TOPAS: network-based structural alignment of RNA sequences.

Motivation: For many RNA families, the secondary structure is known to be better conserved among the member RNAs compared to the primary sequence. For this reason, it is important to consider the underlying folding structures when aligning RNA sequences, especially for those with relatively low sequence identity. Given a set of RNAs with unknown structures, simultaneous RNA alignment and folding algorithms aim to accurately align the RNAs by jointly predicting their consensus secondary structure and the optimal sequence alignment. Despite the improved accuracy of the resulting alignment, the computational complexity of simultaneous alignment and folding for a pair of RNAs is O(N-6), which is too costly to be used for large-scale analysis. Results: In order to address this shortcoming, in this work, we propose a novel network-based scheme for pairwise structural alignment of RNAs. The proposed algorithm, TOPAS, builds on the concept of topological networks that provide structural maps of the RNAs to be aligned. For each RNA sequence, TOPAS first constructs a topological network based on the predicted folding structure, which consists of sequential edges and structural edges weighted by the base-pairing probabilities. The obtained networks can then be efficiently aligned by using probabilistic network alignment techniques, thereby yielding the structural alignment of the RNAs. The computational complexity of our proposed method is significantly lower than that of the Sankoff-style dynamic programming approach, while yielding favorable alignment results. Furthermore, another important advantage of the proposed algorithm is its capability of handling RNAs with pseudoknots while predicting the RNA structural alignment. We demonstrate that TOPAS generally outperforms previous RNA structural alignment methods on RNA benchmarks in terms of both speed and accuracy.