The genotype-phenotype relationship and evolutionary genetics in the light of the Metabolic Control Analysis

Metabolic control analysis has long been used as a systemic model of the genotype-phenotype (GP) relationship. By considering kinetic parameters and enzyme concentrations as reflecting the genotype level and metabolic fluxes or pools as phenotypes related to fitness, MCA has given a biological basis to the relationship between these two levels. The non-linear and concave relationship between enzymes and fluxes can account for common genetic effects that reductionist approaches have been powerless to explain, such as the dominance of active alleles over less active alleles, the various types of epistasis and heterosis, and reveals the structural links between these genetic effects. The summation property of the flux control coefficients accounts for the L-shaped distribution of Quantitative Trait Locus (QTL) effects, irrespective of other possible causes. Metabolic models of response to selection results in evolutionary scenarios that are markedly different from those derived from the classical infinitesimal model of quantitative genetics. In particular, evolution towards selective neutrality appears to be a consequence of the diminishing return of the flux-enzyme relationship. In this paper, we survey the historical and recent achievements of MCA in genetics, quantitative genetics and evolution, focusing on epistasis and the evolution of flux in relation to enzyme concentrations.