE: A genome-wide prediction of enhancer to gene relationships supported by experimental evidence.

Author

Caitlin Mills, Anushya Muruganujan, Dustin Ebert, Crystal N Marconett, Juan Pablo Lewinger, Paul D Thomas, and Huaiyu Mi

Subjects
Medicine, Science
Abstract

Enhancers are powerful and versatile agents of cell-type specific gene regulation, which are thought to play key roles in human disease. Enhancers are short DNA elements that function primarily as clusters of transcription factor binding sites that are spatially coordinated to regulate expression of one or more specific target genes. These regulatory connections between enhancers and target genes can therefore be characterized as enhancer-gene links that can affect development, disease, and homeostatic cellular processes. Despite their implication in disease and the establishment of cell identity during development, most enhancer-gene links remain unknown. Here we introduce a new, publicly accessible database of predicted enhancer-gene links, PEREGRINE. The PEREGRINE human enhancer-gene links interactive web interface incorporates publicly available experimental data from ChIA-PET, eQTL, and Hi-C assays across 78 cell and tissue types to link 449,627 enhancers to 17,643 protein-coding genes. These enhancer-gene links are made available through the new Enhancer module of the PANTHER database and website where the user may easily access the evidence for each enhancer-gene link, as well as query by target gene and enhancer location.

Published
2020
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25. InterPro in 2022

Author

Typhaine Paysan-Lafosse, Matthias Blum, Sara Chuguransky, Tiago Grego, Beatriz Lázaro Pinto, Gustavo A Salazar, Maxwell L Bileschi, Peer Bork, Alan Bridge, Lucy Colwell, Julian Gough, Daniel H Haft, Ivica Letunić, Aron Marchler-Bauer, Huaiyu Mi, Darren A Natale, Christine A Orengo, Arun P Pandurangan, Catherine Rivoire, Christian J A Sigrist, Ian Sillitoe, Narmada Thanki, Paul D Thomas, Silvio C E Tosatto, Cathy H Wu, and Alex Bateman

Subjects
Genetics
Abstract

The InterPro database (https://www.ebi.ac.uk/interpro/) provides an integrative classification of protein sequences into families, and identifies functionally important domains and conserved sites. Here, we report recent developments with InterPro (version 90.0) and its associated software, including updates to data content and to the website. These developments extend and enrich the information provided by InterPro, and provide a more user friendly access to the data. Additionally, we have worked on adding Pfam website features to the InterPro website, as the Pfam website will be retired in late 2022. We also show that InterPro's sequence coverage has kept pace with the growth of UniProtKB. Moreover, we report the development of a card game as a method of engaging the non-scientific community. Finally, we discuss the benefits and challenges brought by the use of artificial intelligence for protein structure prediction.

Published
2022
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26. InterPro in 2017 - beyond protein family and domain annotations.

Author

Robert D. Finn, Teresa K. Attwood, Patricia C. Babbitt, Alex Bateman, Peer Bork, Alan J. Bridge, Hsin-Yu Chang, Zsuzsanna Dosztányi, Sara El-Gebali, Matthew Fraser, Julian Gough, David Haft, Gemma L. Holliday, Hongzhan Huang, Xiaosong Huang, Ivica Letunic, Rodrigo Lopez, Shennan Lu, Aron Marchler-Bauer, Huaiyu Mi, Jaina Mistry, Darren A. Natale, Marco Necci, Gift Nuka, Christine A. Orengo, Young Mi Park, Sebastien Pesseat, Damiano Piovesan, Simon C. Potter, Neil D. Rawlings, Nicole Redaschi, Lorna J. Richardson, Catherine Rivoire, Amaia Sangrador-Vegas, Christian J. A. Sigrist, Ian Sillitoe, Ben Smithers, Silvano Squizzato, Granger G. Sutton, Narmada Thanki, Paul D. Thomas, Silvio C. E. Tosatto, Cathy H. Wu, Ioannis Xenarios, Lai-Su L. Yeh, Siew-Yit Yong, and Alex L. Mitchell

Published
2017
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29. The InterPro protein families database: the classification resource after 15 years.

