arXiv subjects

Alexandru I. Tomescu

Publications and source records attributed to Alexandru I. Tomescu.

At least 37 records · Page 2Linked to original sources

arXiv2022

Fast, Flexible, and Exact Minimum Flow Decompositions via ILP

Minimum flow decomposition (MFD) (the problem of finding a minimum set of paths that perfectly decomposes a flow) is a classical problem in Computer Science, and variants of it are powerful models in multiassembly problems in Bioinformatics (e.g. RNA assembly). However, because this problem and its variants are NP-hard, practical multiassembly tools either use heuristics or solve simpler, polynomial-time solvable versions of the problem, which may yield solutions that are not mini-mal or do not perfectly decompose the flow. Many RNA assemblers also use integer linear programming(ILP) formulations of such practical variants, having the major limitation they need to encode all the potentially exponentially many solution paths. Moreover, the only exact solver for MFD does not scale to large instances and cannot be efficiently generalized to practical MFD variants. In this work, we provide the first practical ILP formulation for MFD (and thus the first fast and exact solver for MFD), based on encoding all of the exponentially many solution paths using only a quadratic number of variables. On both simulated and real flow graphs, our approach solves any instance in under 13 seconds. We also show that our ILP formulation can be easily and efficiently adapted for many practical variants, such as incorporating longer or paired-end reads or minimizing flow errors. We hope that our results can remove the current tradeoff between the complexity of a multi assembly model and its tractability and can lie at the core of future practical RNA assembly tools.

q-bio.GN↗

arXiv2022

Safety and Completeness in Flow Decompositions for RNA Assembly

Decomposing a network flow into weighted paths has numerous applications. Some applications require any decomposition that is optimal w.r.t. some property such as number of paths, robustness, or length. Many bioinformatic applications require a specific decomposition where the paths correspond to some underlying data that generated the flow. For real inputs, no optimization criteria guarantees to uniquely identify the correct decomposition. Therefore, we propose to report safe paths, i.e., subpaths of at least one path in every flow decomposition. Ma, Zheng, and Kingsford [WABI 2020] addressed the existence of multiple optimal solutions in a probabilistic framework, i.e., non-identifiability. Later [RECOMB 2021], they gave a quadratic-time algorithm based on a global criterion for solving a problem called AND-Quant, which generalizes the problem of reporting whether a given path is safe. We give the first local characterization of safe paths for flow decompositions in directed acyclic graphs (DAGs), leading to a practical algorithm for finding the complete set of safe paths. We evaluated our algorithms against the trivial safe algorithms (unitigs, extended unitigs) and the popularly used heuristic (greedy-width) for flow decomposition on RNA transcripts datasets. Despite maintaining perfect precision our algorithm reports significantly higher coverage ($\approx 50\%$ more) than trivial safe algorithms. The greedy-width algorithm though reporting a better coverage, has significantly lower precision on complex graphs. Overall, our algorithm outperforms (by $\approx 20\%$) greedy-width on a unified metric (F-Score) when the dataset has significant number of complex graphs. Moreover, it has superior time ($3-5\times$) and space efficiency ($1.2-2.2\times$), resulting in a better and more practical approach for bioinformatics applications of flow decomposition.

cs.DS↗

arXiv2021

The Hydrostructure: a Universal Framework for Safe and Complete Algorithms for Genome Assembly

Genome assembly is a fundamental problem in Bioinformatics, requiring to reconstruct a source genome from an assembly graph built from a set of reads (short strings sequenced from the genome). A notion of genome assembly solution is that of an arc-covering walk of the graph. Since assembly graphs admit many solutions, the goal is to find what is definitely present in all solutions, or what is safe. Most practical assemblers are based on heuristics having at their core unitigs, namely paths whose internal nodes have unit in-degree and out-degree, and which are clearly safe. The long-standing open problem of finding all the safe parts of the solutions was recently solved [RECOMB 2016] yielding a 60% increase in contig length. This safe and complete genome assembly algorithm was followed by other works improving the time bounds, as well as extending the results for different notions of assembly solution. But it remained open whether one can be complete also for models of genome assembly of practical applicability. In this paper we present a universal framework for obtaining safe and complete algorithms which unify the previous results, while also allowing for easy generalisations to assembly problems including many practical aspects. This is based on a novel graph structure, called the hydrostructure of a walk, which highlights the reachability properties of the graph from the perspective of the walk. The hydrostructure allows for simple characterisations of the existing safe walks, and of their new practical versions. Almost all of our characterisations are directly adaptable to optimal verification algorithms, and simple enumeration algorithms. Most of these algorithms are also improved to optimality using an incremental computation procedure and a previous optimal algorithm of a specific model.

