A New Paradigm for Identifying Reconciliation-Scenario Altering Mutations Conferring Environmental Adaptation

An important goal in microbial computational genomics is to identify crucial events in the evolution of a gene that severely alter the duplication, loss and mobilization patterns of the gene within the genomes in which it disseminates. In this paper, we formalize this microbiological goal as a new pattern-matching problem in the domain of Gene tree and Species tree reconciliation, denoted "Reconciliation-Scenario Altering Mutation (RSAM) Discovery". We propose an O(m * n * k) time algorithm to solve this new problem, where m and n are the number of vertices of the input Gene tree and Species tree, respectively, and k is a user-specified parameter that bounds from above the number of optimal solutions of interest. The algorithm first constructs a hypergraph representing the k highest scoring reconciliation scenarios between the given Gene tree and Species tree, and then interrogates this hypergraph for subtrees matching a pre-specified RSAM Pattern. Our algorithm is optimal in the sense that the number of hypernodes in the hypergraph can be lower bounded by Omega(m * n * k). We implement the new algorithm as a tool, denoted RSAM-finder, and demonstrate its application to the identification of RSAMs in toxins and drug resistance elements across a dataset spanning hundreds of species

Regular expression constrained sequence alignment revisited

International audienceImposing constraints in the form of a finite automaton or a regular expression is an effective way to incorporate additional a priori knowledge into sequence alignment procedures. With this motivation, the Regular Expression Constrained Sequence Alignment Problem was introduced, which proposed an O(n^2t^4) time and O(n^2t^2) space algorithm for solving it, where n is the length of the input strings and t is the number of states in the input non-deterministic automaton. A faster O(n^2t^3) time algorithm for the same problem was subsequently proposed. In this article, we further speed up the algorithms for Regular Language Constrained Sequence Alignment by reducing their worst case time complexity bound to O(n^2t^3/log t). This is done by establishing an optimal bound on the size of Straight-Line Programs solving the maxima computation subproblem of the basic dynamic programming algorithm. We also study another solution based on a Steiner Tree computation. While it does not improve worst case, our simulations show that both approaches are efficient in practice, especially when the input automata are dense

Learning of Structurally Unambiguous Probabilistic Grammars

The problem of identifying a probabilistic context free grammar has two aspects: the first is determining the grammar's topology (the rules of the grammar) and the second is estimating probabilistic weights for each rule. Given the hardness results for learning context-free grammars in general, and probabilistic grammars in particular, most of the literature has concentrated on the second problem. In this work we address the first problem. We restrict attention to structurally unambiguous weighted context-free grammars (SUWCFG) and provide a query learning algorithm for structurally unambiguous probabilistic context-free grammars (SUPCFG). We show that SUWCFG can be represented using co-linear multiplicity tree automata (CMTA), and provide a polynomial learning algorithm that learns CMTAs. We show that the learned CMTA can be converted into a probabilistic grammar, thus providing a complete algorithm for learning a structurally unambiguous probabilistic context free grammar (both the grammar topology and the probabilistic weights) using structured membership queries and structured equivalence queries. We demonstrate the usefulness of our algorithm in learning PCFGs over genomic data

Two algorithms for LCS Consecutive Suffix Alignment

AbstractThe problem of aligning two sequences A and B to determine their similarity is one of the fundamental problems in pattern matching. A challenging, basic variation of the sequence similarity problem is the incremental string comparison problem, denoted Consecutive Suffix Alignment, which is, given two strings A and B, to compute the alignment solution of each suffix of A versus B.Here, we present two solutions to the Consecutive Suffix Alignment Problem under the LCS (Longest Common Subsequence) metric, where the LCS metric measures the subsequence of maximal length common to A and B. The first solution is an O(nL) time and space algorithm for constant alphabets, where the size of the compared strings is O(n) and L⩽n denotes the size of the LCS of A and B.The second solution is an O(nL+nlog|Σ|) time and O(n) space algorithm for general alphabets, where Σ denotes the alphabet of the compared strings

Re-Use Dynamic Programming for Sequence Alignment: An Algorithmic Toolkit

International audienceThe problem of comparing two sequences S and T to determine their similarity is one of the fundamental problems in pattern matching. In this manuscript we will be primarily concerned with sequences as our objects and with various string comparison metrics. Our goal is to survey a methodology for utilizing repetitions in sequences in order to speed up the comparison process. Within this framework we consider various methods of parsing the sequences in order to frame their repetitions, and present a toolkit of various solutions whose time complexity depends both on the chosen parsing method as well as on the string-comparison metric used for the alignment

Approximate Search for Known Gene Clusters in New Genomes Using PQ-Trees

We define a new problem in comparative genomics, denoted PQ-Tree Search, that takes as input a PQ-tree T representing the known gene orders of a gene cluster of interest, a gene-to-gene substitution scoring function h, integer parameters d_T and d_S, and a new genome S. The objective is to identify in S approximate new instances of the gene cluster that could vary from the known gene orders by genome rearrangements that are constrained by T, by gene substitutions that are governed by h, and by gene deletions and insertions that are bounded from above by d_T and d_S, respectively. We prove that the PQ-Tree Search problem is NP-hard and propose a parameterized algorithm that solves the optimization variant of PQ-Tree Search in O^*(2^{?}) time, where ? is the maximum degree of a node in T and O^* is used to hide factors polynomial in the input size. The algorithm is implemented as a search tool, denoted PQFinder, and applied to search for instances of chromosomal gene clusters in plasmids, within a dataset of 1,487 prokaryotic genomes. We report on 29 chromosomal gene clusters that are rearranged in plasmids, where the rearrangements are guided by the corresponding PQ-tree. One of these results, coding for a heavy metal efflux pump, is further analysed to exemplify how PQFinder can be harnessed to reveal interesting new structural variants of known gene clusters

RNAslider: a faster engine for consecutive windows folding and its application to the analysis of genomic folding asymmetry

<p>Abstract</p> <p>Background</p> <p>Scanning large genomes with a sliding window in search of locally stable RNA structures is a well motivated problem in bioinformatics. Given a predefined window size L and an RNA sequence S of size N (L < N), the consecutive windows folding problem is to compute the minimal free energy (MFE) for the folding of each of the L-sized substrings of S. The consecutive windows folding problem can be naively solved in O(NL³) by applying any of the classical cubic-time RNA folding algorithms to each of the N-L windows of size L. Recently an O(NL²) solution for this problem has been described.</p> <p>Results</p> <p>Here, we describe and implement an O(NLψ(L)) engine for the consecutive windows folding problem, where ψ(L) is shown to converge to O(1) under the assumption of a standard probabilistic polymer folding model, yielding an O(L) speedup which is experimentally confirmed. Using this tool, we note an intriguing directionality (5'-3' vs. 3'-5') folding bias, i.e. that the minimal free energy (MFE) of folding is higher in the native direction of the DNA than in the reverse direction of various genomic regions in several organisms including regions of the genomes that do not encode proteins or ncRNA. This bias largely emerges from the genomic dinucleotide bias which affects the MFE, however we see some variations in the folding bias in the different genomic regions when normalized to the dinucleotide bias. We also present results from calculating the MFE landscape of a mouse chromosome 1, characterizing the MFE of the long ncRNA molecules that reside in this chromosome.</p> <p>Conclusion</p> <p>The efficient consecutive windows folding engine described in this paper allows for genome wide scans for ncRNA molecules as well as large-scale statistics. This is implemented here as a software tool, called RNAslider, and applied to the scanning of long chromosomes, leading to the observation of features that are visible only on a large scale.</p