Fast local fragment chaining using sum-of-pair gap costs

<p>Abstract</p> <p>Background</p> <p>Fast seed-based alignment heuristics such as <monospace>BLAST</monospace> and <monospace>BLAT</monospace> have become indispensable tools in comparative genomics for all studies aiming at the evolutionary relations of proteins, genes, and non-coding RNAs. This is true in particular for the large mammalian genomes. The sensitivity and specificity of these tools, however, crucially depend on parameters such as seed sizes or maximum expectation values. In settings that require high sensitivity the amount of short local match fragments easily becomes intractable. Then, fragment chaining is a powerful leverage to quickly connect, score, and rank the fragments to improve the specificity.</p> <p>Results</p> <p>Here we present a fast and flexible fragment chainer that for the first time also supports a sum-of-pair gap cost model. This model has proven to achieve a higher accuracy and sensitivity in its own field of application. Due to a highly time-efficient index structure our method outperforms the only existing tool for fragment chaining under the linear gap cost model. It can easily be applied to the output generated by alignment tools such as <monospace>segemehl</monospace> or <monospace>BLAST</monospace>. As an example we consider homology-based searches for human and mouse snoRNAs demonstrating that a highly sensitive <monospace>BLAST</monospace> search with subsequent chaining is an attractive option. The sum-of-pair gap costs provide a substantial advantage is this context.</p> <p>Conclusions</p> <p>Chaining of short match fragments helps to quickly and accurately identify regions of homology that may not be found using local alignment heuristics alone. By providing both the linear and the sum-of-pair gap cost model, a wider range of application can be covered. The software clasp is available at <url>http://www.bioinf.uni-leipzig.de/Software/clasp/</url>.</p

Computational Molecular Biology

Computational Biology is a fairly new subject that arose in response to the computational problems posed by the analysis and the processing of biomolecular sequence and structure data. The field was initiated in the late 60's and early 70's largely by pioneers working in the life sciences. Physicists and mathematicians entered the field in the 70's and 80's, while Computer Science became involved with the new biological problems in the late 1980's. Computational problems have gained further importance in molecular biology through the various genome projects which produce enormous amounts of data. For this bibliography we focus on those areas of computational molecular biology that involve discrete algorithms or discrete optimization. We thus neglect several other areas of computational molecular biology, like most of the literature on the protein folding problem, as well as databases for molecular and genetic data, and genetic mapping algorithms. Due to the availability of review papers and a bibliography this bibliography

Chaining with Overlaps Revisited

Chaining algorithms aim to form a semi-global alignment of two sequences based on a set of anchoring local alignments as input. Depending on the optimization criteria and the exact definition of a chain, there are several O(n log n) time algorithms to solve this problem optimally, where n is the number of input anchors. In this paper, we focus on a formulation allowing the anchors to overlap in a chain. This formulation was studied by Shibuya and Kurochkin (WABI 2003), but their algorithm comes with no proof of correctness. We revisit and modify their algorithm to consider a strict definition of precedence relation on anchors, adding the required derivation to convince on the correctness of the resulting algorithm that runs in O(n log2 n) time on anchors formed by exact matches. With the more relaxed definition of precedence relation considered by Shibuya and Kurochkin or when anchors are non-nested such as matches of uniform length (k-mers), the algorithm takes O(n log n) time. We also establish a connection between chaining with overlaps and the widely studied longest common subsequence problem. 2012 ACM Subject Classification Theory of computation ! Pattern matching; Theory of computation ! Dynamic programming; Applied computing ! Genomics.Peer reviewe

DIALIGN P: Fast pair-wise and multiple sequence alignment using parallel processors