cs.DM↗

arXiv2021

The Labeled Direct Product Optimally Solves String Problems on Graphs

Suffix trees are an important data structure at the core of optimal solutions to many fundamental string problems, such as exact pattern matching, longest common substring, matching statistics, and longest repeated substring. Recent lines of research focused on extending some of these problems to vertex-labeled graphs, although using ad-hoc approaches which in some cases do not generalize to all input graphs. In the absence of a ubiquitous tool like the suffix tree for labeled graphs, we introduce the labeled direct product of two graphs as a general tool for obtaining optimal algorithms: we obtain conceptually simpler algorithms for the quadratic problems of string matching (SMLG) and longest common substring (LCSP) in labeled graphs. Our algorithms are also more efficient, since they run in time linear in the size of the labeled product graph, which may be smaller than quadratic for some inputs, and their run-time is predictable, because the size of the labeled direct product graph can be precomputed efficiently. We also solve LCSP on graphs containing cycles, which was left as an open problem by Shimohira et al. in 2011. To show the power of the labeled product graph, we also apply it to solve the matching statistics (MSP) and the longest repeated string (LRSP) problems in labeled graphs. Moreover, we show that our (worst-case quadratic) algorithms are also optimal, conditioned on the Orthogonal Vectors Hypothesis. Finally, we complete the complexity picture around LRSP by studying it on undirected graphs.

cs.DS↗

arXiv2021

Sparsifying, Shrinking and Splicing for Minimum Path Cover in Parameterized Linear Time

A minimum path cover (MPC) of a directed acyclic graph (DAG) $G = (V,E)$ is a minimum-size set of paths that together cover all the vertices of the DAG. Computing an MPC is a basic polynomial problem, dating back to Dilworth's and Fulkerson's results in the 1950s. Since the size $k$ of an MPC (also known as the width) can be small in practical applications, research has also studied algorithms whose complexity is parameterized on $k$. We obtain two new MPC parameterized algorithms for DAGs running in time $O(k^2|V|\log{|V|} + |E|)$ and $O(k^3|V| + |E|)$. We also obtain a parallel algorithm running in $O(k^2|V| + |E|)$ parallel steps and using $O(\log{|V|})$ processors (in the PRAM model). Our latter two algorithms are the first solving the problem in parameterized linear time. Finally, we present an algorithm running in time $O(k^2|V|)$ for transforming any MPC to another MPC using less than $2|V|$ distinct edges, which we prove to be asymptotically tight. As such, we also obtain edge sparsification algorithms preserving the width of the DAG with the same running time as our MPC algorithms. At the core of all our algorithms we interleave the usage of three techniques: transitive sparsification, shrinking of a path cover, and the splicing of a set of paths along a given path.

cs.DS↗

arXiv2021

A linear-time parameterized algorithm for computing the width of a DAG

The width $k$ of a directed acyclic graph (DAG) $G = (V, E)$ equals the largest number of pairwise non-reachable vertices. Computing the width dates back to Dilworth's and Fulkerson's results in the 1950s, and is doable in quadratic time in the worst case. Since $k$ can be small in practical applications, research has also studied algorithms whose complexity is parameterized on $k$. Despite these efforts, it is still open whether there exists a linear-time $O(f(k)(|V| + |E|))$ parameterized algorithm computing the width. We answer this question affirmatively by presenting an $O(k^24^k|V| + k2^k|E|)$ time algorithm, based on a new notion of frontier antichains. As we process the vertices in a topological order, all frontier antichains can be maintained with the help of several combinatorial properties, paying only $f(k)$ along the way. The fact that the width can be computed by a single $f(k)$-sweep of the DAG is a new surprising insight into this classical problem. Our algorithm also allows deciding whether the DAG has width at most $w$ in time $O(f(\min(w,k))(|V|+|E|))$.

