RESUMO
An understanding of the distribution of natural patterns of genetic variation is relevant to such fundamental biological fields as evolution and development. One recent approach to understanding such patterns has been to focus on the constraints that may arise as a function of the network or pathway context in which genes are embedded. Despite theoretical expectations of higher evolutionary constraint for genes encoding upstream versus downstream enzymes in metabolic pathways, empirical results have varied. Here we combine two complementary models from population genetics and enzyme kinetics to explore genetic variation as a function of pathway position when selection acts on whole-pathway flux. We are able to qualitatively reproduce empirically observed patterns of polymorphism and divergence and suggest that expectations should vary depending on the evolutionary trajectory of a population. Upstream genes are initially more polymorphic and diverge faster after an environmental change, while we see the opposite trend as the population approaches its fitness optimum.