Integrative methods for discovering generic CIS-regulatory motifs

Ph.DDOCTOR OF PHILOSOPH

Computational annotation of UTR cis-regulatory modules through Frequent Pattern Mining

<p>Abstract</p> <p>Background</p> <p>Many studies report about detection and functional characterization of cis-regulatory motifs in untranslated regions (UTRs) of mRNAs but little is known about the nature and functional role of their distribution. To address this issue we have developed a computational approach based on the use of data mining techniques. The idea is that of mining frequent combinations of translation regulatory motifs, since their significant co-occurrences could reveal functional relationships important for the post-transcriptional control of gene expression. The experimentation has been focused on targeted mitochondrial transcripts to elucidate the role of translational control in mitochondrial biogenesis and function.</p> <p>Results</p> <p>The analysis is based on a two-stepped procedure using a sequential pattern mining algorithm. The first step searches for frequent patterns (FPs) of motifs without taking into account their spatial displacement. In the second step, frequent sequential patterns (FSPs) of spaced motifs are generated by taking into account the conservation of spacers between each ordered pair of co-occurring motifs. The algorithm makes no assumption on the relation among motifs and on the number of motifs involved in a pattern. Different FSPs can be found depending on different combinations of two parameters, i.e. the threshold of the minimum percentage of sequences supporting the pattern, and the granularity of spacer discretization. Results can be retrieved at the UTRminer web site: <url>http://utrminer.ba.itb.cnr.it/</url>. The discovered FPs of motifs amount to 216 in the overall dataset and to 140 in the human subset. For each FP, the system provides information on the discovered FSPs, if any. A variety of search options help users in browsing the web resource. The list of sequence IDs supporting each pattern can be used for the retrieval of information from the UTRminer database.</p> <p>Conclusion</p> <p>Computational prediction of structural properties of regulatory sequences is not trivial. The presented data mining approach is able to overcome some limits observed in other competitive tools. Preliminary results on UTR sequences from nuclear transcripts targeting mitochondria are promising and lead us to be confident on the effectiveness of the approach for future developments.</p

AMD, an Automated Motif Discovery Tool Using Stepwise Refinement of Gapped Consensuses

Motif discovery is essential for deciphering regulatory codes from high throughput genomic data, such as those from ChIP-chip/seq experiments. However, there remains a lack of effective and efficient methods for the identification of long and gapped motifs in many relevant tools reported to date. We describe here an automated tool that allows for de novo discovery of transcription factor binding sites, regardless of whether the motifs are long or short, gapped or contiguous

Improved Algorithms for Discovery of Transcription Factor Binding Sites in DNA Sequences

Understanding the mechanisms that regulate gene expression is a major challenge in biology. One of the most important tasks in this challenge is to identify the transcription factors binding sites (TFBS) in DNA sequences. The common representation of these binding sites is called “motif” and the discovery of TFBS problem is also referred as motif finding problem in computer science. Despite extensive efforts in the past decade, none of the existing algorithms perform very well. This dissertation focuses on this difficult problem and proposes three new methods (MotifEnumerator, PosMotif, and Enrich) with excellent improvements. An improved pattern-driven algorithm, MotifEnumerator, is first proposed to detect the optimal motif with reduced time complexity compared to the traditional exact pattern-driven approaches. This strategy is further extended to allow arbitrary don’t care positions within a motif without much decrease in solvable values of motif length. The performance of this algorithm is comparable to the best existing motif finding algorithms on a large benchmark set of samples. Another algorithm with further post processing, PosMotif, is proposed to use a string representation that allows arbitrary ignored positions within the non-conserved portion of single motifs, and use Markov chains to model the background distributions of motifs of certain length while skipping these positions within each Markov chain. Two post processing steps considering redundancy information are applied in this algorithm. PosMotif demonstrates an improved performance compared to the best five existing motif finding algorithms on several large benchmark sets of samples. The third method, Enrich, is proposed to improve the performance of general motif finding algorithms by adding more sequences to the samples in the existing benchmark datasets. Five famous motif finding algorithms have been chosen to run on the original datasets and the enriched datasets, and the performance comparisons show a general great improvement on the enriched datasets

