Identification of genetic elements in metabolism by high-throughput mouse phenotyping.
| Title: | Identification of genetic elements in metabolism by high-throughput mouse phenotyping. |
|---|---|
| Authors: | Rozman J; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Rathkolb B; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Ludwig-Maximilians-Universität München, Gene Center, Institute of Molecular Animal Breeding and Biotechnology, Feodor-Lynen Strasse 25, 81377, Munich, Germany.; Oestereicher MA; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Schütt C; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Ravindranath AC; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Leuchtenberger S; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Sharma S; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Kistler M; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Willershäuser M; Chair of Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, 85354, Freising, Germany.; EKFZ - Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, 85354, Freising, Germany.; ZIEL - Institute for Food & Health, Technical University of Munich, 85354, Freising, Germany.; Brommage R; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Meehan TF; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.; Mason J; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.; Haselimashhadi H; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.; Hough T; Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Oxfordshire, OX11 0RD, UK.; Mallon AM; Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Oxfordshire, OX11 0RD, UK.; Wells S; Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Oxfordshire, OX11 0RD, UK.; Santos L; Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Oxfordshire, OX11 0RD, UK.; Lelliott CJ; The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.; White JK; The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.; The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.; Sorg T; CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), 1 Rue Laurent Fries, 67404, Illkirch-Graffenstaden, France.; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Parc d'innovation, 1 Rue Laurent Fries - BP 10142, 67404, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale, U964, 67404, Illkirch, France.; Université de Strasbourg, 67404, Illkirch, France.; Champy MF; CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), 1 Rue Laurent Fries, 67404, Illkirch-Graffenstaden, France.; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Parc d'innovation, 1 Rue Laurent Fries - BP 10142, 67404, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale, U964, 67404, Illkirch, France.; Université de Strasbourg, 67404, Illkirch, France.; Bower LR; Mouse Biology Program, University of California, One Shields Avenue, Davis, CA, 95616, USA.; Reynolds CL; Department of Molecular and Human Genetics, Baylor College of Medicine, 7702 Main St, Houston Medical Center, Houston, TX, 77030-4406, USA.; Flenniken AM; The Centre for Phenogenomics, 25 Orde St, Toronto, M5T 3H7, ON, Canada.; The Hospital for Sick Children, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.; Murray SA; The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.; Nutter LMJ; The Centre for Phenogenomics, 25 Orde St, Toronto, M5T 3H7, ON, Canada.; The Hospital for Sick Children, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.; Svenson KL; The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.; West D; Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA, 94609, USA.; Tocchini-Valentini GP; Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology, Adriano Buzzati-Traverso Campus, Via E. Ramarini 32, Monterotondo Scalo, RM, 00015, Italy.; Beaudet AL; The Centre for Phenogenomics, 25 Orde St, Toronto, M5T 3H7, ON, Canada.; The Hospital for Sick Children, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.; Bosch F; Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.; Braun RB; The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.; Dobbie MS; Australian Phenomics Network, John Curtin School of Medical Research, Australian National University, 131 Garran Road, Canberra, ACT, 2601, Australia.; Gao X; SKL of Pharmaceutical Biotechnology and Model Animal Research Center, Collaborative Innovation Center for Genetics and Development, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210061, China.; Herault Y; CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), 1 Rue