Fast Pairwise Structural RNA Alignments by Pruning of the Dynamical Programming Matrix

It has become clear that noncoding RNAs (ncRNA) play important roles in cells, and emerging studies indicate that there might be a large number of unknown ncRNAs in mammalian genomes. There exist computational methods that can be used to search for ncRNAs by comparing sequences from different genomes. One main problem with these methods is their computational complexity, and heuristics are therefore employed. Two heuristics are currently very popular: pre-folding and pre-aligning. However, these heuristics are not ideal, as pre-aligning is dependent on sequence similarity that may not be present and pre-folding ignores the comparative information. Here, pruning of the dynamical programming matrix is presented as an alternative novel heuristic constraint. All subalignments that do not exceed a length-dependent minimum score are discarded as the matrix is filled out, thus giving the advantage of providing the constraints dynamically. This has been included in a new implementation of the FOLDALIGN algorithm for pairwise local or global structural alignment of RNA sequences. It is shown that time and memory requirements are dramatically lowered while overall performance is maintained. Furthermore, a new divide and conquer method is introduced to limit the memory requirement during global alignment and backtrack of local alignment. All branch points in the computed RNA structure are found and used to divide the structure into smaller unbranched segments. Each segment is then realigned and backtracked in a normal fashion. Finally, the FOLDALIGN algorithm has also been updated with a better memory implementation and an improved energy model. With these improvements in the algorithm, the FOLDALIGN software package provides the molecular biologist with an efficient and user-friendly tool for searching for new ncRNAs. The software package is available for download at http://foldalign.ku.dk

Multiple sequence alignment based on set covers

We introduce a new heuristic for the multiple alignment of a set of sequences. The heuristic is based on a set cover of the residue alphabet of the sequences, and also on the determination of a significant set of blocks comprising subsequences of the sequences to be aligned. These blocks are obtained with the aid of a new data structure, called a suffix-set tree, which is constructed from the input sequences with the guidance of the residue-alphabet set cover and generalizes the well-known suffix tree of the sequence set. We provide performance results on selected BAliBASE amino-acid sequences and compare them with those yielded by some prominent approaches

Generalized Buneman pruning for inferring the most parsimonious multi-state phylogeny

Accurate reconstruction of phylogenies remains a key challenge in evolutionary biology. Most biologically plausible formulations of the problem are formally NP-hard, with no known efficient solution. The standard in practice are fast heuristic methods that are empirically known to work very well in general, but can yield results arbitrarily far from optimal. Practical exact methods, which yield exponential worst-case running times but generally much better times in practice, provide an important alternative. We report progress in this direction by introducing a provably optimal method for the weighted multi-state maximum parsimony phylogeny problem. The method is based on generalizing the notion of the Buneman graph, a construction key to efficient exact methods for binary sequences, so as to apply to sequences with arbitrary finite numbers of states with arbitrary state transition weights. We implement an integer linear programming (ILP) method for the multi-state problem using this generalized Buneman graph and demonstrate that the resulting method is able to solve data sets that are intractable by prior exact methods in run times comparable with popular heuristics. Our work provides the first method for provably optimal maximum parsimony phylogeny inference that is practical for multi-state data sets of more than a few characters.Comment: 15 page

Formalization of block pruning: reducing the number of cells computed in exact biological sequence comparison algorithms

This is a pre-copyedited, author-produced version of an article accepted for publication in The Computer Journal following peer review. The version of record Edans F O Sandes, George L M Teodoro, Maria Emilia M T Walter, Xavier Martorell, Eduard Ayguade, Alba C M A Melo; Formalization of Block Pruning: Reducing the Number of Cells Computed in Exact Biological Sequence Comparison Algorithms, The Computer Journal, Volume 61, Issue 5, 1 May 2018, Pages 687–713 is available online at: The Computer Journal https://academic.oup.com/comjnl/article-abstract/61/5/687/4539903 and https://doi.org/10.1093/comjnl/bxx090.Biological sequence comparison algorithms that compute the optimal local and global alignments calculate a dynamic programming (DP) matrix with quadratic time complexity. The DP matrix H is calculated with a recurrence relation in which the value of each cell Hi,j is the result of a maximum operation on the cells’ values Hi-1,j-1, Hi-1,j and Hi,j-1 added or subtracted by a constant value. Therefore, it can be noticed that the difference between the value of cell Hi,j being calculated and the values of direct neighbor cells previously computed respect well-defined upper and lower bounds. Using these bounds, we can show that it is possible to determine the maximum and the minimum value of every cell in H, for a given reference cell. We use this result to define a generic pruning method which determines the cells that can pruned (i.e. no need to be computed since they will not contribute to the final solution), accelerating the computation but keeping the guarantee that the optimal result will be produced. The goal of this paper is thus to investigate and formalize properties of the DP matrix in order to estimate and increase the pruning method efficiency. We also show that the pruning efficiency depends mainly on three characteristics: (a) the order in which the cells of H are calculated, (b) the values of the parameters used in the recurrence relation and (c) the contents of the sequences compared.Peer ReviewedPostprint (author's final draft