Conservation of Expression and Sequence of Metabolic Genes Is Reflected by Activity Across Metabolic States

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Abstract
Variation in gene expression levels on a genomic scale has been detected among different strains, among closely related species, and within populations of genetically identical cells. What are the driving forces that lead to expression divergence in some genes and conserved expression in others? Here we employ flux balance analysis to address this question for metabolic genes. We consider the genome-scale metabolic model of Saccharomyces cerevisiae, and its entire space of optimal and near-optimal flux distributions. We show that this space reveals underlying evolutionary constraints on expression regulation, as well as on the conservation of the underlying gene sequences. Genes that have a high range of optimal flux levels tend to display divergent expression levels among different yeast strains and species. This suggests that gene regulation has diverged in those parts of the metabolic network that are less constrained. In addition, we show that genes that are active in a large fraction of the space of optimal solutions tend to have conserved sequences. This supports the possibility that there is less selective pressure to maintain genes that are relevant for only a small number of metabolic states. The regulation of gene product activity allows cells to efficiently cope with various tasks under varying conditions. Given that, one may have expected that striving for efficiency would cause genetically similar cells to have similar regulation. However, in reality, high variations in gene expression levels are detected between different strains and even between genetically identical cells taken from the same culture. What are the driving forces that lead to expression divergence in some genes and conserved expression in others? To address this question, the authors study the conservation of regulation in yeast metabolism, using a computational model. They find that genes coding for reactions whose flux rates are narrowly constrained by the cellular need to maximize growth rate tend to have strictly conserved regulation and expression. However, when a wide range of flux rates is compatible with high cellular growth rates, the corresponding regulation and expression patterns are free to diverge. Furthermore, enzymes that participate in a large number of alternative metabolic behaviors tend to be encoded by genes with a highly conserved sequence. Taken together, these findings support the hypothesis that maintaining large variability in the overall expression and metabolic repertoire of the cell is under marked evolutionary selection.