In recent times there has been an increase in the amount of individual genomes sequenced for species, which are highly repetitive sequence collections known as pangenomes. Pangenomes can be represented in different ways, from strings to graphs, each with its own advantages and disadvantages. We focus on one of these representations: elastic-degenerate strings. An elastic-degenerate string (EDS) is a string whose symbols, called degenerate symbols , are comprised of one or more strings of any length, including the empty string (hence, we can have several alternatives per symbol). In this paper, we generalize to EDS the Burrows-Wheeler transform extended to a string collection. We define the Burrows-Wheeler transform of an Elastic-Degenerate String (called EDS-BWT), and show that it is a reversible transformation and it can be used for pattern matching, i.e., for finding the occurrences of a standard string pattern within an EDS. In particular, the inner properties of the classical Burrows-Wheeler transform are adapted in order to design a backward search strategy for pattern matching on an EDS. Furthermore, we analyze the worst-case complexity of that backward search. Thanks to our prototype edsBWTSearch , we experimentally compare our pattern matching approach to other existing tools managing elastic degenerate strings.

It is known that the exact form of the Burrows-Wheeler Transform (BWT) of a string collection depends, in most implementations, on the input order of the strings in the collection. Reordering strings of an input collection affects the number of equal-letter runs r, arguably the most important parameter of BWT-based data structures, such as the FM-index or the r-index. Bentley, Gibney, and Thankachan [ESA 2020] introduced a linear-time algorithm for computing the permutation of the input collection which yields the minimum number of runs of the resulting BWT. In this paper, we present the first tool that guarantees a Burrows-Wheeler Transform with minimum number of runs (optBWT), by combining i) an algorithm that builds the BWT from a string collection (either SAIS-based [Boucher et al., SPIRE 2021] or BCR [Bauer et al., CPM 2011]); ii) the SAP array data structure introduced in [Cox et al., Bioinformatics, 2012]; and iii) the algorithm by Bentley et al. We present results both on real-life and simulated data, showing that the improvement achieved in terms of r with respect to the input order is significant and the overhead created by the computation of the optimal BWT negligible, making our tool competitive with other tools for BWT-computation in terms of running time and space usage. In particular, on real data the optBWT obtains up to 31 times fewer runs with only a 1.39$\times$ slowdown. Source code is available at https://github.com/davidecenzato/optimalBWT.git.

Introduced about thirty years ago in the field of data compression, the Burrows-Wheeler Transform (BWT) is a string transformation that, besides being a booster of the performance of memoryless compressors, plays a fundamental role in the design of efficient self-indexing compressed data structures. Finding other string transformations with the same remarkable properties of BWT has been a challenge for many researchers for a long time. Among the known BWT variants, the only one that has been recently shown to be a valid alternative to BWT is the Alternating BWT (ABWT), an invertible string transformation introduced about ten years ago in connection with a generalization of Lyndon words. In this paper, we introduce a whole class of new string transformations, called local orderings-based transformations, which have all the “myriad virtues” of BWT. We show that this new family is a special case of a much larger class of transformations, based on context adaptive alphabet orderings, that includes BWT and ABWT. Although all transformations support pattern search, we show that, in the general case, the transformations within our larger class may take quadratic time for inversion and pattern search. As a further result, we show that the local orderings-based transformations can be used for the construction of the recently introduced r-index, which makes them suitable also for highly repetitive collections. In this context, we consider the problem of finding, for a given string, the BWT variant that minimizes the number of runs in the transformed string, and we provide an algorithm solving this problem in linear time.

Molecular phylogenetics is a fundamental branch of biology. It studies the evolutionary relationships among the individuals of a population through their biological sequences, and may provide insights about the origin and the evolution of viral diseases, or highlight complex evolutionary trajectories. In this paper we develop a method called phyBWT, describing how to use the extended Burrows-Wheeler Transform (eBWT) for a collection of DNA sequences to directly reconstruct phylogeny, bypassing the alignment against a reference genome or de novo assembly. Our phyBWT hinges on the combinatorial properties of the eBWT positional clustering framework. We employ eBWT to detect relevant blocks of the longest shared substrings of varying length (unlike the k-mer-based approaches that need to fix the length k a priori), and build a suitable decomposition leading to a phylogenetic tree, step by step. As a result, phyBWT is a new alignment-, assembly-, and reference-free method that builds a partition tree without relying on the pairwise comparison of sequences, thus avoiding to use a distance matrix to infer phylogeny. The preliminary experimental results on sequencing data show that our method can handle datasets of different types (short reads, contigs, or entire genomes), producing trees of quality comparable to that found in the benchmark phylogeny.

