Abstract
Recent reports indicate that mutations in viral genomes tend to preserve RNA secondary structure, and those mutations that disrupt secondary structural elements may reduce gene expression levels, thereby serving as a functional knockout. In this article, we explore the conservation of secondary structures of mRNA coding regions, a previously unknown factor in bacterial evolution, by comparing the structural consequences of mutations in essential and nonessential Escherichia coli genes accumulated over 40 000 generations in the course of the ‘long-term evolution experiment’. We monitored the extent to which mutations influence minimum free energy (MFE) values, assuming that a substantial change in MFE is indicative of structural perturbation. Our principal finding is that purifying selection tends to eliminate those mutations in essential genes that lead to greater changes of MFE values and, therefore, may be more disruptive for the corresponding mRNA secondary structures. This effect implies that synonymous mutations disrupting mRNA secondary structures may directly affect the fitness of the organism. These results demonstrate that the need to maintain intact mRNA structures imposes additional evolutionary constraints on bacterial genomes, which go beyond preservation of structure and function of the encoded proteins.
Highlights
Increasing experimental [1] and computational [2,3] evidence points to the existence of extensive RNA structures in the coding regions of mRNA molecules
The main scientific questions we addressed in this study are whether purifying selection tends to eliminate mutations that are disruptive for mRNA structures, and whether this effect is more pronounced in essential genes compared with dispensable ones
minimum free energy (MFE) was calculated for the ancestor mRNA as well as for the mRNA of the 40 000th generation mutant experimentally observed in a Petri dish and for those of the in silico mutants
Summary
Increasing experimental [1] and computational [2,3] evidence points to the existence of extensive RNA structures in the coding regions of mRNA molecules. RNA secondary structures have been implicated in regulation of translation initiation, elongation and termination in both prokaryotes and eukaryotes [4,5]. The mRNA coding regions appear to be more structured than the untranslated regions [1] and have lower minimum folding free energies. The mRNA coding regions appear to have more stable structures than codon-randomized sequences [12]. Owing to the need to simultaneously preserve both the function and structure of the encoded protein, as well as the structural elements of the RNA molecule itself, mRNA coding regions are subject to dual selection pressure
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