Flexible RNA design under structure and sequence constraints using formal languages

The problem of RNA secondary structure design (also called inverse folding) is the following: given a target secondary structure, one aims to create a sequence that folds into, or is compatible with, a given structure. In several practical applications in biology, additional constraints must be taken into account, such as the presence/absence of regulatory motifs, either at a specific location or anywhere in the sequence. In this study, we investigate the design of RNA sequences from their targeted secondary structure, given these additional sequence constraints. To this purpose, we develop a general framework based on concepts of language theory, namely context-free grammars and finite automata. We efficiently combine a comprehensive set of constraints into a unifying context-free grammar of moderate size. From there, we use generic generic algorithms to perform a (weighted) random generation, or an exhaustive enumeration, of candidate sequences. The resulting method, whose complexity scales linearly with the length of the RNA, was implemented as a standalone program. The resulting software was embedded into a publicly available dedicated web server. The applicability demonstrated of the method on a concrete case study dedicated to Exon Splicing Enhancers, in which our approach was successfully used in the design of \emph{in vitro} experiments.Comment: ACM BCB 2013 - ACM Conference on Bioinformatics, Computational Biology and Biomedical Informatics (2013

An output-sensitive algorithm for the minimization of 2-dimensional String Covers

String covers are a powerful tool for analyzing the quasi-periodicity of 1-dimensional data and find applications in automata theory, computational biology, coding and the analysis of transactional data. A \emph{cover} of a string $T$ is a string $C$ for which every letter of $T$ lies within some occurrence of $C$. String covers have been generalized in many ways, leading to \emph{k-covers}, \emph{$\lambda$-covers}, \emph{approximate covers} and were studied in different contexts such as \emph{indeterminate strings}. In this paper we generalize string covers to the context of 2-dimensional data, such as images. We show how they can be used for the extraction of textures from images and identification of primitive cells in lattice data. This has interesting applications in image compression, procedural terrain generation and crystallography

Improved algorithms for string searching problems

We present improved practically efficient algorithms for several string searching problems, where we search for a short string called the pattern in a longer string called the text. We are mainly interested in the online problem, where the text is not preprocessed, but we also present a light indexing approach to speed up exact searching of a single pattern. The new algorithms can be applied e.g. to many problems in bioinformatics and other content scanning and filtering problems. In addition to exact string matching, we develop algorithms for several other variations of the string matching problem. We study algorithms for approximate string matching, where a limited number of errors is allowed in the occurrences of the pattern, and parameterized string matching, where a substring of the text matches the pattern if the characters of the substring can be renamed in such a way that the renamed substring matches the pattern exactly. We also consider searching multiple patterns simultaneously and searching weighted patterns, where the weight of a character at a given position reflects the probability of that character occurring at that position. Many of the new algorithms use the backward matching principle, where the characters of the text that are aligned with the pattern are read backward, i.e. from right to left. Another common characteristic of the new algorithms is the use of q-grams, i.e. q consecutive characters are handled as a single character. Many of the new algorithms are bit parallel, i.e. they pack several variables to a single computer word and update all these variables with a single instruction. We show that the q-gram backward string matching algorithms that solve the exact, approximate, or multiple string matching problems are optimal on average. We also show that the q-gram backward string matching algorithm for the parameterized string matching problem is sublinear on average for a class of moderately repetitive patterns. All the presented algorithms are also shown to be fast in practice when compared to earlier algorithms. We also propose an alphabet sampling technique to speed up exact string matching. We choose a subset of the alphabet and select the corresponding subsequence of the text. String matching is then performed on this reduced subsequence and the found matches are verified in the original text. We show how to choose the sampled alphabet optimally and show that the technique speeds up string matching especially for moderate to long patterns

Developing bioinformatics approaches for the analysis of influenza virus whole genome sequence data

Influenza viruses represent a major public health burden worldwide, resulting in an estimated 500,000 deaths per year, with potential for devastating pandemics. Considerable effort is expended in the surveillance of influenza, including major World Health Organization (WHO) initiatives such as the Global Influenza Surveillance and Response System (GISRS). To this end, whole-genome sequencning (WGS), and corresponding bioinformatics pipelines, have emerged as powerful tools. However, due to the inherent diversity of influenza genomes, circulation in several different host species, and noise in short-read data, several pitfalls can appear during bioinformatics processing and analysis. 2.1.2 Results Conventional mapping approaches can be insufficient when a sub-optimal reference strain is chosen. For short-read datasets simulated from human-origin influenza H1N1 HA sequences, read recovery after single-reference mapping was routinely as low as 90% for human-origin influenza sequences, and often lower than 10% for those from avian hosts. To this end, I developed software using de Bruijn 47Graphs (DBGs) for classification of influenza WGS datasets: VAPOR. In real data benchmarking using 257 WGS read sets with corresponding de novo assemblies, VAPOR provided classifications for all samples with a mean of >99.8% identity to assembled contigs. This resulted in an increase of the number of mapped reads by 6.8% on average, up to a maximum of 13.3%. Additionally, using simulations, I demonstrate that classification from reads may be applied to detection of reassorted strains. 2.1.3 Conclusions The approach used in this study has the potential to simplify bioinformatics pipelines for surveillance, providing a novel method for detection of influenza strains of human and non-human origin directly from reads, minimization of potential data loss and bias associated with conventional mapping, and facilitating alignments that would otherwise require slow de novo assembly. Whilst with expertise and time these pitfalls can largely be avoided, with pre-classification they are remedied in a single step. Furthermore, this algorithm could be adapted in future to surveillance of other RNA viruses. VAPOR is available at https://github.com/connor-lab/vapor. Lastly, VAPOR could be improved by future implementation in C++, and should employ more efficient methods for DBG representation

Suffix Structures and Circular Pattern Problems

The suffix tree is a data structure used to represent all the suffixes in a string. However, a major problem with the suffix tree is its practical space requirement. In this dissertation, we propose an efficient data structure -- the virtual suffix tree (VST) -- which requires less space than other recently proposed data structures for suffix trees and suffix arrays. On average, the space requirement (including that for suffix arrays and suffix links) is 13.8n bytes for the regular VST, and 12.05n bytes in its compact form, where n is the length of the sequence.;Markov models are very popular for modeling complex sequences. In this dissertation, we present the probabilistic suffix array (PSA), a space-efficient alternative to the probabilistic suffix tree (PST) used to represent Markov models. The PSA provides all the capabilities of the PST, such as learning and prediction, and maintains the same linear time construction (linearity with respect to sequence length). The PSA, however, has a significantly smaller memory requirement than the PST, for both the construction stage, and at the time of usage.;Using the proposed suffix data structures, we study the circular pattern matching (CPM) problem. We provide a linear time, linear space algorithm to solve the exact circular pattern matching problem. We then present four algorithms to address the approximate circular pattern matching (ACPM) problem. Our bidirectional ACPM algorithm provides the best time complexity when compared with other algorithms proposed in the literature. Further, we define the circular pattern discovery (CPD) problem and present algorithms to solve this problem. Using the proposed circular pattern matching algorithms, we perform experiments on computational analysis and function prediction for multidomain proteins