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Cell. 2014 Sep 11;158(6):1415-1430. doi: 10.1016/j.cell.2014.07.039.

Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population.

Author information

1
Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich (ETHZ), Zurich 8093, Switzerland.
2
Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
3
Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases and Department of Pediatrics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
4
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
5
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.
6
Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne 1010, Switzerland; Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
7
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.
8
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.

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.

PMID:
25215496
PMCID:
PMC4179868
DOI:
10.1016/j.cell.2014.07.039
[Indexed for MEDLINE]
Free PMC Article
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