cs.DS↗

arXiv2020

Genome assembly, from practice to theory: safe, complete and linear-time

Genome assembly asks to reconstruct an unknown string from many shorter substrings of it. Even though it is one of the key problems in Bioinformatics, it is generally lacking major theoretical advances. Its hardness stems both from practical issues (size and errors of real data), and from the fact that problem formulations inherently admit multiple solutions. Given these, at their core, most state-of-the-art assemblers are based on finding non-branching paths (unitigs) in an assembly graph. If one defines a genome assembly solution as a closed arc-covering walk of the graph, then unitigs appear in all solutions, being thus safe partial solutions. All all such safe walks were recently characterized as omnitigs, leading to the first safe and complete genome assembly algorithm. Even if omnitig finding was improved to quadratic time, it remained open whether the crucial linear-time feature of finding unitigs can be attained with omnitigs. We describe a surprising $O(m)$-time algorithm to identify all maximal omnitigs of a graph with $n$ nodes and $m$ arcs, notwithstanding the existence of families of graphs with $Θ(mn)$ total maximal omnitig size. This is based on the discovery of a family of walks (macrotigs) with the property that all the non-trivial omnitigs are univocal extensions of subwalks of a macrotig, with two consequences: (1) A linear-time output-sensitive algorithm enumerating all maximal omnitigs. (2) A compact $O(m)$ representation of all maximal omnitigs, which allows, e.g., for $O(m)$-time computation of various statistics on them. Our results close a long-standing theoretical question inspired by practical genome assemblers, originating with the use of unitigs in 1995. We envision our results to be at the core of a reverse transfer from theory to practical and complete genome assembly programs, as has been the case for other key Bioinformatics problems.

cs.DM↗

arXiv2020

Safety in $s$-$t$ Paths, Trails and Walks

Given a directed graph $G$ and a pair of nodes $s$ and $t$, an \emph{$s$-$t$ bridge} of $G$ is an edge whose removal breaks all $s$-$t$ paths of $G$ (and thus appears in all $s$-$t$ paths). Computing all $s$-$t$ bridges of $G$ is a basic graph problem, solvable in linear time. In this paper, we consider a natural generalisation of this problem, with the notion of "safety" from bioinformatics. We say that a walk $W$ is \emph{safe} with respect to a set $\mathcal{W}$ of $s$-$t$ walks, if $W$ is a subwalk of all walks in $\mathcal{W}$. We start by considering the maximal safe walks when $\mathcal{W}$ consists of: all $s$-$t$ paths, all $s$-$t$ trails, or all $s$-$t$ walks of $G$. We show that the first two problems are immediate linear-time generalisations of finding all $s$-$t$ bridges, while the third problem is more involved. In particular, we show that there exists a compact representation computable in linear time, that allows outputting all maximal safe walks in time linear in their length. We further generalise these problems, by assuming that safety is defined only with respect to a subset of \emph{visible} edges. Here we prove a dichotomy between the $s$-$t$ paths and $s$-$t$ trails cases, and the $s$-$t$ walks case: the former two are NP-hard, while the latter is solvable with the same complexity as when all edges are visible. We also show that the same complexity results hold for the analogous generalisations of \emph{$s$-$t$ articulation points} (nodes appearing in all $s$-$t$ paths). We thus obtain the best possible results for natural "safety"-generalisations of these two fundamental graph problems. Moreover, our algorithms are simple and do not employ any complex data structures, making them ideal for use in practice.

