Evolutionary study of metabolic pathways from a topogical and functional network perspective

Abstract

Relationships between evolutionary rates and gene properties on genomic, functional, pathway or system levels, are being explored to unravel the principles of the evolutionary process. In particular, network properties, both topological and functional, have been analyzed to recognize the constraints they may impose on the evolutionary fate of genes. Topological properties have been analyzed to date, at a small scale, on a small number of specific metabolic pathways. Results show that a fraction of the variance in evolu- tionary rates of the enzyme-coding genes is indeed accounted for by their topological position within the metabolic network, however no general pattern has been identified. Here we undertake the study of the whole set of human metabolic pathways to derive a general picture of how selection is distributed over metabolic networks. Functional network properties on the other hand have been loosely explored because of the lack of dynamical characterization for the most of the known systems and pathways. However, a specific metabolic system, the core metabolic network in human erythrocytes, is endowed with a comprehensive kinetic model that allows analyzing the rela- tionship between the evolutionary rates of its genes and a relevant functional network property: the metabolic flux distribution throughout it. Our results show that while topology is a common determinant of evolutionary rates in human metabolic pathways, dynamical system-level properties also exert constraints on the evolution of the underlying genes. In particular we found that, in the erythrocyte core metabolic network, enzymes carrying high metabolic fluxes are more constrained in their evolution. The results demonstrate the importance of considering the dynamical functioning of gene networks when assessing the action of selection on system-level properties.