Comparing RNA structures using a full set of biologically relevant edit operations is intractable

7 pagesArc-annotated sequences are useful for representing structural information of RNAs and have been extensively used for comparing RNA structures in both terms of sequence and structural similarities. Among the many paradigms referring to arc-annotated sequences and RNA structures comparison (see \cite{IGMA_BliDenDul08} for more details), the most important one is the general edit distance. The problem of computing an edit distance between two non-crossing arc-annotated sequences was introduced in \cite{Evans99}. The introduced model uses edit operations that involve either single letters or pairs of letters (never considered separately) and is solvable in polynomial-time \cite{ZhangShasha:1989}. To account for other possible RNA structural evolutionary events, new edit operations, allowing to consider either silmutaneously or separately letters of a pair were introduced in \cite{jiangli}; unfortunately at the cost of computational tractability. It has been proved that comparing two RNA secondary structures using a full set of biologically relevant edit operations is {\sf\bf NP}-complete. Nevertheless, in \cite{DBLP:conf/spire/GuignonCH05}, the authors have used a strong combinatorial restriction in order to compare two RNA stem-loops with a full set of biologically relevant edit operations; which have allowed them to design a polynomial-time and space algorithm for comparing general secondary RNA structures. In this paper we will prove theoretically that comparing two RNA structures using a full set of biologically relevant edit operations cannot be done without strong combinatorial restrictions

Efficient Algorithms for Probing the RNA Mutation Landscape

The diversity and importance of the role played by RNAs in the regulation and development of the cell are now well-known and well-documented. This broad range of functions is achieved through specific structures that have been (presumably) optimized through evolution. State-of-the-art methods, such as McCaskill's algorithm, use a statistical mechanics framework based on the computation of the partition function over the canonical ensemble of all possible secondary structures on a given sequence. Although secondary structure predictions from thermodynamics-based algorithms are not as accurate as methods employing comparative genomics, the former methods are the only available tools to investigate novel RNAs, such as the many RNAs of unknown function recently reported by the ENCODE consortium. In this paper, we generalize the McCaskill partition function algorithm to sum over the grand canonical ensemble of all secondary structures of all mutants of the given sequence. Specifically, our new program, RNAmutants, simultaneously computes for each integer k the minimum free energy structure MFE(k) and the partition function Z(k) over all secondary structures of all k-point mutants, even allowing the user to specify certain positions required not to mutate and certain positions required to base-pair or remain unpaired. This technically important extension allows us to study the resilience of an RNA molecule to pointwise mutations. By computing the mutation profile of a sequence, a novel graphical representation of the mutational tendency of nucleotide positions, we analyze the deleterious nature of mutating specific nucleotide positions or groups of positions. We have successfully applied RNAmutants to investigate deleterious mutations (mutations that radically modify the secondary structure) in the Hepatitis C virus cis-acting replication element and to evaluate the evolutionary pressure applied on different regions of the HIV trans-activation response element. In particular, we show qualitative agreement between published Hepatitis C and HIV experimental mutagenesis studies and our analysis of deleterious mutations using RNAmutants. Our work also predicts other deleterious mutations, which could be verified experimentally. Finally, we provide evidence that the 3′ UTR of the GB RNA virus C has been optimized to preserve evolutionarily conserved stem regions from a deleterious effect of pointwise mutations. We hope that there will be long-term potential applications of RNAmutants in de novo RNA design and drug design against RNA viruses. This work also suggests potential applications for large-scale exploration of the RNA sequence-structure network. Binary distributions are available at http://RNAmutants.csail.mit.edu/

A novel approach to represent and compare RNA secondary structures

Structural information is crucial in ribonucleic acid (RNA) analysis and functional annotation; nevertheless, how to include such structural data is still a debated problem. Dot-bracket notation is the most common and simple representation for RNA secondary structures but its simplicity leads also to ambiguity requiring further processing steps to dissolve. Here we present BEAR (Brand nEw Alphabet for RNA), a new context-aware structural encoding represented by a string of characters. Each character in BEAR encodes for a specific secondary structure element (loop, stem, bulge and internal loop) with specific length. Furthermore, exploiting this informative and yet simple encoding in multiple alignments of related RNAs, we captured how much structural variation is tolerated in RNA families and convert it into transition rates among secondary structure elements. This allowed us to compute a substitution matrix for secondary structure elements called MBR (Matrix of BEAR-encoded RNA secondary structures), of which we tested the ability in aligning RNA secondary structures. We propose BEAR and the MBR as powerful resources for the RNA secondary structure analysis, comparison and classification, motif finding and phylogeny