cs.DS↗

arXiv2020

Computing all $s$-$t$ bridges and articulation points simplified

Given a directed graph $G$ and a pair of nodes $s$ and $t$, an $s$-$t$ bridge of $G$ is an edge whose removal breaks all $s$-$t$ paths of $G$. Similarly, an $s$-$t$ articulation point of $G$ is a node whose removal breaks all $s$-$t$ paths of $G$. Computing the sequence of all $s$-$t$ bridges of $G$ (as well as the $s$-$t$ articulation points) is a basic graph problem, solvable in linear time using the classical min-cut algorithm. When dealing with cuts of unit size ($s$-$t$ bridges) this algorithm can be simplified to a single graph traversal from $s$ to $t$ avoiding an arbitrary $s$-$t$ path, which is interrupted at the $s$-$t$ bridges. Further, the corresponding proof is also simplified making it independent of the theory of network flows.

cs.DS↗

arXiv2020

Linear Time Construction of Indexable Founder Block Graphs

We introduce a compact pangenome representation based on an optimal segmentation concept that aims to reconstruct founder sequences from a multiple sequence alignment (MSA). Such founder sequences have the feature that each row of the MSA is a recombination of the founders. Several linear time dynamic programming algorithms have been previously devised to optimize segmentations that induce founder blocks that then can be concatenated into a set of founder sequences. All possible concatenation orders can be expressed as a founder block graph. We observe a key property of such graphs: if the node labels (founder segments) do not repeat in the paths of the graph, such graphs can be indexed for efficient string matching. We call such graphs segment repeat-free founder block graphs. We give a linear time algorithm to construct a segment repeat-free founder block graph given an MSA. The algorithm combines techniques from the founder segmentation algorithms (Cazaux et al. SPIRE 2019) and fully-functional bidirectional Burrows-Wheeler index (Belazzougui and Cunial, CPM 2019). We derive a succinct index structure to support queries of arbitrary length in the paths of the graph. Experiments on an MSA of SAR-CoV-2 strains are reported. An MSA of size $410\times 29811$ is compacted in one minute into a segment repeat-free founder block graph of 3900 nodes and 4440 edges. The maximum length and total length of node labels is 12 and 34968, respectively. The index on the graph takes only $3\%$ of the size of the MSA.

cs.DS↗

arXiv2020

Graphs cannot be indexed in polynomial time for sub-quadratic time string matching, unless SETH fails

We consider the following string matching problem on a node-labeled graph $G=(V,E)$: given a pattern string $P$, decide whether there exists a path in $G$ whose concatenation of node labels equals $P$. This is a basic primitive in various problems in bioinformatics, graph databases, or networks. The hardness results of Backurs and Indyk (FOCS 2016) imply that this problem cannot be solved in better than $O(|E||P|)$ time, under the Orthogonal Vectors Hypothesis (OVH), and this holds even under various restrictions on the graph (Equi et al., ICALP 2019). In this paper we consider its offline version, namely the one in which we are allowed to index the graph in order to support time-efficient string matching queries. Indeed, it was tantalizing in the string matching community to believe that sub-quadratic time queries can be achieved, e.g. at the cost of a high-degree polynomial-time indexing. We disprove this belief, showing that, under OVH, no polynomial-time index can support querying $P$ in time $O(|E|^δ|P|^β)$, with either $δ< 1$ or $β< 1$. We prove this tight bound employing a known self-reducibility technique, e.g. from the field of dynamic algorithms, which translates conditional lower bounds for an online problem to its offline version. As a side-contribution, we formalize this technique with the notion of linear independent-components reduction, allowing for a simple proof of our result. As another illustration of our technique, we also translate the quadratic conditional lower bound of Backurs and Indyk (STOC 2015) for the problem of matching a query string inside a text, under edit distance. We obtain an analogous tight quadratic lower bound for its offline version, improving the recent result of Cohen-Addad, Feuilloley and Starikovskaya (SODA 2019), but with a slightly different boundary condition.

cs.CC↗

arXiv2019

On the Complexity of Exact Pattern Matching in Graphs: Determinism and Zig-Zag Matching