Author

Alex L. Mitchell, Hsin-Yu Chang, Louise C. Daugherty, Matthew Fraser, Sarah Hunter, Rodrigo Lopez, Craig McAnulla, Conor McMenamin, Gift Nuka, Sebastien Pesseat, Amaia Sangrador-Vegas, Maxim Scheremetjew, Claudia Rato, Siew-Yit Yong, Alex Bateman, Marco Punta, Teresa K. Attwood, Christian J. A. Sigrist, Nicole Redaschi, Catherine Rivoire, Ioannis Xenarios, Daniel Kahn, Dominique Guyot, Peer Bork, Ivica Letunic, Julian Gough, Matt E. Oates, Daniel H. Haft, Hongzhan Huang, Darren A. Natale, Cathy H. Wu, Christine A. Orengo, Ian Sillitoe, Huaiyu Mi, Paul D. Thomas, and Robert D. Finn

Published
2015
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35. InterPro in 2011: new developments in the family and domain prediction database.

Author

Sarah Hunter, Philip Jones, Alex L. Mitchell, Rolf Apweiler, Teresa K. Attwood, Alex Bateman, Thomas Bernard, David Binns, Peer Bork, Sarah W. Burge, Edouard De Castro, Penny C. Coggill, Matthew Corbett, Ujjwal Das, Louise C. Daugherty, Lauranne Duquenne, Robert D. Finn, Matthew Fraser, Julian Gough, Daniel H. Haft, Nicolas Hulo, Daniel Kahn, Elizabeth Kelly, Ivica Letunic, David Lonsdale, Rodrigo Lopez, Martin Madera, John Maslen, Craig McAnulla, Jennifer McDowall, Conor McMenamin, Huaiyu Mi, Prudence Mutowo-Meullenet, Nicola J. Mulder, Darren A. Natale, Christine A. Orengo, Sebastien Pesseat, Marco Punta, Antony F. Quinn, Catherine Rivoire, Amaia Sangrador-Vegas, Jeremy D. Selengut, Christian J. A. Sigrist, Maxim Scheremetjew, John G. Tate, Manjulapramila Thimmajanarthanan, Paul D. Thomas, Cathy H. Wu, Corin Yeats, and Siew-Yit Yong

Published
2012
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38. InterPro: the integrative protein signature database.

Author

Sarah Hunter, Rolf Apweiler, Teresa K. Attwood, Amos Bairoch, Alex Bateman, David Binns, Peer Bork, Ujjwal Das, Louise C. Daugherty, Lauranne Duquenne, Robert D. Finn, Julian Gough, Daniel H. Haft, Nicolas Hulo, Daniel Kahn, Elizabeth Kelly, Aurélie Laugraud, Ivica Letunic, David Lonsdale, Rodrigo Lopez, Martin Madera, John Maslen, Craig McAnulla, Jennifer McDowall, Jaina Mistry, Alex L. Mitchell, Nicola J. Mulder, Darren A. Natale, Christine A. Orengo, Antony F. Quinn, Jeremy D. Selengut, Christian J. A. Sigrist, Manjula Thimma, Paul D. Thomas, Franck Valentin, Derek Wilson, Cathy H. Wu, and Corin Yeats

Published
2009
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40. New developments in the InterPro database.

Author

Nicola J. Mulder, Rolf Apweiler, Teresa K. Attwood, Amos Bairoch, Alex Bateman, David Binns, Peer Bork, Virginie Buillard, Lorenzo Cerutti, Richard R. Copley, Emmanuel Courcelle, Ujjwal Das, Louise C. Daugherty, Mark Dibley, Robert D. Finn, Wolfgang Fleischmann, Julian Gough, Daniel H. Haft, Nicolas Hulo, Sarah Hunter, Daniel Kahn, Alexander Kanapin, Anish Kejariwal, Alberto Labarga, Petra S. Langendijk-Genevaux, David Lonsdale, Rodrigo Lopez, Ivica Letunic, Martin Madera, John Maslen, Craig McAnulla, Jennifer McDowall, Jaina Mistry, Alex L. Mitchell, Anastasia N. Nikolskaya, Sandra E. Orchard, Christine A. Orengo, Robert Petryszak, Jeremy D. Selengut, Christian J. A. Sigrist, Paul D. Thomas, Franck Valentin, Derek Wilson, Cathy H. Wu, and Corin Yeats

Published
2007
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45. The Celera Discovery SystemTM.

