Specificity of RNA folding and its association with evolutionarily adaptive mRNA secondary structure

Abstract

Secondary structure is a fundamental feature for both noncoding and messenger RNA. However, our understandings about the secondary structure of mRNA, especially for the coding regions, remain elusive, likely due to translation and the lack of RNA binding proteins that sustain the consensus structure, such as those bind to noncoding RNA. Indeed, mRNA has recently been found to bear pervasive alternative structures, whose overall evolutionary and functional significance remained untested. We hereby approached this problem by estimating folding specificity, the probability that a fragment of RNA folds back to the same partner once re-folded. We showed that folding specificity for mRNA is lower than noncoding RNA, and displays moderate evolutionary conservation between orthologs and between paralogs. More importantly, we found that specific rather than alternative folding is more likely evolutionarily adaptive, since it is more frequently associated with functionally important genes or sites within a gene. Additional analysis in combination with ribosome density suggests the capability of modulating ribosome movement as one potential functional advantage provided by specific folding. Our findings revealed a novel facet of RNA structome with important functional and evolutionary implications, and points to a potential way of disentangling mRNA secondary structures maintained by natural selection from molecular noise.