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The metabolome provides clues to gene function
By Bijal P. Trivedi

Of every genome that is sequenced, the role of about half the genes is unknown. Out of the 6000 genes in yeast, for example, between two and three thousand have no known function. Now, Stephen Oliver of the University of Manchester, UK, is using a new strategy to unmask the role these genes play inside the cell.

Oliver takes the yeast mutants, each missing a different gene, and then takes a snapshot or fingerprint of each mutant's "metabolome." The metabolome refers to the entire collection of small molecules—sugars, salts, amino acids, and nucleotides—and all the intermediates that exist inside a cell during their production or breakdown. These metabolites are players in essential cellular processes like converting glucose to energy, and producing amino acids and nucleotides for constructing large molecules like proteins and DNA respectively.

Geneticists can learn a great deal about a gene by deleting it and watching the effect on the organism; does it die, grow faster, behave differently, or lack body parts. In many cases these studies yield the gene's function. Or researchers may find that their gene of interest is similar to a gene in another organism and infer the biological role by making comparisons. Often however, the effects of losing a gene can be subtle and not detectable by such crude observational means.

Oliver combines a couple of sensitive analytical techniques that permit him to scan the metabolome of each mutant and identify, and quantify, the approximately 600 metabolites that are present in a single yeast cell. If the absence of a gene can be associated with changing concentrations of particular metabolites, the expectation is that it could tie the gene to specific metabolic pathways in the cell, and possibly even point to a unique function.

At present Oliver and his colleagues have scanned the metabolome of several hundred mutants.

This method will allow genes that share similar metabolome profiles to be grouped together. Ideally, the metabolome profiles of genes with known functions will match unknown profiles and anchor the unknown genes to activities within the cell, says Oliver.

Oliver's team will also collect metabolome profiles for healthy yeast under different environmental conditions to understand how chemical changes link to physiological stresses.

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Raamsdonk, L. M. et al. A functional genomics strategy that uses metabolome data to reveal the phenotype of silent mutations. Nat Biotechnol 19, 45-50 (January 2001).

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