Time series motif discovery

Programa doutoral MAP-i em Computer ScienceTime series data are daily produced in massive proportions in virtually every field. Most of the data are stored in time series databases. To find patterns in the databases is an important problem. These patterns, also known as motifs, provide useful insight to the domain expert and summarize the database. They have been widely used in areas as diverse as finance and medicine. Despite there are many algorithms for the task, they typically do not scale and need to set several parameters. We propose a novel algorithm that runs in linear time, is also space efficient and only needs to set one parameter. It fully exploits the state of the art time series representation (SAX _ Symbolic Aggregate Approximation) technique to extract motifs at several resolutions. This property allows the algorithm to skip expensive distance calculations that are typically employed by other algorithms. We also propose an approach to calculate time series motifs statistical significance. Despite there are many approaches in the literature to find time series motifs e_ciently, surprisingly there is no approach that calculates a motifs statistical significance. Our proposal leverages work from the bioinformatics community by using a symbolic definition of time series motifs to derive each motif's p-value. We estimate the expected frequency of a motif by using Markov Chain models. The p-value is then assessed by comparing the actual frequency to the estimated one using statistical hypothesis tests. Our contribution gives means to the application of a powerful technique - statistical tests - to a time series setting. This provides researchers and practitioners with an important tool to evaluate automatically the degree of relevance of each extracted motif. Finally, we propose an approach to automatically derive the Symbolic Aggregate Approximation (iSAX) time series representation's parameters. This technique is widely used in time series data mining. Its popularity arises from the fact that it is symbolic, reduces the dimensionality of the series, allows lower bounding and is space efficient. However, the need to set the symbolic length and alphabet size parameters limits the applicability of the representation since the best parameter setting is highly application dependent. Typically, these are either set to a fixed value (e.g. 8) or experimentally probed for the best configuration. The technique, referred as AutoiSAX, not only discovers the best parameter setting for each time series in the database but also finds the alphabet size for each iSAX symbol within the same word. It is based on the simple and intuitive ideas of time series complexity and standard deviation. The technique can be smoothly embedded in existing data mining tasks as an efficient sub-routine. We analyse the impact of using AutoiSAX in visualization interpretability, classification accuracy and motif mining results. Our contribution aims to make iSAX a more general approach as it evolves towards a parameter-free method.As séries temporais são produzidas diariamente em quantidades massivas em diferentes áreas de trabalho. Estes dados são guardados em bases de dados de séries temporais. Descobrir padrões desconhecidos e repetidos em bases de dados de séries temporais é um desafio pertinente. Estes padrões, também conhecidos como motivos, dão uma nova perspectiva da base de dados, ajudando a explorá-la e sumarizá-la. São frequentemente utilizados em áreas tão diversas como as finanças ou a medicina. Apesar de existirem diversos algoritmos destinados à execução desta tarefa, geralmente não apresentam uma boa escalabilidade e exigem a configuração de vários parâmetros. Propomos, neste trabalho, a criação de um novo algoritmo que executa em tempo linear e que é igualmente eficiente em termos de memória usada, necessitando apenas de um parâmetro. Este algoritmo usufrui da melhor técnica de representação de séries temporais para extrair motivos em várias resoluções (SAX). Esta propriedade permite evitar o cálculo de distâncias que têm um custo computacional muito elevado, cálculo este geralmente presente noutros algoritmos. Nesta tese também fazemos uma proposta para calcular a significância estatística de motivos em séries temporais. Apesar de existirem muitas propostas para a detecção eficiente de motivos em séries temporais, surpreendentemente não existe nenhuma aproximação para calcular a sua significância estatística. A nossa proposta é enriquecida pelo trabalho da área bioinformática, sendo usada uma definição simbólica de motivo para derivar o seu respectivo p-value. Estimamos a frequência esperada de um motivo usando modelos de cadeias de Markov. O p-value associado a um teste estatístico é calculado comparando a frequência real com a frequência estimada de cada padrão. A nossa contribuição permite a aplicação de uma técnica poderosa, testes estatísticos, para a área das séries temporais. Proporciona assim, aos investigadores e utilizadores, uma ferramenta importante para avaliarem, de forma automática, a relevância de cada motivo extraído dos seus dados. Por fim, propomos uma metodologia para derivar de forma automática os parâmetros da representação de séries temporais Symbolic Aggregate Approximation (iSAX). Esta técnica é vastamente utilizada na área de Extracção de Conhecimento em séries temporais. A sua popularidade surge associada ao facto de ser simbólica, de reduzir o tamanho das séries, de permitir aproximar a Distância Euclidiana nas séries originais e ser eficiente em termos de espaço. Contudo, a necessidade de definir os parâmetros comprimento da representação e tamanho do alfabeto limita a sua utilização na prática, uma vez que o parâmetro mais adequado está dependente da área em causa. Normalmente, estes são definidos quer para um valor fixo (por exemplo, 8). A técnica, designada por AutoiSAX, não só extrai a melhor configuração do parâmetro para cada série temporal da base de dados como consegue encontrar a dimensão do alfabeto para cada símbolo iSAX dentro da mesma palavra. Baseia-se em ideias simples e intuitivas como a complexidade das séries temporais e no desvio padrão. A técnica pode ser facilmente incorporada como uma sub-rotina eficiente em tarefas existentes de extracção de conhecimento. Analisamos também o impacto da utilização do AutoiSAX na capacidade interpretativa em tarefas de visualização, exactidão da classificação e na qualidade dos motivos extraídos. A nossa proposta pretende que a iSAX se consolide como uma abordagem mais geral à medida que se vai constituindo como uma metodologia livre de parâmetros.Fundação para a Ciência e Tecnologia (FCT) - SFRH / BD / 33303 / 200

gene regulatory element prediction with bayesian networks

Ph.DDOCTOR OF PHILOSOPH

Detection of generic spaced motifs using submotif pattern mining

10.1093/bioinformatics/btm118Bioinformatics23121476-1485BOIN

Detection of generic spaced motifs using submotif pattern mining

Motivation: Identification of motifs is one of the critical stages in studying the regulatory interactions of genes. Motifs can have complicated patterns. In particular, spaced motifs, an important class of motifs, consist of several short segments separated by spacers of different lengths. Locating spaced motifs is not trivial. Existing motif-finding algorithms are either designed for monad motifs (short contiguous patterns with some mismatches) or have assumptions on the spacer lengths or can only handle at most two segments. An effective motif finder for generic spaced motifs is highly desirable. Results: This article proposes a novel approach for identifying spaced motifs with any number of spacers of different lengths. We introduce the notion of submotifs to capture the segments in the spaced motif and formulate the motif-finding problem as a frequent submotif mining problem. We provide an algorithm called SPACE to solve the problem. Based on experiments on real biological datasets, synthetic datasets and the motif assessment benchmarks by Tompa et al., we show that our algorithm performs better than existing tools for spaced motifs with improvements in both sensitivity and specificity and for monads, SPACE performs as good as other tools. © The Author 2007. Published by Oxford University Press. All rights reserved.link_to_OA_fulltex