title: Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population.
abstract: The manner by which genotype and environment affect complex phenotypes is one of the fundamental questions in biology. In this study, we quantified the transcriptome--a subset of the metabolome--and, using targeted proteomics, quantified a subset of the liver proteome from 40 strains of the BXD mouse genetic reference population on two diverse diets. We discovered dozens of transcript, protein, and metabolite QTLs, several of which linked to metabolic phenotypes. Most prominently, Dhtkd1 was identified as a primary regulator of 2-aminoadipate, explaining variance in fasted glucose and diabetes status in both mice and humans. These integrated molecular profiles also allowed further characterization of complex pathways, particularly the mitochondrial unfolded protein response (UPR(mt)). UPR(mt) shows strikingly variant responses at the transcript and protein level that are remarkably conserved among C. elegans, mice, and humans. Overall, these examples demonstrate the value of an integrated multilayered omics approach to characterize complex metabolic phenotypes.
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich (ETHZ), Zurich 8093, Switzerland.
authors.forename: Yibo
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
authors.forename: Evan G
authors.initials: EG
authors.lastname: Williams
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich (ETHZ), Zurich 8093, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dubuis
authors.affiliation: Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Mottis
authors.affiliation: Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
authors.forename: Virginija
authors.initials: V
authors.lastname: Jovaisaite
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases and Department of Pediatrics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Carmen A
authors.initials: CA
authors.lastname: Argmann
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich (ETHZ), Zurich 8093, Switzerland; Department of Traditional Pharmacy, School of Pharmacy and Pharmaceutical Sciences, Shiraz University of Medical Sciences, Shiraz 71349-14693, Iran.
authors.forename: Pouya
authors.initials: P
authors.lastname: Faridi
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich (ETHZ), Zurich 8093, Switzerland.
authors.forename: Witold
authors.initials: W
authors.lastname: Wolski
authors.affiliation: Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne 1010, Switzerland; Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kutalik
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich (ETHZ), Zurich 8093, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zamboni
authors.affiliation: Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland. Electronic address: admin.auwerx@epfl.ch.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich (ETHZ), Zurich 8093, Switzerland; Faculty of Science, University of Zurich, Zurich 8057, Switzerland. Electronic address: aebersold@imsb.biol.ethz.ch.
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007658:Ketone Oxidoreductases / Q000378:metabolism; D008099:Liver / Q000737:chemistry* / Q000166:cytology / Q000378:metabolism; D051379:Mice / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008928:Mitochondria / Q000737:chemistry* / Q000378:metabolism; D020543:Proteome / Q000032:analysis*; D040641:Quantitative Trait Loci; D044967:Serum / Q000737:chemistry* / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D020543:Proteome; D007658:Ketone Oxidoreductases; D005947:Glucose