Coevolution in RNA Molecules Driven by Selective Constraints: Evidence from 5S rRNA

Abstract

Understanding intra-molecular coevolution helps to elucidate various structural and functional constraints acting on molecules and might have practical applications in predicting molecular structure and interactions. In this study, we used 5S rRNA as a template to investigate how selective constraints have shaped the RNA evolution. We have observed the nonrandom occurrence of paired differences along the phylogenetic trees, the high rate of compensatory evolution, and the high TIR scores (the ratio of the numbers of terminal to intermediate states), all of which indicate that significant positive selection has driven the evolution of 5S rRNA. We found three mechanisms of compensatory evolution: Watson-Crick interaction (the primary one), complex interactions between multiple sites within a stem, and interplay of stems and loops. Coevolutionary interactions between sites were observed to be highly dependent on the structural and functional environment in which they occurred. Coevolution occurred mostly in those sites closest to loops or bulges within structurally or functionally important helices, which may be under weaker selective constraints than other stem positions. Breaking these pairs would directly increase the size of the adjoining loop or bulge, causing a partial or total structural rearrangement. In conclusion, our results indicate that sequence coevolution is a direct result of maintaining optimal structural and functional integrity.

Evolutionary biochemistry: revealing the historical and physical causes of protein properties

“…We conclude with thoughts about the future of the field. Although we focus on proteins, the concepts and techniques we discuss can also be applied to DNA and RNA evolution 38-41 . We highlight experimental work, but computational and theoretical explorations have also contributed to the development of the new field 42,43 .…”

Evidence of Pervasive Biologically Functional Secondary Structures within the Genomes of Eukaryotic Single-Stranded DNA Viruses

“…Specifically, although biologically functional secondary-structural elements should be evolutionarily conserved across diverse viral lineages, the nucleotide sequences from which these elements are composed should display distinctive signals of natural selection favoring the maintenance of these structures. Whereas in coding regions these signals might include codon usage biases (54,55) and decreased rates of synonymous substitution (56), throughout the genome these signals could also include high rates of reversion substitution (51,57) and increased frequencies of complementarily coevolving nucleotide pairs, particularly among those nucleotides predicted to be base paired within secondary-structural elements (58)(59)(60).…”

Genome-Wide Analysis of Selective Constraints on High Stability Regions of mRNA Reveals Multiple Compensatory Mutations in Escherichia coli

“…Paired means that the first mutated base is paired with the second mutated base, while the unpaired means that the two mutated bases are unpaired. We calculated the ratio paired/unpaired and surprisingly found that the ratio is lower than the expected value in the two species ( t -test, all p- values <10 −7 , Table 3), which is different from the pattern inferred from the conserved secondary structure (the ratio is higher than the expected value) [27]. This result is consistent with the idea that structural stability instead of structural conformation in HSR is conserved during evolution [16], [35].…”

“…Besides the strategy involving the reduction of the substitution rate on key sites (as suggested in previous section), another strategy is used to decrease the harm of the mutations on key sites. That is, a second (so called “compensatory”) mutation occurs on the specific site to restore the original conformation [27], [50], [51]. Previous studies on conserved secondary structure have revealed that the compensatory mutations should have a fitness equivalent to the wild type, resulting in an increasing of the substitution rate among these specific sites compared with that of key sites [52].…”

“…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. Besides its functions, numerous studies have focused on the evolution of RNA secondary structure [14], [25]–[29] and revealed several mechanisms to maintain the secondary structure, including lower substitution rate [30] and compensatory mutations [27].…”