Abstract
Despite mounting evidence that in clonal bacterial populations, phenotypic variability originates from stochasticity in gene expression, little is known about noise-shaping evolutionary forces and how expression noise translates to phenotypic differences. Here we developed a high-throughput assay that uses a redox-sensitive dye to couple growth of thousands of bacterial colonies to their respiratory activity and show that in Escherichia coli, noisy regulation of lower glycolysis and citric acid cycle is responsible for large variations in respiratory metabolism. We found that these variations are Pareto optimal to maximization of growth rate and minimization of lag time, two objectives competing between fermentative and respiratory metabolism. Metabolome-based analysis revealed the role of respiratory metabolism in preventing the accumulation of toxic intermediates of branched chain amino acid biosynthesis, thereby supporting early onset of cell growth after carbon starvation. We propose that optimal metabolic tradeoffs play a key role in shaping and preserving phenotypic heterogeneity and adaptation to fluctuating environments.
Highlights
Despite mounting evidence that in clonal bacterial populations, phenotypic variability originates from stochasticity in gene expression, little is known about noise-shaping evolutionary forces and how expression noise translates to phenotypic differences
By developing an assay to directly measure variability in the respiratory rates among colonies of Escherichia coli growing on solid media, we show that noisy transcriptional regulation of lower glycolytic and citric acid (TCA) cycle enzymes can be readily transmitted to metabolic heterogeneity
Essential genes on average exhibited low deviating noise levels (p-value ≤ 0.05), indicating that there may be selective pressures for noise reduction[26]. These results suggest that, despite the key role in bacterial fitness of proteins involved in central metabolism, fluctuations in their expression, translation, or degradation may have been preserved by evolution and can be a major source of phenotypic heterogeneity
Summary
Despite mounting evidence that in clonal bacterial populations, phenotypic variability originates from stochasticity in gene expression, little is known about noise-shaping evolutionary forces and how expression noise translates to phenotypic differences. We developed a high-throughput assay that uses a redox-sensitive dye to couple growth of thousands of bacterial colonies to their respiratory activity and show that in Escherichia coli, noisy regulation of lower glycolysis and citric acid cycle is responsible for large variations in respiratory metabolism. We found that these variations are Pareto optimal to maximization of growth rate and minimization of lag time, two objectives competing between fermentative and respiratory metabolism. We propose that variability in respiro-/fermentative metabolism can be fitness invariant, allowing cells to maintain a greater variation in enzyme expression and potentially employ diverse adaptive strategies to environmental changes
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