A detailed genome-wide reconstruction of mouse metabolism based on human Recon 1.

TitleA detailed genome-wide reconstruction of mouse metabolism based on human Recon 1.
Publication TypeJournal Article
Year of Publication2010
AuthorsSigurdsson MI, Jamshidi N, Steingrimsson E, Thiele I, Palsson BØ
JournalBMC systems biology
Volume4
Pagination140
PubMed Date2010
ISSN1752-0509
KeywordsAlgorithms, Animals, Cattle, Genome, Human, Humans, Lipoprotein Lipase, Metabolic Networks and Pathways, Metabolomics, Mice, Models, Biological, Phenotype, Rats, Reproducibility of Results, Sequence Homology, Nucleic Acid
Abstract

BACKGROUND: Well-curated and validated network reconstructions are extremely valuable tools in systems biology. Detailed metabolic reconstructions of mammals have recently emerged, including human reconstructions. They raise the question if the various successful applications of microbial reconstructions can be replicated in complex organisms.

RESULTS: We mapped the published, detailed reconstruction of human metabolism (Recon 1) to other mammals. By searching for genes homologous to Recon 1 genes within mammalian genomes, we were able to create draft metabolic reconstructions of five mammals, including the mouse. Each draft reconstruction was created in compartmentalized and non-compartmentalized version via two different approaches. Using gap-filling algorithms, we were able to produce all cellular components with three out of four versions of the mouse metabolic reconstruction. We finalized a functional model by iterative testing until it passed a predefined set of 260 validation tests. The reconstruction is the largest, most comprehensive mouse reconstruction to-date, accounting for 1,415 genes coding for 2,212 gene-associated reactions and 1,514 non-gene-associated reactions.We tested the mouse model for phenotype prediction capabilities. The majority of predicted essential genes were also essential in vivo. However, our non-tissue specific model was unable to predict gene essentiality for many of the metabolic genes shown to be essential in vivo. Our knockout simulation of the lipoprotein lipase gene correlated well with experimental results, suggesting that softer phenotypes can also be simulated.

CONCLUSIONS: We have created a high-quality mouse genome-scale metabolic reconstruction, iMM1415 (Mus Musculus, 1415 genes). We demonstrate that the mouse model can be used to perform phenotype simulations, similar to models of microbe metabolism. Since the mouse is an important experimental organism, this model should become an essential tool for studying metabolic phenotypes in mice, including outcomes from drug screening.

Alternate JournalBMC Syst Biol
PubMed ID20959003

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