An elastic-degenerate (ED) string is a sequence of $n$ sets of strings of total length $N$ which was recently proposed to model a set of similar sequences. The ED string matching (EDSM) problem is to find all occurrences of a pattern of length $m$ in an ED text. The EDSM problem has recently received some attention in the combinatorial pattern matching community, and an $\mathcal{O}(nm^{1.5}\sqrt{\log m} + N)$-time algorithm is known [Aoyama et al., CPM 2018]. The standard assumption in the prior work on this question is that $N$ is substantially larger than both $n$ and $m$, and thus we would like to have a linear dependency on the former. Under this assumption, the natural open problem is whether we can decrease the 1.5 exponent in the time complexity, similarly as in the related (but, to the best of our knowledge, not equivalent) word break problem [Backurs and Indyk, FOCS 2016]. Our starting point is a conditional lower bound for the EDSM problem. We use the popular combinatorial Boolean matrix multiplication (BMM) conjecture stating that there is no truly subcubic combinatorial algorithm for BMM [Abboud and Williams, FOCS 2014]. By designing an appropriate reduction, we show that a combinatorial algorithm solving the EDSM problem in $\mathcal{O}(nm^{1.5-\epsilon} + N)$ time, for any $\epsilon>0$, refutes this conjecture. Our reduction should be understood as an indication that decreasing the exponent requires fast matrix multiplication. String periodicity and fast Fourier transform are two standard tools in string algorithms. Our main technical contribution is that we successfully combine these tools with fast matrix multiplication to design a noncombinatorial $\tilde{\mathcal{O}}(nm^{\omega-1}+N)$-time algorithm for EDSM, where $\omega$ denotes the matrix multiplication exponent and the $\tilde{\mathcal{O}}(\cdot)$ notation suppresses polylog factors. To the best of our knowledge, we are the first to combine these tools. In particular, using the fact that $\omega<2.373$ [Alman and Williams, SODA 2021; Le Gall, ISSAC 2014; Williams, STOC 2012], we obtain an $\mathcal{O}(nm^{1.373} + N)$-time algorithm for EDSM. An important building block in our solution that might find applications in other problems is a method of selecting a small set of length-$\ell$ substrings of the pattern, called anchors, so that any occurrence of a string from an ED text set contains at least one but not too many (on average) such anchors inside.

String data are often disseminated to support applications such as location-based service provision or DNA sequence analysis. This dissemination, however, may expose sensitive patterns that model confidential knowledge (e.g., trips to mental health clinics from a string representing a user’s location history). In this article, we consider the problem of sanitizing a string by concealing the occurrences of sensitive patterns, while maintaining data utility, in two settings that are relevant to many common string processing tasks. In the first setting, we aim to generate the minimal-length string that preserves the order of appearance and frequency of all non-sensitive patterns. Such a string allows accurately performing tasks based on the sequential nature and pattern frequencies of the string. To construct such a string, we propose a time-optimal algorithm, TFS-ALGO. We also propose another time-optimal algorithm, PFS-ALGO, which preserves a partial order of appearance of non-sensitive patterns but produces a much shorter string that can be analyzed more efficiently. The strings produced by either of these algorithms are constructed by concatenating non-sensitive parts of the input string. However, it is possible to detect the sensitive patterns by “reversing” the concatenation operations. In response, we propose a heuristic, MCSR-ALGO, which replaces letters in the strings output by the algorithms with carefully selected letters, so that sensitive patterns are not reinstated, implausible patterns are not introduced, and occurrences of spurious patterns are prevented. In the second setting, we aim to generate a string that is at minimal edit distance from the original string, in addition to preserving the order of appearance and frequency of all non-sensitive patterns. To construct such a string, we propose an algorithm, ETFS-ALGO, based on solving specific instances of approximate regular expression matching. We implemented our sanitization approach that applies TFS-ALGO, PFS-ALGO, and then MCSR-ALGO, and experimentally show that it is effective and efficient. We also show that TFS-ALGO is nearly as effective at minimizing the edit distance as ETFS-ALGO, while being substantially more efficient than ETFS-ALGO.

