A detailed genome-wide reconstruction of mouse metabolism based on human Recon 1.
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.
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Martin I
MI
Sigurdsson
Neema
N
Jamshidi
Eirikur
E
Steingrimsson
Ines
I
Thiele
Bernhard Ø
BØ
Palsson
D000465:Algorithms; D000818:Animals; D002417:Cattle; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008071:Lipoprotein Lipase / Q000172:deficiency; D053858:Metabolic Networks and Pathways / Q000235:genetics; D055432:Metabolomics / Q000379:methods*; D051379:Mice / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D010641:Phenotype; D051381:Rats; D015203:Reproducibility of Results; D012689:Sequence Homology, Nucleic Acid
D008071:Lipoprotein Lipase