Abstract
Message RNA (mRNA) carries a large number of local secondary structures, with structural stability to participate in the regulations of gene expression. A worthy question is how the local structural stability is maintained under the constraint that multiple selective pressures are imposed on mRNA local regions. Here, we performed the first genome-wide study of natural selection operating on high structural stability regions (HSRs) of mRNAs in Escherichia coli. We found that HSR tends to adjust the folded conformation to reduce the harm of mutations, showing a high level of mutational robustness. Moreover, guanine preference in HSR was observed, supporting the hypothesis that the selective constraint for high structural stability may partly account for the high percentage of G content in Escherichia coli genome. Notably, we found a substantially reduced synonymous substitution rate in HSRs compared with that in their adjacent regions. Surprisingly and interestingly, the non-key sites in HSRs, which have slight effect on structural stability, have synonymous substitution rate equivalent to background regions. To explain this result, we identified compensatory mutations in HSRs based on structural stability, and found that a considerable number of synonymous mutations occur to restore the structural stability decreased heavily by the mutations on key sites. Overall, these results suggest a significant role of local structural stability as a selective force operating on mRNA, which furthers our understanding of the constraints imposed on protein-coding RNAs.
Highlights
RNA molecules tend to adopt a folded conformation through the formation of Watson-Crick base pairing between complementary nucleotides
We identified 6352 conserved high structural stability regions (HSRs) between Escherichia coli and Escherichia fergusonii (Table 1, Table S3), which are located in 2256 genes (84.3% of all orthologs)
4202 and 4306 specific HSRs were detected in Escherichia coli and Escherichia fergusonii, respectively
Summary
RNA molecules tend to adopt a folded conformation through the formation of Watson-Crick base pairing between complementary nucleotides. By surveying secondary structures in various genomes, previous studies have revealed that a large number of genomes are being transcribed to produce non-coding RNAs that generally contain a conserved secondary structure [5,6,7,8,9]. A strong association between structural stability and protein abundance was observed in yeast [24]. These results suggest an important role of mRNA structural stability, which might be different from the roles of conserved secondary structures reported by previous studies. Numerous studies have focused on the evolution of RNA secondary structure [14,25,26,27,28,29] and revealed several mechanisms to maintain the secondary structure, including lower substitution rate [30] and compensatory mutations [27]
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