Format

Send to

Choose Destination
Nat Commun. 2018 Jan 18;9(1):288. doi: 10.1038/s41467-017-01995-2.

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

Collaborators (202)

Aguilar-Pimentel A, Becker L, Treise I, Moreth K, Garrett L, Hölter SM, Zimprich A, Marschall S, Amarie OV, Calzada-Wack J, Neff F, Brachthäuser L, Lengger C, Stoeger C, Zapf L, Cho YL, da Silva-Buttkus P, Kraiger MJ, Mayer-Kuckuk P, Gampe KK, Wu M, Conte N, Warren J, Chen CK, Tudose I, Relac M, Matthews P, Cater HL, Natukunda HP, Cleak J, Teboul LM, Clementson-Mobbs S, Szoke-Kovacs Z, Walling AP, Johnson SJ, Codner GF, Fiegel T, Ring N, Westerberg H, Greenaway S, Sneddon D, Morgan H, Loeffler J, Stewart ME, Ramirez-Solis R, Bradley A, Skarnes WC, Steel KP, Maguire SA, Dench J, Lafont D, Vancollie VE, Pearson SA, Gates AS, Sanderson M, Shannon C, Anthony LFE, Sumowski MT, McLaren RSB, Doe B, Wardle-Jones H, Griffiths MND, Galli A, Swiatkowska A, Isherwood CM, Speak AO, Cambridge EL, Wilson HM, Caetano SS, Maguire AKB, Adams DJ, Bottomley J, Ryder E, Gleeson D, Pouilly L, Rousseau S, Auburtin A, Reilly P, Ayadi A, Selloum M, Wood JA, Clary D, Havel P, Tolentino T, Tolentino H, Schuchbauer M, Pedroia S, Trainor A, Djan E, Pham M, Huynh A, De Vera V, Seavitt J, Gallegos J, Garza A, Mangin E, Senderstrom J, Lazo I, Mowrey K, Bohat R, Samaco R, Veeraragavan S, Beeton C, Kalaga S, Kelsey L, Vukobradovic I, Berberovic Z, Owen C, Qu D, Guo R, Newbigging S, Morikawa L, Law N, Shang X, Feugas P, Wang Y, Eskandarian M, Zhu Y, Penton P, Laurin V, Clarke S, Lan Q, Sleep G, Creighton A, Jacob E, Danisment O, Gertsenstein M, Pereira M, MacMaster S, Tondat S, Carroll T, Cabezas J, Hunter J, Clark G, Bubshait M, Miller D, Sohel K, Adissu H, Ganguly M, Bezginov A, Chiani F, Di Pietro C, Di Segni G, Ermakova O, Ferrara F, Fruscoloni P, Gambadoro A, Gastaldi S, Golini E, La Sala G, Mandillo S, Marazziti D, Massimi M, Matteoni R, Orsini T, Pasquini M, Raspa M, Rauch A, Rossi G, Rossi N, Putti S, Scavizzi F, Tocchini-Valentini GD, Wakana S, Suzuki T, Tamura M, Kaneda H, Furuse T, Kobayashi K, Miura I, Yamada I, Obata Y, Yoshiki A, Ayabe S, Chambers JN, Chalupsky K, Seisenberger C, Bürger A, Beig J, Kühn R, Hörlein A, Schick J, Oritz O, Giesert F, Graw J, Ollert M, Schmidt-Weber C, Stoeger T, Önder Yildirim A, Eickelberg O, Klopstock T, Busch DH, Bekeredjian R, Zimmer A, Jacobsen JO, Smedley D, Dickinson ME, Benso F, Morse I, Kim HC, Lee H, Cho SY.

Author information

1
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
2
German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
3
Ludwig-Maximilians-Universität München, Gene Center, Institute of Molecular Animal Breeding and Biotechnology, Feodor-Lynen Strasse 25, 81377, Munich, Germany.
4
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
5
Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
6
Chair of Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, 85354, Freising, Germany.
7
EKFZ - Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, 85354, Freising, Germany.
8
ZIEL - Institute for Food & Health, Technical University of Munich, 85354, Freising, Germany.
9
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
10
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Oxfordshire, OX11 0RD, UK.
11
The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
12
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
13
CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), 1 Rue Laurent Fries, 67404, Illkirch-Graffenstaden, France.
14
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Parc d'innovation, 1 Rue Laurent Fries - BP 10142, 67404, Illkirch, France.
15
Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France.
16
Institut National de la Santé et de la Recherche Médicale, U964, 67404, Illkirch, France.
17
Université de Strasbourg, 67404, Illkirch, France.
18
Mouse Biology Program, University of California, One Shields Avenue, Davis, CA, 95616, USA.
19
Department of Molecular and Human Genetics, Baylor College of Medicine, 7702 Main St, Houston Medical Center, Houston, TX, 77030-4406, USA.
20
The Centre for Phenogenomics, 25 Orde St, Toronto, M5T 3H7, ON, Canada.
21
The Hospital for Sick Children, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.
22
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.
23
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA, 94609, USA.
24
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.
25
Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
26
Australian Phenomics Network, John Curtin School of Medical Research, Australian National University, 131 Garran Road, Canberra, ACT, 2601, Australia.
27
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.
28
Department of Ophthalmology & Vision Science, School of Medicine, U.C. Davis, 77 Cadillac Drive, Sacramento, 95825, CA, USA.
29
William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, U.C. Davis, One Shields Avenue, Davis, 95616, CA, USA.
30
RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki, 305-0074, Japan.
31
Czech Centre for Phenogenomics, Institute of Molecular Genetics, Prumyslova 595, 252 50, Vestec, Czech Republic.
32
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.
33
National Laboratory Animal Center, National Applied Research Laboratories (NARLabs), 128 Yen-Chiou-Yuan Rd., Sec. 2, Nankang, Taipei, 11529, Taiwan.
34
IMPC, San Anselmo, CA, 94960, USA.
35
Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany.
36
Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333, Munich, Germany.
37
Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.
38
Chair of Developmental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.
39
Deutsches Institut für Neurodegenerative Erkrankungen (DZNE) Site Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany.
40
Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 17, 81377, Munich, Germany.
41
Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354, Freising, Germany.
42
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, 72076, Tübingen, Germany.
43
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.
44
Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
45
Clinical Cooperation Group Type 2 Diabetes, Helmholtz Zentrum München and Ludwig-Maximilians Universität München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
46
Internal Medicine Nephrology and Center for Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
47
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.
48
German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany. hrabe@helmholtz-muenchen.de.
49
Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354, Freising, Germany. hrabe@helmholtz-muenchen.de.

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.

PMID:
29348434
PMCID:
PMC5773596
DOI:
10.1038/s41467-017-01995-2
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center