Exact pattern matching in labeled graphs is the problem of searching paths of a graph $G=(V,E)$ that spell the same string as the given pattern $P[1..m]$. This basic problem can be found at the heart of more complex operations on variation graphs in computational biology, query operations in graph databases, and analysis of heterogeneous networks, where the nodes of some paths must match a sequence of labels or types. In our recent work we described a conditional lower bound stating that the exact pattern matching problem in labeled graphs cannot be solved in less than quadratic time, namely, $O(|E|^{1 - ε} \, m)$ time or $O(|E| \, m^{1 - ε})$ time for any constant $ε>0$, unless the Strong Exponential Time Hypothesis (SETH) is false. The result holds even if node labels and pattern $P$ are drawn from a binary alphabet, and $G$ is restricted to undirected graphs of maximum degree three or directed acyclic graphs of maximum sum of indegree and outdegree three. It was left open what happens on undirected graphs of maximum degree two, i.e., when the pattern can have a zig-zag match in a (cyclic) bidirectional string. Also, the reduction created a non-determistic directed acyclic graph, and it was left open if determinism would make the problem easier. In this work, we show through the Orthogonal Vectors hypothesis (OV) that the same conditional lower bound holds even for these restricted cases.

cs.CC↗

arXiv2018

Hardness of Covering Alignment: Phase Transition in Post-Sequence Genomics

Covering alignment problems arise from recent developments in genomics; so called pan-genome graphs are replacing reference genomes, and advances in haplotyping enable full content of diploid genomes to be used as basis of sequence analysis. In this paper, we show that the computational complexity will change for natural extensions of alignments to pan-genome representations and to diploid genomes. More broadly, our approach can also be seen as a minimal extension of sequence alignment to labelled directed acyclic graphs (labeled DAGs). Namely, we show that finding a \emph{covering alignment} of two labeled DAGs is NP-hard even on binary alphabets. A covering alignment asks for two paths $R_1$ (red) and $G_1$ (green) in DAG $D_1$ and two paths $R_2$ (red) and $G_2$ (green) in DAG $D_2$ that cover the nodes of the graphs and maximize the sum of the global alignment scores: $\mathsf{as}(\mathsf{sp}(R_1),\mathsf{sp}(R_2))+\mathsf{as}(\mathsf{sp}(G_1),\mathsf{sp}(G_2))$, where $\mathsf{sp}(P)$ is the concatenation of labels on the path $P$. Pair-wise alignment of haplotype sequences forming a diploid chromosome can be converted to a two-path coverable labelled DAG, and then the covering alignment models the similarity of two diploids over arbitrary recombinations. We also give a reduction to the other direction, to show that such a recombination-oblivious diploid alignment is NP-hard on alphabets of size $3$.

cs.CC↗

arXiv2018

Using Minimum Path Cover to Boost Dynamic Programming on DAGs: Co-Linear Chaining Extended

Aligning sequencing reads on graph representations of genomes is an important ingredient of pan-genomics. Such approaches typically find a set of local anchors that indicate plausible matches between substrings of a read to subpaths of the graph. These anchor matches are then combined to form a (semi-local) alignment of the complete read on a subpath. Co-linear chaining is an algorithmically rigorous approach to combine the anchors. It is a well-known approach for the case of two sequences as inputs. Here we extend the approach so that one of the inputs can be a directed acyclic graph (DAGs), e.g. a splicing graph in transcriptomics or a variant graph in pan-genomics. This extension to DAGs turns out to have a tight connection to the minimum path cover problem, asking for a minimum-cardinality set of paths that cover all the nodes of a DAG. We study the case when the size $k$ of a minimum path cover is small, which is often the case in practice. First, we propose an algorithm for finding a minimum path cover of a DAG $(V,E)$ in $O(k|E|\log|V|)$ time, improving all known time-bounds when $k$ is small and the DAG is not too dense. Second, we introduce a general technique for extending dynamic programming (DP) algorithms from sequences to DAGs. This is enabled by our minimum path cover algorithm, and works by mimicking the DP algorithm for sequences on each path of the minimum path cover. This technique generally produces algorithms that are slower than their counterparts on sequences only by a factor $k$. Our technique can be applied, for example, to the classical longest increasing subsequence and longest common subsequence problems, extended to labeled DAGs. Finally, we apply this technique to the co-linear chaining problem. We also implemented the new co-linear chaining approach. Experiments on splicing graphs show that the new method is efficient also in practice.

cs.DS↗

arXiv2018

Perfect phylogenies via branchings in acyclic digraphs and a generalization of Dilworth's theorem

