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

Non-alignment comparison of human and high primate genomes

Compositional spectra (CS) analysis based on k-mer scoring of DNA sequences was employed in this study for dot-plot comparison of human and primate genomes. The detection of extended conserved synteny regions was based on continuous fuzzy similarity rather than on chains of discrete anchors (genes or highly conserved noncoding elements). In addition to the high correspondence found in the comparisons of whole-genome sequences, a good similarity was also found after masking gene sequences, indicating that CS analysis manages to reveal phylogenetic signal in the organization of noncoding part of the genome sequences, including repetitive DNA and the genome "dark matter". Obviously, the possibility to reveal parallel ordering depends on the signal of common ancestor sequence organization varying locally along the corresponding segments of the compared genomes. We explored two sources contributing to this signal: sequence composition (GC content) and sequence organization (abundances of k-mers in the usual A,T,G,C or purine-pyrimidine alphabets). Whole-genome comparisons based on GC distribution along the analyzed sequences indeed gives reasonable results, but combining it with k-mer abundances dramatically improves the ordering quality, indicating that compositional and organizational heterogeneity comprise complementary sources of information on evolutionary conserved similarity of genome sequences

Significant speedup of database searches with HMMs by search space reduction with PSSM family models

Motivation: Profile hidden Markov models (pHMMs) are currently the most popular modeling concept for protein families. They provide sensitive family descriptors, and sequence database searching with pHMMs has become a standard task in today's genome annotation pipelines. On the downside, searching with pHMMs is computationally expensive

Structator: fast index-based search for RNA sequence-structure patterns

Background The secondary structure of RNA molecules is intimately related to their function and often more conserved than the sequence. Hence, the important task of searching databases for RNAs requires to match sequence-structure patterns. Unfortunately, current tools for this task have, in the best case, a running time that is only linear in the size of sequence databases. Furthermore, established index data structures for fast sequence matching, like suffix trees or arrays, cannot benefit from the complementarity constraints introduced by the secondary structure of RNAs. Results We present a novel method and readily applicable software for time efficient matching of RNA sequence-structure patterns in sequence databases. Our approach is based on affix arrays, a recently introduced index data structure, preprocessed from the target database. Affix arrays support bidirectional pattern search, which is required for efficiently handling the structural constraints of the pattern. Structural patterns like stem-loops can be matched inside out, such that the loop region is matched first and then the pairing bases on the boundaries are matched consecutively. This allows to exploit base pairing information for search space reduction and leads to an expected running time that is sublinear in the size of the sequence database. The incorporation of a new chaining approach in the search of RNA sequence-structure patterns enables the description of molecules folding into complex secondary structures with multiple ordered patterns. The chaining approach removes spurious matches from the set of intermediate results, in particular of patterns with little specificity. In benchmark experiments on the Rfam database, our method runs up to two orders of magnitude faster than previous methods. Conclusions The presented method's sublinear expected running time makes it well suited for RNA sequence-structure pattern matching in large sequence databases. RNA molecules containing several stem-loop substructures can be described by multiple sequence-structure patterns and their matches are efficiently handled by a novel chaining method. Beyond our algorithmic contributions, we provide with Structator a complete and robust open-source software solution for index-based search of RNA sequence-structure patterns. The Structator software is available at http://www.zbh.uni-hamburg.de/Structator webcite.Deutsche Forschungsgemeinschaft (grant WI 3628/1-1

Data Structures for Efficient String Algorithms

This thesis deals with data structures that are mostly useful in the area of string matching and string mining. Our main result is an O(n)-time preprocessing scheme for an array of n numbers such that subsequent queries asking for the position of a minimum element in a specified interval can be answered in constant time (so-called RMQs for Range Minimum Queries). The space for this data structure is 2n+o(n) bits, which is shown to be asymptotically optimal in a general setting. This improves all previous results on this problem. The main techniques for deriving this result rely on combinatorial properties of arrays and so-called Cartesian Trees. For compressible input arrays we show that further space can be saved, while not affecting the time bounds. For the two-dimensional variant of the RMQ-problem we give a preprocessing scheme with quasi-optimal time bounds, but with an asymptotic increase in space consumption of a factor of log(n). It is well known that algorithms for answering RMQs in constant time are useful for many different algorithmic tasks (e.g., the computation of lowest common ancestors in trees); in the second part of this thesis we give several new applications of the RMQ-problem. We show that our preprocessing scheme for RMQ (and a variant thereof) leads to improvements in the space- and time-consumption of the Enhanced Suffix Array, a collection of arrays that can be used for many tasks in pattern matching. In particular, we will see that in conjunction with the suffix- and LCP-array 2n+o(n) bits of additional space (coming from our RMQ-scheme) are sufficient to find all occ occurrences of a (usually short) pattern of length m in a (usually long) text of length n in O(m*s+occ) time, where s denotes the size of the alphabet. This is certainly optimal if the size of the alphabet is constant; for non-constant alphabets we can improve this to O(m*log(s)+occ) locating time, replacing our original scheme with a data structure of size approximately 2.54n bits. Again by using RMQs, we then show how to solve frequency-related string mining tasks in optimal time. In a final chapter we propose a space- and time-optimal algorithm for computing suffix arrays on texts that are logically divided into words, if one is just interested in finding all word-aligned occurrences of a pattern. Apart from the theoretical improvements made in this thesis, most of our algorithms are also of practical value; we underline this fact by empirical tests and comparisons on real-word problem instances. In most cases our algorithms outperform previous approaches by all means