Identification of genetic elements in metabolism by high-throughput mouse phenotyping

Jan Rozman, Birgit Rathkolb, Manuela A. Oestereicher, Christine Schütt, Aakash Chavan Ravindranath, Stefanie Leuchtenberger, Sapna Sharma, Martin Kistler, Monja Willershäuser, Robert Brommage, Terrence F. Meehan, Jeremy Mason, Hamed Haselimashhadi, Antonio Aguilar-Pimentel, Lore Becker, Irina Treise, Kristin Moreth, Lillian Garrett, Sabine M. Hölter, Annemarie ZimprichSusan Marschall, Oana V. Amarie, Julia Calzada-Wack, Frauke Neff, Laura Brachthäuser, Christoph Lengger, Claudia Stoeger, Lilly Zapf, Yi Li Cho, Patricia Da Silva-Buttkus, Markus J. Kraiger, Philipp Mayer-Kuckuk, Karen Kristine Gampe, Moya Wu, Nathalie Conte, Jonathan Warren, Chao Kung Chen, Ilinca Tudose, Mike Relac, Peter Matthews, Heather L. Cater, Helen P. Natukunda, James Cleak, Lydia M. Teboul, Sharon Clementson-Mobbs, Zsombor Szoke-Kovacs, Alison P. Walling, Sara J. Johnson, Gemma F. Codner, Tanja Fiegel, Natalie Ring, Henrik Westerberg, Simon Greenaway, Duncan Sneddon, Hugh Morgan, Jorik Loeffler, Michelle E. Stewart, Ramiro Ramirez-Solis, Allan Bradley, William C. Skarnes, Karen P. Steel, Simon A. Maguire, Joshua Dench, David Lafont, Valerie E. Vancollie, Selina A. Pearson, Amy S. Gates, Mark Sanderson, Carl Shannon, Lauren F.E. Anthony, Maksymilian T. Sumowski, Robbie S.B. McLaren, Brendan Doe, Hannah Wardle-Jones, Mark N.D. Griffiths, Antonella Galli, Agnieszka Swiatkowska, Christopher M. Isherwood, Anneliese O. Speak, Emma L. Cambridge, Heather M. Wilson, Susana S. Caetano, Anna Karin B. Maguire, David J. Adams, Joanna Bottomley, Ed Ryder, Diane Gleeson, Laurent Pouilly, Stephane Rousseau, Aurélie Auburtin, Patrick Reilly, Abdel Ayadi, Mohammed Selloum, Joshua Wood, Dave Clary, Peter J Havel, Todd Tolentino, Heather Tolentino, Mike Schuchbauer, Sheryl Pedroia, Amanda Trainor, Esi Djan, Milton Pham, Alison Huynh, Vincent De Vera, John Seavitt, Juan Gallegos, Arturo Garza, Elise Mangin, Joel Senderstrom, Iride Lazo, Kate Mowrey, Ritu Bohat, Rodney Samaco, Surabi Veeraragavan, Christine Beeton, Sowmya Kalaga, Lois Kelsey, Igor Vukobradovic, Zorana Berberovic, Celeste Owen, Dawei Qu, Ruolin Guo, Susan Newbigging, Lily Morikawa, Napoleon Law, Xueyuan Shang, Patricia Feugas, Yanchun Wang, Mohammad Eskandarian, Yingchun Zhu, Patricia Penton, Valerie Laurin, Shannon Clarke, Qing Lan, Gillian Sleep, Amie Creighton, Elsa Jacob, Ozge Danisment, Marina Gertsenstein, Monica Pereira, Suzanne MacMaster, Sandra Tondat, Tracy Carroll, Jorge Cabezas, Jane Hunter, Greg Clark, Mohammed Bubshait, David Miller, Khondoker Sohel, Hibret Adissu, Milan Ganguly, Alexandr Bezginov, Francesco Chiani, Chiara Di Pietro, Gianfranco Di Segni, Olga Ermakova, Filomena Ferrara, Paolo Fruscoloni, Aalessia Gambadoro, Serena Gastaldi, Elisabetta Golini, Gina La Sala, Silvia Mandillo, Daniela Marazziti, Marzia Massimi, Rafaele Matteoni, Tiziana Orsini, Miriam Pasquini, Marcello Raspa, Aline Rauch, Gianfranco Rossi, Nicoletta Rossi, Sabrina Putti, Ferdinando Scavizzi, Giuseppe D. Tocchini-Valentini, Shigeharu Wakana, Tomohiro Suzuki, Masaru Tamura, Hideki Kaneda, Tamio Furuse, Kimio Kobayashi, Ikuo Miura, Ikuko Yamada, Yuichi Obata, Atsushi Yoshiki, Shinya Ayabe, J. Nicole Chambers, Karel Chalupsky, Claudia Seisenberger, Antje Bürger, Joachim Beig, Ralf Kühn, Andreas Hörlein, Joel Schick, Oskar Oritz, Florian Giesert, Jochen Graw, Markus Ollert, Carsten Schmidt-Weber, Tobias Stoeger, Ali Önder Yildirim, Oliver Eickelberg, Thomas Klopstock, Dirk H. Busch, Raffi Bekeredjian, Andreas Zimmer, Jules O. Jacobsen, Damian Smedley, Mary E. Dickinson, Frank Benso, Iva Morse, Hyoung Chin Kim, Ho Lee, Soo Young Cho, Tertius Hough, Ann Marie Mallon, Sara Wells, Luis Santos, Christopher J. Lelliott, Jacqueline K. White, Tania Sorg, Marie France Champy, Lynette R. Bower, Corey L. Reynolds, Ann M. Flenniken, Stephen A. Murray, Lauryl M.J. Nutter, Karen L. Svenson, David West, Glauco P. Tocchini-Valentini, Arthur L. Beaudet, Fatima Bosch, Robert B. Braun, Michael S. Dobbie, Xiang Gao, Yann Herault, Ala Moshiri, Bret A. Moore, Kevin C K Lloyd, Colin McKerlie, Hiroshi Masuya, Nobuhiko Tanaka, Paul Flicek, Helen E. Parkinson, Radislav Sedlacek, Je Kyung Seong, Chi Kuang Leo Wang, Mark Moore, Steve D. Brown, Matthias H. Tschöp, Wolfgang Wurst, Martin Klingenspor, Eckhard Wolf, Johannes Beckers, Fausto MacHicao, Andreas Peter, Harald Staiger, Hans Ulrich Häring, Harald Grallert, Monica Campillos, Holger Maier, Helmut Fuchs, Valerie Gailus-Durner, Thomas Werner, Martin Hrabe De Angelis

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.

Original languageEnglish (US)
Article number288
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Rozman, J., Rathkolb, B., Oestereicher, M. A., Schütt, C., Ravindranath, A. C., Leuchtenberger, S., Sharma, S., Kistler, M., Willershäuser, M., Brommage, R., Meehan, T. F., Mason, J., Haselimashhadi, H., Aguilar-Pimentel, A., Becker, L., Treise, I., Moreth, K., Garrett, L., Hölter, S. M., ... De Angelis, M. H. (2018). Identification of genetic elements in metabolism by high-throughput mouse phenotyping. Nature Communications, 9(1), [288]. https://doi.org/10.1038/s41467-017-01995-2