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BIOLOGICAL SCIENCES / GENETICS
Plasticity of genetic interactions in metabolic networks of yeast
*Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom; and Department of Zoology, University of Oxford, Oxford OX1 3PS, United Kingdom
Edited by Charles R. Cantor, Sequenom, Inc., San Diego, CA, and approved December 12, 2006 (received for review August 17, 2006)
Why are most genes dispensable? The impact of gene deletions may depend on the environment (plasticity), the presence of compensatory mechanisms (mutational robustness), or both. Here, we analyze the interaction between these two forces by exploring the condition-dependence of synthetic genetic interactions that define redundant functions and alternative pathways. We performed systems-level flux balance analysis of the yeast (Saccharomyces cerevisiae) metabolic network to identify genetic interactions and then tested the model's predictions with in vivo gene-deletion studies. We found that the majority of synthetic genetic interactions are restricted to certain environmental conditions, partly because of the lack of compensation under some (but not all) nutrient conditions. Moreover, the phylogenetic cooccurrence of synthetically interacting pairs is not significantly different from random expectation. These findings suggest that these gene pairs have at least partially independent functions, and, hence, compensation is only a byproduct of their evolutionary history. Experimental analyses that used multiple gene deletion strains not only confirmed predictions of the model but also showed that investigation of false predictions may both improve functional annotation within the model and also lead to the discovery of higher-order genetic interactions. Our work supports the view that functional redundancy may be more apparent than real, and it offers a unified framework for the evolution of environmental adaptation and mutational robustness.
epistasis | genetic robustness | Saccharomyces cerevisiae | environmental dependence | flux balance analysis
Author contributions: R.H. and B.P. contributed equally to this work; B.P., S.G.O., and D.D. designed research; R.H., B.P., and D.D. performed research; R.H., B.P., C.P., and S.G.O. analyzed data; and B.P., C.P., S.G.O., and D.D. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0607153104/DC1.
To whom correspondence may be addressed. E-mail: steve.oliver{at}manchester.ac.uk or d.delneri{at}manchester.ac.uk
© 2007 by The National Academy of Sciences of the USA
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