Epistasis and the Kinetics of Phenotypic Robustness in Metabolic Pathways

It is an open question whether phenomena such as phenotypic robustness to mutation evolve as adaptations or are simply an inherent property of genetic systems. We examine this question in the context of metabolic physiology. Traditionally, the conclusion that has been derived from Metabolic Control Analysis (MCA) has been that phenotypic robustness to mutation (e.g. dominance) is an inevitable property of multienzyme systems and, hence, does not require an evolutionary explanation. However, it is shown here that for mutations involving finite changes (of any magnitude) in enzyme concentration, the conclusions from MCA regarding phenotypic robustness do not hold. It is shown that robustness is not a necessary property of metabolic pathways. Furthermore, in scenarios where one allows for expected nonlinearities such as those caused by enzyme saturation, robustness levels can be modified by mutations that affect saturation levels. The implication is that robustness levels in metabolism can be subject to evolutionary modification.