Multilayered Genetic and Omics Dissection of Mitochondrial Activity in a Mouse Reference Population
Open accessAbstract
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.
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A number of studies have shown that while levels of many proteins are strongly correlated with their transcript levels, with coincident eQTL and pQTL, the correlations for most protein-transcript pairs are modest.
“A number of studies have now shown that while levels of many proteins are strongly correlated with their transcript levels, with coincident eQTL and protein QTL (pQTL), the correlations for most protein–transcript pairs are modest [51–58].”
From Multi-omics approaches to disease (2017) · cites this paper as [58]
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- Authors
- Wu, Y., Williams, E. G., Dubuis, S., Mottis, A., Jovaisaite, V., Houten, S. M., Argmann, C. A., Faridi, P., Wolski, W., Kutalik, Z., Zamboni, N., Auwerx, J., & Aebersold, R.
- Affiliations
- ETH Zurich (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- Amsterdam UMC Location University of Amsterdam (NL)
- Shiraz University of Medical Sciences (IR)
- SIB Swiss Institute of Bioinformatics (CH)
- University of Zurich (CH)
- Corresponding author
- Auwerx, Johan
- Aebersold, Ruedi
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 158
- Issue
- 6
- Pages
- 1415-1430
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4179868
- OpenAlex
- W2065070435
- Cited by
- 244
- References
- 53
- Citations by year
- 2026: 5 · 2025: 17 · 2024: 8 · 2023: 21 · 2022: 14 · 2021: 22 · 2020: 25 · 2019: 31 · 2018: 23 · 2017: 22 · 2016: 25 · 2015: 26 · 2014: 5
- FWCI
- 10.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IRIS (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by-nc-sa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- SERVAL (Université de Lausanne) (submittedVersion, other-oa)
- Funders
- National Science Foundation (33CSCO-122661)
- GlaxoSmithKline (33CSCO-122661)
- Velux Stiftung
- École Polytechnique Fédérale de Lausanne (2013/153)
- Branco Weiss Fellowship – Society in Science
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (136201, 140780, 122661, 107679, 143914, 33CSCO, 151019, 31003A, 231138, 3100A0)
- Université de Lausanne
- Chinese Society of Clinical Oncology
- National Institutes of Health
- National Institute on Aging (R01AG043930)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- mitochondrial unfolded protein response, BXD mouse strains, transcriptome, liver proteome, metabolome, quantitative trait loci, diabetes mellitus, gene-environment interaction, metabolic phenotypes
- MeSH terms
- Animals, Glucose, Humans, Ketone Oxidoreductases, Liver, Mice, Inbred C57BL, Mice, Inbred DBA, Mitochondria, Proteome, Gene Expression Profiling, Quantitative Trait Loci, Serum, Mice, Unfolded Protein Response
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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