The selective force driving metabolic operon assembly

Abstract

AbstractThe origin and evolution of operons have puzzled evolutionary biologists since their discovery. To date, many theories have been proposed to explain their evolution, among which reduced recombination rate within clustered genes, co-expression, simultaneous horizontal transfer and transcription/translation coupling. Most focus on the possible advantages provided by an already structured operon, while they all fall short in explaining the accretion of scattered genes into gene clusters and then operon. Here we argue that the way in which DNA replication and cell division are coupled in microbial species is a key feature in determining the clustering of genes on their chromosomes. More specifically, we start from the observation that bacterial species can accumulate several active replication forks by a partial decoupling of DNA replication and cytokinesis, which can lead to differences in copy numbers of genes that are found at distant loci on the same chromosome arm. We provide theoretical considerations suggesting that when genes belonging to the same metabolic process are far away on the chromosome, changes in the number of active replication forks result in perturbations to metabolic homeostasis, thereby introducing a selective force that promotes gene clustering. By deriving a formalization of the effect of active DNA replication on metabolic homeostasis based on Metabolic Control Analysis, we show that the above situation provides a selective force that can drive functionally related genes at nearby loci in evolution, which we interpret as the fundamental pre-requisite for operon formation. Finally, we confirmed that, in present-day genomes, this force is significantly stronger in those species where the average number of active replication forks is larger.