Do deleterious mutations act synergistically? Metabolic control theory provides a partial answer

Abstract

Metabolic control theory is used to derive conditions under which two deleterious mutations affecting the dynamics of a metabolic pathway act synergistically. It is found that two mutations tend to act mostly synergistically when they reduce the activity of the same enzyme. If the two mutations affect different enzymes, the conclusion depends on the way that fitness is determined by aspects of the pathway. The cases analyzed are: selection for (1) maximal flux, (2) maximal equilibrium concentration (pool size) of an intermediate, (3) optimal flux, (4) optimal pool size. The respective types of epistasis found are: (1) antagonistic, (2) partly synergistic, (3-4) synergism is likely to predominate over antagonism. This results in somewhat different predictions concerning the effect of metabolic mutations on fitness in prokaryotes and eukaryotes. The fact that bacteria are largely clonal but have often a mosaic gene structure is consistent with expectations from the model.