BACKGROUND: The development of Next Generation Sequencing (NGS) has had a major impact on the study of genetic sequences. Among problems that researchers in the field have to face, one of the most challenging is the taxonomic classification of metagenomic reads, i.e., identifying the microorganisms that are present in a sample collected directly from the environment. The analysis of environmental samples (metagenomes) are particularly important to figure out the microbial composition of different ecosystems and it is used in a wide variety of fields: for instance, metagenomic studies in agriculture can help understanding the interactions between plants and microbes, or in ecology, they can provide valuable insights into the functions of environmental communities. RESULTS: In this paper, we describe a new lightweight alignment-free and assembly-free framework for metagenomic classification that compares each unknown sequence in the sample to a collection of known genomes. We take advantage of the combinatorial properties of an extension of the Burrows-Wheeler transform, and we sequentially scan the required data structures, so that we can analyze unknown sequences of large collections using little internal memory. The tool LiME (Lightweight Metagenomics via eBWT) is available at https://github.com/veronicaguerrini/LiME . CONCLUSIONS: In order to assess the reliability of our approach, we run several experiments on NGS data from two simulated metagenomes among those provided in benchmarking analysis and on a real metagenome from the Human Microbiome Project. The experiment results on the simulated data show that LiME is competitive with the widely used taxonomic classifiers. It achieves high levels of precision and specificity - e.g. 99.9% of the positive control reads are correctly assigned and the percentage of classified reads of the negative control is less than 0.01% - while keeping a high sensitivity. On the real metagenome, we show that LiME is able to deliver classification results comparable to that of MagicBlast. Overall, the experiments confirm the effectiveness of our method and its high accuracy even in negative control samples.

BACKGROUND: In [Prezza et al., AMB 2019], a new reference-free and alignment-free framework for the detection of SNPs was suggested and tested. The framework, based on the Burrows-Wheeler Transform (BWT), significantly improves sensitivity and precision of previous de Bruijn graphs based tools by overcoming several of their limitations, namely: (i) the need to establish a fixed value, usually small, for the order k, (ii) the loss of important information such as k-mer coverage and adjacency of k-mers within the same read, and (iii) bad performance in repeated regions longer than k bases. The preliminary tool, however, was able to identify only SNPs and it was too slow and memory consuming due to the use of additional heavy data structures (namely, the Suffix and LCP arrays), besides the BWT. RESULTS: In this paper, we introduce a new algorithm and the corresponding tool ebwt2InDel that (i) extend the framework of [Prezza et al., AMB 2019] to detect also INDELs, and (ii) implements recent algorithmic findings that allow to perform the whole analysis using just the BWT, thus reducing the working space by one order of magnitude and allowing the analysis of full genomes. Finally, we describe a simple strategy for effectively parallelizing our tool for SNP detection only. On a 24-cores machine, the parallel version of our tool is one order of magnitude faster than the sequential one. The tool ebwt2InDel is available at github.com/nicolaprezza/ebwt2InDel . CONCLUSIONS: Results on a synthetic dataset covered at 30x (Human chromosome 1) show that our tool is indeed able to find up to 83% of the SNPs and 72% of the existing INDELs. These percentages considerably improve the 71% of SNPs and 51% of INDELs found by the state-of-the art tool based on de Bruijn graphs. We furthermore report results on larger (real) Human whole-genome sequencing experiments. Also in these cases, our tool exhibits a much higher sensitivity than the state-of-the art tool.

Uncertain sequences are compact representations of sets of similar strings. They highlight common segments by collapsing them, and explicitly represent varying segments by listing all possible options. A generalized degenerate string (GD string) is a type of uncertain sequence. Formally, a GD string Ŝ is a sequence of n sets of strings of total size N, where the ith set contains strings of the same length ki but this length can vary between different sets. We denote by W the sum of these lengths k0, k1, . . . , kn-1. Our main result is an 𝒪(N + M)-time algorithm for deciding whether two GD strings of total sizes N and M, respectively, over an integer alphabet, have a non-empty intersection. This result is based on a combinatorial result of independent interest: although the intersection of two GD strings can be exponential in the total size of the two strings, it can be represented in linear space. We then apply our string comparison tool to devise a simple algorithm for computing all palindromes in Ŝ in 𝒪(min{W, n2}N)-time. We complement this upper bound by showing a similar conditional lower bound for computing maximal palindromes in Ŝ. We also show that a result, which is essentially the same as our string comparison linear-time algorithm, can be obtained by employing an automata-based approach.

