Selection on metabolic pathway function in the presence of mutation-selection-drift balance leads to rate-limiting steps that are not evolutionarily stable

BACKGROUND: While commonly assumed in the biochemistry community that the control of metabolic pathways is thought to be critical to cellular function, it is unclear if metabolic pathways generally have evolutionarily stable rate limiting (flux controlling) steps. RESULTS: A set of evolutionary simulations using a kinetic model of a metabolic pathway was performed under different conditions to evaluate the evolutionary stability of rate limiting steps. Simulations used combinations of selection for steady state flux, selection against the cost of molecular biosynthesis, and selection against the accumulation of high concentrations of a deleterious intermediate. Two mutational regimes were used, one with mutations that on average were neutral to molecular phenotype and a second with a preponderance of activity-destroying mutations. The evolutionary stability of rate limiting steps was low in all simulations with non-neutral mutational processes. Clustering of parameter co-evolution showed divergent inter-molecular evolutionary patterns under different evolutionary regimes. CONCLUSIONS: This study provides a null model for pathway evolution when compensatory processes dominate with potential applications to predicting pathway functional change. This result also suggests a possible mechanism in which studies in statistical genetics that aim to associate a genotype to a phenotype assuming independent action of variants may be mis-specified through a mis-characterization of the link between individual gene function and pathway function. A better understanding of the genotype-phenotype map has potential applications in differentiating between compensatory changes and directional selection on pathways as well as detecting SNPs and fixed differences that might have phenotypic effects. REVIEWERS: This article was reviewed by Arne Elofsson, David Ardell, and Shamil Sunyaev. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13062-016-0133-6) contains supplementary material, which is available to authorized users.