Abstract
Pairwise sequence covariations are a signal of conserved RNA secondary structure. We describe a method for distinguishing when lack of covariation signal can be taken as evidence against a conserved RNA structure, as opposed to when a sequence alignment merely has insufficient variation to detect covariations. We find that alignments for several long non-coding RNAs previously shown to lack covariation support do have adequate covariation detection power, providing additional evidence against their proposed conserved structures.Availability and implementationThe R-scape web server is at eddylab.org/R-scape, with a link to download the source code.Supplementary information Supplementary data are available at Bioinformatics online.
Highlights
Lack of significant covariation signal does not necessarily mean there is no conserved RNA structure
Many details of an alignment affect covariation analysis, but we hypothesized that detection power should depend primarily on the total number of single residue substitutions si,j in two alignment columns i and j in a proposed consensus pair
We use R-scape on each alignment to determine the number of basepairs with significant covariation support (E-value < 0.05)
Summary
Given an input RNA sequence alignment, R-scape infers a maximum likelihood phylogenetic tree using FastTree (version 2.1.10)[23], infers a maximum parsimony assignment of substitutions at each independent column i to each branch of the tree using our implementation of the Fitch algorithm[13]. Given an input sequence alignment with a consensus RNA secondary structure, R-scape-sim calculates a maximum likelihood phylogenetic tree with branch lengths. The evolutionary model consists of rate matrices for single (unpaired) residue substitution, pairwise (basepair) substitution, insertion, and deletion events8;14 We used this simulation procedure on the Rfam Cobalamin riboswitch alignment (RF00174) to generate 29,976 synthetic alignments with sequence number ranging from five to 190, and average percentage identity ranging from 30% to 100%. For each of 7,012 annotated consensus basepairs in 87 RNA families Rfam v14.0 with known three dimensional structures, we use R-scape to calculate the statistical significance (expectation value, E-value) and estimate sij for each proposed pair in Rfam “seed” alignments.
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