Laurent Fries, 67404, Illkirch-Graffenstaden, France.; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Parc d'innovation, 1 Rue Laurent Fries - BP 10142, 67404, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale, U964, 67404, Illkirch, France.; Université de Strasbourg, 67404, Illkirch, France.; Moshiri A; Department of Ophthalmology & Vision Science, School of Medicine, U.C. Davis, 77 Cadillac Drive, Sacramento, 95825, CA, USA.; Moore BA; William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, U.C. Davis, One Shields Avenue, Davis, 95616, CA, USA.; Kent Lloyd KC; Mouse Biology Program, University of California, One Shields Avenue, Davis, CA, 95616, USA.; McKerlie C; The Centre for Phenogenomics, 25 Orde St, Toronto, M5T 3H7, ON, Canada.; The Hospital for Sick Children, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.; Masuya H; RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki, 305-0074, Japan.; Tanaka N; RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki, 305-0074, Japan.; Flicek P; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.; Parkinson HE; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.; Sedlacek R; Czech Centre for Phenogenomics, Institute of Molecular Genetics, Prumyslova 595, 252 50, Vestec, Czech Republic.; Seong JK; Korea Mouse Phenotyping Consortium (KMPC) and BK21 Program for Veterinary Science, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 599 Gwanangno, Gwanak-gu, Seoul, 151-742, South Korea.; Wang CL; National Laboratory Animal Center, National Applied Research Laboratories (NARLabs), 128 Yen-Chiou-Yuan Rd., Sec. 2, Nankang, Taipei, 11529, Taiwan.; Moore M; IMPC, San Anselmo, CA, 94960, USA.; Brown SD; Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Oxfordshire, OX11 0RD, UK.; Tschöp MH; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany.; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333, Munich, Germany.; Wurst W; Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.; Chair of Developmental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.; Deutsches Institut für Neurodegenerative Erkrankungen (DZNE) Site Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 17, 81377, Munich, Germany.; Klingenspor M; Chair of Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, 85354, Freising, Germany.; EKFZ - Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, 85354, Freising, Germany.; ZIEL - Institute for Food & Health, Technical University of Munich, 85354, Freising, Germany.; Wolf E; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Ludwig-Maximilians-Universität München, Gene Center, Institute of Molecular Animal Breeding and Biotechnology, Feodor-Lynen Strasse 25, 81377, Munich, Germany.; Beckers J; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354, Freising, Germany.; Machicao F; Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, 72076, Tübingen, Germany.; Peter A; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, 72076, Tübingen, Germany.; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard-Karls-University of Tuebingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.; Staiger H; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard-Karls-University of Tuebingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.; Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.; Häring HU; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, 72076, Tübingen, Germany.; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard-Karls-University of Tuebingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.; Grallert H; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Clinical Cooperation Group Type 2 Diabetes, Helmholtz Zentrum München and Ludwig-Maximilians Universität München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Campillos M; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Maier H; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Fuchs H; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Gailus-Durner V; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.; Werner T; Internal Medicine Nephrology and Center for Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.; Hrabe de Angelis M; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany. hrabe@helmholtz-muenchen.de.; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany. hrabe@helmholtz-muenchen.de.; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354, Freising, Germany. hrabe@helmholtz-muenchen.de. |
| Corporate Authors: | IMPC Consortium |
