Nature Biotechnology
19, 45 - 50 (2001)
doi:10.1038/83496
A functional genomics strategy that uses metabolome data to reveal the
phenotype of silent mutationsLéonie M. Raamsdonk1, Bas Teusink1, 2, David Broadhurst3, Nianshu Zhang4, Andrew Hayes4, Michael C. Walsh1, 5, Jan A. Berden1, Kevin M. Brindle6, Douglas B. Kell3, Jem J. Rowland7, Hans V. Westerhoff1, 8, Karel van Dam1
& Stephen G. Oliver41
Swammerdam Institute for Life Sciences, BioCentrum
Amsterdam, University of Amsterdam, Plantage Muidergracht 12
, NL-1018 TV Amsterdam, The Netherlands
. 2
Current address: TNO-Prevention and Health,
Zernikedreef 9, NL-2333 CK, Leiden,
The Netherlands. 3
Institute of Biological Sciences, Cledwyn Building,
University of Wales, Aberystwyth, Aberystwyth
SY23 3DD, UK. 4
School of Biological Sciences, University of Manchester,
2.205 Stopford Building, Oxford Road, Manchester
M13 9PT, UK. 5
Current address: Heineken Technical Services B.V.
P.O. Box 510, NL-2380 BB Zoeterwoude,
The Netherlands. 6
Department of Biochemistry, University of Cambridge,
Old Addenbrooke's Site, 80 Tennis Court Road,
Cambridge CB2 1GA, UK. 7
Department of Computer Science, University of Wales
, Aberystwyth, Aberystwyth SY23 3DB,
UK. 8
Department of Molecular Cell Physiology, BioCentrum
Amsterdam, Free University, De Boelelaan 1087,
NL-1081 HV, Amsterdam, The Netherlands.
Correspondence should be addressed to Stephen G. Oliver steve.oliver@man.ac.uk
functional genomicsmetabolomeyeastSaccharomyces cerevisiaesilent mutationsphenotype analysismetabolic control analysisco-response analysisA large proportion of the 6,000 genes present in the genome of Saccharomyces
cerevisiae, and of those sequenced in other organisms, encode proteins
of unknown function. Many of these genes are "silent," that is,
they show no overt phenotype, in terms of growth rate or other fluxes, when
they are deleted from the genome. We demonstrate how the intracellular concentrations
of metabolites can reveal phenotypes for proteins active in metabolic regulation.
Quantification of the change of several metabolite concentrations relative
to the concentration change of one selected metabolite can reveal the site
of action, in the metabolic network, of a silent gene. In the same way, comprehensive
analyses of metabolite concentrations in mutants, providing "metabolic
snapshots," can reveal functions when snapshots from strains deleted
for unstudied genes are compared to those deleted for known genes. This approach
to functional analysis, using comparative metabolomics, we call FANCY—an
abbreviation for functional analysis by co-responses in yeast.
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