The selective force driving metabolic genes clustering

The evolution of operons has puzzled evolutionary biologists since their discovery and many theories exist to explain their emergence and spreading. The presence of several plausible hypotheses dealing with operon emergence/evolution/spreading is indicative of the absence of a universal causal factor for this evolutionary process. Here, we argue that the way in which DNA replication and cell division are coupled in microbial species introduces an additional selective force that may be responsible for the clustering of functionally related genes on chromosomes. We interpret this as a preliminary and necessary step in operon formation. Specifically, we start from the observation that during DNA replication differences in copy number of genes that are found at distant loci on the same chromosome arm exist. We provide theoretical considerations suggesting that, when genes of the same metabolic process are far away on the chromosome, this results in perturbations to metabolic homeostasis. By formalizing the effect of DNA replication on metabolic homeostasis based on Metabolic Control Analysis, we show that the above situation provides a selective force that can drive the formation of gene clusters and operons. 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 and quantify the theoretical contribution of this feature on the distribution of extant gene clusters and operons.