The Burrows-Wheeler Transform is a string transformation that plays a fundamental role for the design of self-indexing compressed data structures. Over the years, researchers have successfully extended this transformation outside the domains of strings. However, efforts to find non-trivial alternatives of the original, now 25 years old, Burrows-Wheeler string transformation have met limited success. In this paper we bring new lymph to this area by introducing a whole new family of transformations that have all the "myriad virtues" of the BWT: they can be computed and inverted in linear time, they produce provably highly compressible strings, and they support linear time pattern search directly on the transformed string. This new family is a special case of a more general class of transformations based on context adaptive alphabet orderings, a concept introduced here. This more general class includes also the Alternating BWT, another invertible string transforms recently introduced in connection with a generalization of Lyndon words.

We show that the Longest Common Prefix Array of a text collection of total size n on alphabet [1,sigma] can be computed from the Burrows-Wheeler transformed collection in O(n log sigma) time using o(n log sigma) bits of working space on top of the input and output. Our result improves (on small alphabets) and generalizes (to string collections) the previous solution from Beller et al., which required O(n) bits of extra working space. We also show how to merge the BWTs of two collections of total size n within the same time and space bounds. The procedure at the core of our algorithms can be used to enumerate suffix tree intervals in succinct space from the BWT, which is of independent interest. An engineered implementation of our first algorithm on DNA alphabet induces the LCP of a large (16 GiB) collection of short (100 bases) reads at a rate of 2.92 megabases per second using in total 1.5 Bytes per base in RAM. Our second algorithm merges the BWTs of two short-reads collections of 8 GiB each at a rate of 1.7 megabases per second and uses 0.625 Bytes per base in RAM. An extension of this algorithm that computes also the LCP array of the merged collection processes the data at a rate of 1.48 megabases per second and uses 1.625 Bytes per base in RAM.

An elastic-degenerate (ED) string is a sequence of n sets of strings of total length N, which was recently proposed to model a set of similar sequences. The ED string matching (EDSM) problem is to find all occurrences of a pattern of length m in an ED text. The EDSM problem has recently received some attention in the combinatorial pattern matching community, and an O(nm^{1.5}sqrt{log m} + N)-time algorithm is known [Aoyama et al., CPM 2018]. The standard assumption in the prior work on this question is that N is substantially larger than both n and m, and thus we would like to have a linear dependency on the former. Under this assumption, the natural open problem is whether we can decrease the 1.5 exponent in the time complexity, similarly as in the related (but, to the best of our knowledge, not equivalent) word break problem [Backurs and Indyk, FOCS 2016]. Our starting point is a conditional lower bound for the EDSM problem. We use the popular combinatorial Boolean matrix multiplication (BMM) conjecture stating that there is no truly subcubic combinatorial algorithm for BMM [Abboud and Williams, FOCS 2014]. By designing an appropriate reduction we show that a combinatorial algorithm solving the EDSM problem in O(nm^{1.5-epsilon} + N) time, for any epsilon>0, refutes this conjecture. Of course, the notion of combinatorial algorithms is not clearly defined, so our reduction should be understood as an indication that decreasing the exponent requires fast matrix multiplication. Two standard tools used in algorithms on strings are string periodicity and fast Fourier transform. Our main technical contribution is that we successfully combine these tools with fast matrix multiplication to design a non-combinatorial O(nm^{1.381} + N)-time algorithm for EDSM. To the best of our knowledge, we are the first to do so.

A generalised degenerate string (GD string) S^ is a sequence of n sets of strings of total size N, where the ith set contains strings of the same length k_i but this length can vary between different sets. We denote the sum of these lengths k_0, k_1,...,k_{n-1} by W. This type of uncertain sequence can represent, for example, a gapless multiple sequence alignment of width W in a compact form. Our first result in this paper is an O(N+M)-time algorithm for deciding whether the intersection of two GD strings of total sizes N and M, respectively, over an integer alphabet, is non-empty. This result is based on a combinatorial result of independent interest: although the intersection of two GD strings can be exponential in the total size of the two strings, it can be represented in only linear space. A similar result can be obtained by employing an automata-based approach but its cost is alphabet-dependent. We then apply our string comparison algorithm to compute palindromes in GD strings. We present an O(min{W,n^2}N)-time algorithm for computing all palindromes in S^. Furthermore, we show a similar conditional lower bound for computing maximal palindromes in S^. Finally, proof-of-concept experimental results are presented using real protein datasets.