Author

Anthony R. Kerlavage, Vivien Bonazzi, Matteo di Tommaso, Charles Lawrence, Peter Li, Frank Mayberry, Richard J. Mural, Marc Nodell, Mark Yandell, Jinghui Zhang, and Paul D. Thomas

Published
2002
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47. Ontologies and standards in bioscience research: for machine or for human

Author

Huaiyu eMi and Paul D Thomas

Subjects
Systems Biology, Pathway, ontology, standard, Physiology, QP1-981
Abstract

Ontologies and standards are very important parts of today’s bioscience research. With the rapid increase of biological knowledge, they provide mechanisms to better store and represent data in a controlled and structured way, so that scientists can share the data, and utilize a wide variety of software and tools to manage and analyze the data. Most of these standards are initially designed for computers to access large amounts of data that are difficult for human biologists to handle, and it is important to keep in mind that ultimately biologists are going to produce and interpret the data. While ontologies and standards must follow strict semantic rules that may not be familiar to biologists, effort must be spent to lower the learning barrier by involving biologists in the process of development, and by providing software and tool support. A standard will not succeed without support from the wider bioscience research community. Thus, it is crucial that these standards be designed not only for machines to read, but also to be scientifically accurate and intuitive to human biologists.

Published
2011
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48. The use of orthologous sequences to predict the impact of amino acid substitutions on protein function.

Author

Nicholas J Marini, Paul D Thomas, and Jasper Rine

Subjects
Genetics, QH426-470
Abstract

Computational predictions of the functional impact of genetic variation play a critical role in human genetics research. For nonsynonymous coding variants, most prediction algorithms make use of patterns of amino acid substitutions observed among homologous proteins at a given site. In particular, substitutions observed in orthologous proteins from other species are often assumed to be tolerated in the human protein as well. We examined this assumption by evaluating a panel of nonsynonymous mutants of a prototypical human enzyme, methylenetetrahydrofolate reductase (MTHFR), in a yeast cell-based functional assay. As expected, substitutions in human MTHFR at sites that are well-conserved across distant orthologs result in an impaired enzyme, while substitutions present in recently diverged sequences (including a 9-site mutant that "resurrects" the human-macaque ancestor) result in a functional enzyme. We also interrogated 30 sites with varying degrees of conservation by creating substitutions in the human enzyme that are accepted in at least one ortholog of MTHFR. Quite surprisingly, most of these substitutions were deleterious to the human enzyme. The results suggest that selective constraints vary between phylogenetic lineages such that inclusion of distant orthologs to infer selective pressures on the human enzyme may be misleading. We propose that homologous proteins are best used to reconstruct ancestral sequences and infer amino acid conservation among only direct lineal ancestors of a particular protein. We show that such an "ancestral site preservation" measure outperforms other prediction methods, not only in our selected set for MTHFR, but also in an exhaustive set of E. coli LacI mutants.

Published
2010
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50. Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene.

Author

Liam R Brunham, Roshni R Singaraja, Terry D Pape, Anish Kejariwal, Paul D Thomas, and Michael R Hayden

Subjects
Genetics, QH426-470
Abstract

The human genome contains an estimated 100,000 to 300,000 DNA variants that alter an amino acid in an encoded protein. However, our ability to predict which of these variants are functionally significant is limited. We used a bioinformatics approach to define the functional significance of genetic variation in the ABCA1 gene, a cholesterol transporter crucial for the metabolism of high density lipoprotein cholesterol. To predict the functional consequence of each coding single nucleotide polymorphism and mutation in this gene, we calculated a substitution position-specific evolutionary conservation score for each variant, which considers site-specific variation among evolutionarily related proteins. To test the bioinformatics predictions experimentally, we evaluated the biochemical consequence of these sequence variants by examining the ability of cell lines stably transfected with the ABCA1 alleles to elicit cholesterol efflux. Our bioinformatics approach correctly predicted the functional impact of greater than 94% of the naturally occurring variants we assessed. The bioinformatics predictions were significantly correlated with the degree of functional impairment of ABCA1 mutations (r2 = 0.62, p = 0.0008). These results have allowed us to define the impact of genetic variation on ABCA1 function and to suggest that the in silico evolutionary approach we used may be a useful tool in general for predicting the effects of DNA variation on gene function. In addition, our data suggest that considering patterns of positive selection, along with patterns of negative selection such as evolutionary conservation, may improve our ability to predict the functional effects of amino acid variation.

Published
2005
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