| Source: | Nature communications [Nat Commun] 2018 Jan 18; Vol. 9 (1), pp. 288. Date of Electronic Publication: 2018 Jan 18. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : Nature Pub. Group |
| MeSH Terms: | Basal Metabolism/*genetics ; Blood Glucose/*metabolism ; Body Weight/*genetics ; Diabetes Mellitus, Type 2/*genetics ; Obesity/*genetics ; Oxygen Consumption/*genetics ; Triglycerides/*metabolism; Metabolic Diseases/genetics ; Animals ; Area Under Curve ; Gene Regulatory Networks ; Genome-Wide Association Study ; High-Throughput Screening Assays ; Humans ; Mice ; Mice, Knockout ; Phenotype |
| 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. |
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| Grant Information: | U24 DK092993 United States DK NIDDK NIH HHS; UM1 OD023221 United States OD NIH HHS; R24 OD011883 United States OD NIH HHS; U42 OD012210 United States OD NIH HHS; MC_U142684172 United Kingdom MRC_ Medical Research Council; UM1 HG006370 United States HG NHGRI NIH HHS; U54 HG006348 United States HG NHGRI NIH HHS; MR/N012119/1 United Kingdom MRC_ Medical Research Council; K08 EY027463 United States EY NEI NIH HHS; U42 RR024244 United States RR NCRR NIH HHS; U42 RR033193 United States RR NCRR NIH HHS; UM1 OD023222 United States OD NIH HHS; U54 HG006332 United States HG NHGRI NIH HHS; G0300212 United Kingdom MRC_ Medical Research Council; U54 HG006364 United States HG NHGRI NIH HHS; UM1 HG006348 United States HG NHGRI NIH HHS; U42 OD011174 United States OD NIH HHS; U54 HG006370 United States HG NHGRI NIH HHS; MC_QA137918 United Kingdom MRC_ Medical Research Council; U42 OD011175 United States OD NIH HHS; United Kingdom WT_ Wellcome Trust; MC_UP_1502/3 United Kingdom MRC_ Medical Research Council; MC_U142684171 United Kingdom MRC_ Medical Research Council; U42 OD011185 United States OD NIH HHS; U2C DK092993 United States DK NIDDK NIH HHS |
| Contributed Indexing: | Investigator: A Aguilar-Pimentel; L Becker; I Treise; K Moreth; L Garrett; SM Hölter; A Zimprich; S Marschall; OV Amarie; J Calzada-Wack; F Neff; L Brachthäuser; C Lengger; C Stoeger; L Zapf; YL Cho; P da Silva-Buttkus; MJ Kraiger; P Mayer-Kuckuk; KK Gampe; M Wu; N Conte; J Warren; CK Chen; I Tudose; M Relac; P Matthews; HL Cater; HP Natukunda; J Cleak; LM Teboul; S Clementson-Mobbs; Z Szoke-Kovacs; AP Walling; SJ Johnson; GF Codner; T Fiegel; N Ring; H Westerberg; S Greenaway; D Sneddon; H Morgan; J Loeffler; ME Stewart; R Ramirez-Solis; A Bradley; WC Skarnes; KP Steel; SA Maguire; J Dench; D Lafont; VE Vancollie; SA Pearson; AS Gates; M Sanderson; C Shannon; LFE Anthony; MT Sumowski; RSB McLaren; B Doe; H Wardle-Jones; MND Griffiths; A Galli; A Swiatkowska; CM Isherwood; AO Speak; EL Cambridge; HM Wilson; SS Caetano; AKB Maguire; DJ Adams; J Bottomley; E Ryder; D Gleeson; L Pouilly; S Rousseau; A Auburtin; P Reilly; A Ayadi; M Selloum; JA Wood; D Clary; P Havel; T Tolentino; H Tolentino; M Schuchbauer; S Pedroia; A Trainor; E Djan; M Pham; A Huynh; V De Vera; J Seavitt; J Gallegos; A Garza; E Mangin; J Senderstrom; I Lazo; K Mowrey; R Bohat; R Samaco; S Veeraragavan; C Beeton; S Kalaga; L Kelsey; I Vukobradovic; Z Berberovic; C Owen; D Qu; R Guo; S Newbigging; L Morikawa; N Law; X Shang; P Feugas; Y Wang; M Eskandarian; Y Zhu; P Penton; V Laurin; S Clarke; Q Lan; G Sleep; A Creighton; E Jacob; O Danisment; M Gertsenstein; M Pereira; S MacMaster; S Tondat; T Carroll; J Cabezas; J Hunter; G Clark; M Bubshait; D Miller; K Sohel; H Adissu; M Ganguly; A Bezginov; F Chiani; C Di Pietro; G Di Segni; O Ermakova; F Ferrara; P Fruscoloni; A Gambadoro; S Gastaldi; E Golini; G La Sala; S Mandillo; D Marazziti; M Massimi; R Matteoni; T Orsini; M Pasquini; M Raspa; A Rauch; G Rossi; N Rossi; S Putti; F Scavizzi; GD Tocchini-Valentini; S Wakana; T Suzuki; M Tamura; H Kaneda; T Furuse; K Kobayashi; I Miura; I Yamada; Y Obata; A Yoshiki; S Ayabe; JN Chambers; K Chalupsky; C Seisenberger; A Bürger; J Beig; R Kühn; A Hörlein; J Schick; O Oritz; F Giesert; J Graw; M Ollert; C Schmidt-Weber; T Stoeger; A Önder Yildirim; O Eickelberg; T Klopstock; DH Busch; R Bekeredjian; A Zimmer; JO Jacobsen; D Smedley; ME Dickinson; F Benso; I Morse; HC Kim; H Lee; SY Cho |
| Substance Nomenclature: | 0 (Blood Glucose); 0 (Triglycerides) |
| Entry Date(s): | Date Created: 20180120 Date Completed: 20181212 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC5773596 |
| DOI: | 10.1038/s41467-017-01995-2 |
| PMID: | 29348434 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't