Motivated by applications in cancer genomics and following the work of Hajirasouliha and Raphael (WABI 2014), Hujdurović et al. (IEEE TCBB, to appear) introduced the minimum conflict-free row split (MCRS) problem: split each row of a given binary matrix into a bitwise OR of a set of rows so that the resulting matrix corresponds to a perfect phylogeny and has the minimum possible number of rows among all matrices with this property. Hajirasouliha and Raphael also proposed the study of a similar problem, in which the task is to minimize the number of distinct rows of the resulting matrix. Hujdurović et al. proved that both problems are NP-hard, gave a related characterization of transitively orientable graphs, and proposed a polynomial-time heuristic algorithm for the MCRS problem based on coloring cocomparability graphs. We give new, more transparent formulations of the two problems, showing that the problems are equivalent to two optimization problems on branchings in a derived directed acyclic graph. Building on these formulations, we obtain new results on the two problems, including: (i) a strengthening of the heuristic by Hujdurović et al. via a new min-max result in digraphs generalizing Dilworth's theorem, which may be of independent interest, (ii) APX-hardness results for both problems, (iii) approximation algorithms, and (iv) exponential-time algorithms solving the two problems to optimality faster than the naïve brute-force approach. Our work relates to several well studied notions in combinatorial optimization: chain partitions in partially ordered sets, laminar hypergraphs, and (classical and weighted) colorings of graphs.

cs.DM↗

arXiv2016

Safe and complete contig assembly via omnitigs

Contig assembly is the first stage that most assemblers solve when reconstructing a genome from a set of reads. Its output consists of contigs -- a set of strings that are promised to appear in any genome that could have generated the reads. From the introduction of contigs 20 years ago, assemblers have tried to obtain longer and longer contigs, but the following question was never solved: given a genome graph $G$ (e.g. a de Bruijn, or a string graph), what are all the strings that can be safely reported from $G$ as contigs? In this paper we finally answer this question, and also give a polynomial time algorithm to find them. Our experiments show that these strings, which we call omnitigs, are 66% to 82% longer on average than the popular unitigs, and 29% of dbSNP locations have more neighbors in omnitigs than in unitigs.

q-bio.QM↗

arXiv2016

Complexity and algorithms for finding a perfect phylogeny from mixed tumor samples

Recently, Hajirasouliha and Raphael (WABI 2014) proposed a model for deconvoluting mixed tumor samples measured from a collection of high-throughput sequencing reads. This is related to understanding tumor evolution and critical cancer mutations. In short, their formulation asks to split each row of a binary matrix so that the resulting matrix corresponds to a perfect phylogeny and has the minimum number of rows among all matrices with this property. In this paper we disprove several claims about this problem, including an NP-hardness proof of it. However, we show that the problem is indeed NP-hard, by providing a different proof. We also prove NP-completeness of a variant of this problem proposed in the same paper. On the positive side, we propose an efficient (though not necessarily optimal) heuristic algorithm based on coloring co-comparability graphs, and a polynomial time algorithm for solving the problem optimally on matrix instances in which no column is contained in both columns of a pair of conflicting columns. Implementations of these algorithms are freely available at https://github.com/alexandrutomescu/MixedPerfectPhylogeny

q-bio.PE↗

arXiv2014

Motif matching using gapped patterns

We present new algorithms for the problem of multiple string matching of gapped patterns, where a gapped pattern is a sequence of strings such that there is a gap of fixed length between each two consecutive strings. The problem has applications in the discovery of transcription factor binding sites in DNA sequences when using generalized versions of the Position Weight Matrix model to describe transcription factor specificities. In these models a motif can be matched as a set of gapped patterns with unit-length keywords. The existing algorithms for matching a set of gapped patterns are worst-case efficient but not practical, or vice versa, in this particular case. The novel algorithms that we present are based on dynamic programming and bit-parallelism, and lie in a middle-ground among the existing algorithms. In fact, their time complexity is close to the best existing bound and, yet, they are also practical. We also provide experimental results which show that the presented algorithms are fast in practice, and preferable if all the strings in the patterns have unit-length.

cs.DS↗