Specificity of RNA Folding and Its Association with Evolutionarily Adaptive mRNA Secondary Structures.

Abstract

The secondary structure is a fundamental feature of both noncoding and messenger RNAs. However, our understanding of the secondary structure of mRNA, especially that of the coding regions, remains elusive, likely due to translation and the lack of RNA-binding proteins that sustain the consensus structure, such as those that bind to noncoding RNA. Indeed, mRNA has recently been found to adopt diverse alternative structures, the overall functional significance of which remains untested. We hereby approached this problem by estimating the folding specificity, i.e., the probability that a fragment of RNA folds back to the same partner once refolded. We showed that the folding specificity of mRNA is lower than that of noncoding RNA and exhibits moderate evolutionary conservation. Notably, we found that specific rather than alternative folding is likely evolutionarily adaptive since specific folding is frequently associated with functionally important genes or sites within a gene. Additional analysis in combination with ribosome density suggests the ability to modulate ribosome movement as one potential functional advantage provided by specific folding. Our findings revealed a novel facet of the RNA structurome with important functional and evolutionary implications and indicated a potential method for distinguishing the mRNA secondary structures maintained by natural selection from molecular noise.