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Pairs of nucleotides within functional nucleic acid secondary structures often display evidence of coevolution that is consistent with the maintenance of base-pairing. Here we introduce a sequence evolution model, MESSI, that infers coevolution associated with base-paired sites in DNA or RNA sequence alignments. MESSI can estimate coevolution whilst accounting for an unknown secondary structure. MESSI can also use GPU parallelism to increase computational speed. We used MESSI to infer coevolution associated with GC, AU (AT in DNA), GU (GT in DNA) pairs in non-coding RNA alignments, and in single-stranded RNA and DNA virus alignments. Estimates of GU pair coevolution were found to be higher at base-paired sites in single-stranded RNA viruses and non-coding RNAs than estimates of GT pair coevolution in single-stranded DNA viruses. A potential biophysical explanation is that GT pairs do not stabilise DNA secondary structures to the same extent that GU pairs do in RNA. Additionally, MESSI estimates the degrees of coevolution at individual base-paired sites in an alignment. These estimates were computed for a SHAPE-MaP-determined HIV-1 NL4-3 RNA secondary structure. We found that estimates of coevolution were more strongly correlated with experimentally-determined SHAPE-MaP pairing scores than three non-evolutionary measures of base-pairing covariation. To assist researchers in prioritising substructures with potential functionality, MESSI automatically ranks substructures by degrees of coevolution at base-paired sites within them. Such a ranking was created for an HIV-1 subtype B alignment, revealing an excess of top-ranking substructures that have been previously identified as having structure-related functional importance, amongst several uncharacterised top-ranking substructures.

Original publication




Journal article


Mol Biol Evol

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