In this paper we develop a theory describing how the extended Burrows-Wheeler Transform (eBWT) of a collection of DNA fragments tends to cluster together the copies of nucleotides sequenced from a genome G. Our theory accurately predicts how many copies of any nucleotide are expected inside each such cluster, and how an elegant and precise LCP array based procedure can locate these clusters in the eBWT. Our findings are very general and can be applied to a wide range of different problems. In this paper, we consider the case of alignment-free and reference-free SNPs discovery in multiple collections of reads. We note that, in accordance with our theoretical results, SNPs are clustered in the eBWT of the reads collection, and we develop a tool finding SNPs with a simple scan of the eBWT and LCP arrays. Preliminary results show that our method requires much less coverage than state-of-the-art tools while drastically improving precision and sensitivity.

Pattern matching on a set of similar texts has received much attention, especially recently, mainly due to its application in cataloguing human genetic variation. In particular, many different algorithms have been proposed for the off-line version of this problem; that is, constructing a compressed index for a set of similar texts in order to answer pattern matching queries efficiently. However, the on-line, more fundamental, version of this problem is a rather undeveloped topic. Solutions to the on-line version can be beneficial for a number of reasons; for instance, efficient on-line solutions can be used in combination with partial indexes as practical trade-offs. We make here an attempt to close this gap via proposing two efficient algorithms for this problem. Notably, one of the algorithms requires time linear in the size of the texts' representation, for short patterns. Furthermore, experimental results confirm our theoretical findings in practical terms.

The Burrows-Wheeler Transform is a well known transformation widely used in Data Compression: important competitive compression software, such as Bzip (cf. [1]) and Szip (cf. [2]) and some indexing software, like the FM-index (cf. [3]), are deeply based on the Burrows Wheeler Transform. The main ad vantage of using BWT for data compression consists in its feature of “clustering” together equal characters. In this paper we show the existence of fixed points of BWT, i.e., words on which BWT has no effect. We show a characterization of the permutations associated to BWT of fixed points and we give the explicit form of fixed points on a binary ordered alphabet {a, b} having at most four b’s and those having at most four a’s.

MOTIVATION: Rapid technological progress in DNA sequencing has stimulated interest in compressing the vast datasets that are now routinely produced. Relatively little attention has been paid to compressing the quality scores that are assigned to each sequence, even though these scores may be harder to compress than the sequences themselves. By aggregating a set of reads into a compressed index, we find that the majority of bases can be predicted from the sequence of bases that are adjacent to them and, hence, are likely to be less informative for variant calling or other applications. The quality scores for such bases are aggressively compressed, leaving a relatively small number at full resolution. As our approach relies directly on redundancy present in the reads, it does not need a reference sequence and is, therefore, applicable to data from metagenomics and de novo experiments as well as to re-sequencing data. RESULTS: We show that a conservative smoothing strategy affecting 75% of the quality scores above Q2 leads to an overall quality score compression of 1 bit per value with a negligible effect on variant calling. A compression of 0.68 bit per quality value is achieved using a more aggressive smoothing strategy, again with a very small effect on variant calling. AVAILABILITY: Code to construct the BWT and LCP-array on large genomic data sets is part of the BEETL library, available as a github repository at [email protected]:BEETL/BEETL.git.

MOTIVATION: The Burrows-Wheeler transform (BWT) is the foundation of many algorithms for compression and indexing of text data, but the cost of computing the BWT of very large string collections has prevented these techniques from being widely applied to the large sets of sequences often encountered as the outcome of DNA sequencing experiments. In previous work, we presented a novel algorithm that allows the BWT of human genome scale data to be computed on very moderate hardware, thus enabling us to investigate the BWT as a tool for the compression of such datasets. RESULTS: We first used simulated reads to explore the relationship between the level of compression and the error rate, the length of the reads and the level of sampling of the underlying genome and compare choices of second-stage compression algorithm. We demonstrate that compression may be greatly improved by a particular reordering of the sequences in the collection and give a novel 'implicit sorting' strategy that enables these benefits to be realized without the overhead of sorting the reads. With these techniques, a 45× coverage of real human genome sequence data compresses losslessly to under 0.5 bits per base, allowing the 135.3 Gb of sequence to fit into only 8.2 GB of space (trimming a small proportion of low-quality bases from the reads improves the compression still further). This is >4 times smaller than the size achieved by a standard BWT-based compressor (bzip2) on the untrimmed reads, but an important further advantage of our approach is that it facilitates the building of compressed full text indexes such as the FM-index on large-scale DNA sequence collections. AVAILABILITY: Code to construct the BWT and SAP-array on large genomic datasets is part of the BEETL library, available as a github repository at https://github.com/BEETL/BEETL.