Algorithms for Molecular Biology最新文献

Motivation: Many bioinformatics problems can be approached as optimization or controlled sampling tasks, and solved exactly and efficiently using Dynamic Programming (DP). However, such exact methods are typically tailored towards specific settings, complex to develop, and hard to implement and adapt to problem variations.

Methods: We introduce the Infrared framework to overcome such hindrances for a large class of problems. Its underlying paradigm is tailored toward problems that can be declaratively formalized as sparse feature networks, a generalization of constraint networks. Classic Boolean constraints specify a search space, consisting of putative solutions whose evaluation is performed through a combination of features. Problems are then solved using generic cluster tree elimination algorithms over a tree decomposition of the feature network. Their overall complexities are linear on the number of variables, and only exponential in the treewidth of the feature network. For sparse feature networks, associated with low to moderate treewidths, these algorithms allow to find optimal solutions, or generate controlled samples, with practical empirical efficiency.

Results: Implementing these methods, the Infrared software allows Python programmers to rapidly develop exact optimization and sampling applications based on a tree decomposition-based efficient processing. Instead of directly coding specialized algorithms, problems are declaratively modeled as sets of variables over finite domains, whose dependencies are captured by constraints and functions. Such models are then automatically solved by generic DP algorithms. To illustrate the applicability of Infrared in bioinformatics and guide new users, we model and discuss variants of bioinformatics applications. We provide reimplementations and extensions of methods for RNA design, RNA sequence-structure alignment, parsimony-driven inference of ancestral traits in phylogenetic trees/networks, and design of coding sequences. Moreover, we demonstrate multidimensional Boltzmann sampling. These applications of the framework-together with our novel results-underline the practical relevance of Infrared. Remarkably, the achieved complexities are typically equivalent to the ones of specialized algorithms and implementations.

Availability: Infrared is available at https://amibio.gitlabpages.inria.fr/Infrared with extensive documentation, including various usage examples and API reference; it can be installed using Conda or from source.

Gene trees can be different from the species tree due to biological processes and inference errors. One way to obtain a species tree is to find one that maximizes some measure of similarity to a set of gene trees. The number of shared quartets between a potential species tree and gene trees provides a statistically justifiable score; if maximized properly, it could result in a statistically consistent estimator of the species tree under several statistical models of discordance. However, finding the median quartet score tree, one that maximizes this score, is NP-Hard, motivating several existing heuristic algorithms. These heuristics do not follow the hill-climbing paradigm used extensively in phylogenetics. In this paper, we make theoretical contributions that enable an efficient hill-climbing approach. Specifically, we show that a subtree of size m can be placed optimally on a tree of size n in quasi-linear time with respect to n and (almost) independently of m. This result enables us to perform subtree prune and regraft (SPR) rearrangements as part of a hill-climbing search. We show that this approach can slightly improve upon the results of widely-used methods such as ASTRAL in terms of the optimization score but not necessarily accuracy.

We introduce a new algorithm for constructing the generalized suffix array of a collection of highly similar strings. As a first step, we construct a compressed representation of the matching statistics of the collection with respect to a reference string. We then use this data structure to distribute suffixes into a partial order, and subsequently to speed up suffix comparisons to complete the generalized suffix array. Our experimental evidence with a prototype implementation (a tool we call sacamats) shows that on string collections with highly similar strings we can construct the suffix array in time competitive with or faster than the fastest available methods. Along the way, we describe a heuristic for fast computation of the matching statistics of two strings, which may be of independent interest.

Motivation: Computational RNA secondary structure prediction by free energy minimization is indispensable for analyzing structural RNAs and their interactions. These methods find the structure with the minimum free energy (MFE) among exponentially many possible structures and have a restrictive time and space complexity ( $O\left(n^3\right)$ time and $O\left(n^2\right)$ space for pseudoknot-free structures) for longer RNA sequences. Furthermore, accurate free energy calculations, including dangle contributions can be difficult and costly to implement, particularly when optimizing for time and space requirements.

Results: Here we introduce a fast and efficient sparsified MFE pseudoknot-free structure prediction algorithm, SparseRNAFolD, that utilizes an accurate energy model that accounts for dangle contributions. While the sparsification technique was previously employed to improve the time and space complexity of a pseudoknot-free structure prediction method with a realistic energy model, SparseMFEFold, it was not extended to include dangle contributions due to the complexity of computation. This may come at the cost of prediction accuracy. In this work, we compare three different sparsified implementations for dangle contributions and provide pros and cons of each method. As well, we compare our algorithm to LinearFold, a linear time and space algorithm, where we find that in practice, SparseRNAFolD has lower memory consumption across all lengths of sequence and a faster time for lengths up to 1000 bases.

Conclusion: Our SparseRNAFolD algorithm is an MFE-based algorithm that guarantees optimality of result and employs the most general energy model, including dangle contributions. We provide a basis for applying dangles to sparsified recursion in a pseudoknot-free model that has the potential to be extended to pseudoknots.

One of the most fundamental problems in genome rearrangement studies is the (genomic) distance problem. It is typically formulated as finding the minimum number of rearrangements under a model that are needed to transform one genome into the other. A powerful multi-chromosomal model is the Double Cut and Join (DCJ) model.While the DCJ model is not able to deal with some situations that occur in practice, like duplicated or lost regions, it was extended over time to handle these cases. First, it was extended to the DCJ-indel model, solving the issue of lost markers. Later ILP-solutions for so called natural genomes, in which each genomic region may occur an arbitrary number of times, were developed, enabling in theory to solve the distance problem for any pair of genomes. However, some theoretical and practical issues remained unsolved. On the theoretical side of things, there exist two disparate views of the DCJ-indel model, motivated in the same way, but with different conceptualizations that could not be reconciled so far. On the practical side, while ILP solutions for natural genomes typically perform well on telomere to telomere resolved genomes, they have been shown in recent years to quickly loose performance on genomes with a large number of contigs or linear chromosomes. This has been linked to a particular technique, namely capping. Simply put, capping circularizes linear chromosomes by concatenating them during solving time, increasing the solution space of the ILP superexponentially. Recently, we introduced a new conceptualization of the DCJ-indel model within the context of another rearrangement problem. In this manuscript, we will apply this new conceptualization to the distance problem. In doing this, we uncover the relation between the disparate conceptualizations of the DCJ-indel model. We are also able to derive an ILP solution to the distance problem that does not rely on capping. This solution significantly improves upon the performance of previous solutions on genomes with high numbers of contigs while still solving the problem exactly and being competitive in performance otherwise. We demonstrate the performance advantage on simulated genomes as well as showing its practical usefulness in an analysis of 11 Drosophila genomes.