BACKGROUND: Parallel computing is frequently used to speed up computationally expensive tasks in Bioinformatics. RESULTS: Herein, a parallel version of the multi-alignment program DIALIGN is introduced. We propose two ways of dividing the program into independent sub-routines that can be run on different processors: (a) pair-wise sequence alignments that are used as a first step to multiple alignment account for most of the CPU time in DIALIGN. Since alignments of different sequence pairs are completely independent of each other, they can be distributed to multiple processors without any effect on the resulting output alignments. (b) For alignments of large genomic sequences, we use a heuristics by splitting up sequences into sub-sequences based on a previously introduced anchored alignment procedure. For our test sequences, this combined approach reduces the program running time of DIALIGN by up to 97%. CONCLUSIONS: By distributing sub-routines to multiple processors, the running time of DIALIGN can be crucially improved. With these improvements, it is possible to apply the program in large-scale genomics and proteomics projects that were previously beyond its scope

Segment-based multiple sequence alignment

Motivation: Many multiple sequence alignment tools have been developed in the past, progressing either in speed or alignment accuracy. Given the importance and wide-spread use of alignment tools, progress in both categories is a contribution to the community and has driven research in the field so far. Results: We introduce a graph-based extension to the consistency-based, progressive alignment strategy. We apply the consistency notion to segments instead of single characters. The main problem we solve in this context is to define segments of the sequences in such a way that a graph-based alignment is possible. We implemented the algorithm using the SeqAn library and report results on amino acid and DNA sequences. The benefit of our approach is threefold: (1) sequences with conserved blocks can be rapidly aligned, (2) the implementation is conceptually easy, generic and fast and (3) the consistency idea can be extended to align multiple genomic sequences. Availability: The segment-based multiple sequence alignment tool can be downloaded from http://www.seqan.de/projects/msa.html. A novel version of T-Coffee interfaced with the tool is available from http://www.tcoffee.org. The usage of the tool is described in both documentations. Contact: [email protected]

SeqAn An efficient, generic C++ library for sequence analysis

<p>Abstract</p> <p>Background</p> <p>The use of novel algorithmic techniques is pivotal to many important problems in life science. For example the sequencing of the human genome <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> would not have been possible without advanced assembly algorithms. However, owing to the high speed of technological progress and the urgent need for bioinformatics tools, there is a widening gap between state-of-the-art algorithmic techniques and the actual algorithmic components of tools that are in widespread use.</p> <p>Results</p> <p>To remedy this trend we propose the use of SeqAn, a library of efficient data types and algorithms for sequence analysis in computational biology. SeqAn comprises implementations of existing, practical state-of-the-art algorithmic components to provide a sound basis for algorithm testing and development. In this paper we describe the design and content of SeqAn and demonstrate its use by giving two examples. In the first example we show an application of SeqAn as an experimental platform by comparing different exact string matching algorithms. The second example is a simple version of the well-known MUMmer tool rewritten in SeqAn. Results indicate that our implementation is very efficient and versatile to use.</p> <p>Conclusion</p> <p>We anticipate that SeqAn greatly simplifies the rapid development of new bioinformatics tools by providing a collection of readily usable, well-designed algorithmic components which are fundamental for the field of sequence analysis. This leverages not only the implementation of new algorithms, but also enables a sound analysis and comparison of existing algorithms.</p

Co-Linear Chaining on Pangenome Graphs

Pangenome reference graphs are useful in genomics because they compactly represent the genetic diversity within a species, a capability that linear references lack. However, efficiently aligning sequences to these graphs with complex topology and cycles can be challenging. The seed-chain-extend based alignment algorithms use co-linear chaining as a standard technique to identify a good cluster of exact seed matches that can be combined to form an alignment. Recent works show how the co-linear chaining problem can be efficiently solved for acyclic pangenome graphs by exploiting their small width [Makinen et al., TALG\u2719] and how incorporating gap cost in the scoring function improves alignment accuracy [Chandra and Jain, RECOMB\u2723]. However, it remains open on how to effectively generalize these techniques for general pangenome graphs which contain cycles. Here we present the first practical formulation and an exact algorithm for co-linear chaining on cyclic pangenome graphs. We rigorously prove the correctness and computational complexity of the proposed algorithm. We evaluate the empirical performance of our algorithm by aligning simulated long reads from the human genome to a cyclic pangenome graph constructed from 95 publicly available haplotype-resolved human genome assemblies. While the existing heuristic-based algorithms are faster, the proposed algorithm provides a significant advantage in terms of accuracy