Spectral Sequence Motif Discovery

Sequence discovery tools play a central role in several fields of computational biology. In the framework of Transcription Factor binding studies, motif finding algorithms of increasingly high performance are required to process the big datasets produced by new high-throughput sequencing technologies. Most existing algorithms are computationally demanding and often cannot support the large size of new experimental data. We present a new motif discovery algorithm that is built on a recent machine learning technique, referred to as Method of Moments. Based on spectral decompositions, this method is robust under model misspecification and is not prone to locally optimal solutions. We obtain an algorithm that is extremely fast and designed for the analysis of big sequencing data. In a few minutes, we can process datasets of hundreds of thousand sequences and extract motif profiles that match those computed by various state-of-the-art algorithms.Comment: 20 pages, 3 figures, 1 tabl

Bayesian Centroid Estimation for Motif Discovery

Biological sequences may contain patterns that are signal important biomolecular functions; a classical example is regulation of gene expression by transcription factors that bind to specific patterns in genomic promoter regions. In motif discovery we are given a set of sequences that share a common motif and aim to identify not only the motif composition, but also the binding sites in each sequence of the set. We present a Bayesian model that is an extended version of the model adopted by the Gibbs motif sampler, and propose a new centroid estimator that arises from a refined and meaningful loss function for binding site inference. We discuss the main advantages of centroid estimation for motif discovery, including computational convenience, and how its principled derivation offers further insights about the posterior distribution of binding site configurations. We also illustrate, using simulated and real datasets, that the centroid estimator can differ from the maximum a posteriori estimator.Comment: 24 pages, 9 figure

Model selection and sensitivity analysis for sequence pattern models

In this article we propose a maximal a posteriori (MAP) criterion for model selection in the motif discovery problem and investigate conditions under which the MAP asymptotically gives a correct prediction of model size. We also investigate robustness of the MAP to prior specification and provide guidelines for choosing prior hyper-parameters for motif models based on sensitivity considerations.Comment: Published in at http://dx.doi.org/10.1214/193940307000000301 the IMS Collections (http://www.imstat.org/publications/imscollections.htm) by the Institute of Mathematical Statistics (http://www.imstat.org

Sequence information gain based motif analysis

Background: The detection of regulatory regions in candidate sequences is essential for the understanding of the regulation of a particular gene and the mechanisms involved. This paper proposes a novel methodology based on information theoretic metrics for finding regulatory sequences in promoter regions. Results: This methodology (SIGMA) has been tested on genomic sequence data for Homo sapiens and Mus musculus. SIGMA has been compared with different publicly available alternatives for motif detection, such as MEME/MAST, Biostrings (Bioconductor package), MotifRegressor, and previous work such Qresiduals projections or information theoretic based detectors. Comparative results, in the form of Receiver Operating Characteristic curves, show how, in 70 % of the studied Transcription Factor Binding Sites, the SIGMA detector has a better performance and behaves more robustly than the methods compared, while having a similar computational time. The performance of SIGMA can be explained by its parametric simplicity in the modelling of the non-linear co-variability in the binding motif positions. Conclusions: Sequence Information Gain based Motif Analysis is a generalisation of a non-linear model of the cis-regulatory sequences detection based on Information Theory. This generalisation allows us to detect transcription factor binding sites with maximum performance disregarding the covariability observed in the positions of the training set of sequences. SIGMA is freely available to the public at http://b2slab.upc.edu.Postprint (published version

Multiple sequence alignment based on set covers

We introduce a new heuristic for the multiple alignment of a set of sequences. The heuristic is based on a set cover of the residue alphabet of the sequences, and also on the determination of a significant set of blocks comprising subsequences of the sequences to be aligned. These blocks are obtained with the aid of a new data structure, called a suffix-set tree, which is constructed from the input sequences with the guidance of the residue-alphabet set cover and generalizes the well-known suffix tree of the sequence set. We provide performance results on selected BAliBASE amino-acid sequences and compare them with those yielded by some prominent approaches

Gapped consensus motif discovery: evaluation of a new algorithm based on local multiple alignments and a sampling strategy

We check the efficiency and faisability of a novel method designed for the discovery of a priori unknown motifs described as gaps alternating with specific regions. Such motifs are searched for as consensi of non homologous biological sequences. The only specifications required concern the maximal gap length, the minimal frequency for specific characters and the minimal percentage (quorum) of sequences sharing the motif. Our method is based on a cooperation between a multiple alignment method for a quick detection of local similarities and a sampling strategy running candidate position specific scoring matrices to convergence. This rather original way implemented for converging to the solution proves efficient both on simulated data, gapped instances of the so-called challenge problem, promoter sites in Dicot plants and transcription factor binding sites in E.Coli. Our algorithm compares favorably with the MEME and STARS approaches in terms of accuracy

Transcription Factor-DNA Binding Via Machine Learning Ensembles

We present ensemble methods in a machine learning (ML) framework combining predictions from five known motif/binding site exploration algorithms. For a given TF the ensemble starts with position weight matrices (PWM's) for the motif, collected from the component algorithms. Using dimension reduction, we identify significant PWM-based subspaces for analysis. Within each subspace a machine classifier is built for identifying the TF's gene (promoter) targets (Problem 1). These PWM-based subspaces form an ML-based sequence analysis tool. Problem 2 (finding binding motifs) is solved by agglomerating k-mer (string) feature PWM-based subspaces that stand out in identifying gene targets. We approach Problem 3 (binding sites) with a novel machine learning approach that uses promoter string features and ML importance scores in a classification algorithm locating binding sites across the genome. For target gene identification this method improves performance (measured by the F1 score) by about 10 percentage points over the (a) motif scanning method and (b) the coexpression-based association method. Top motif outperformed 5 component algorithms as well as two other common algorithms (BEST and DEME). For identifying individual binding sites on a benchmark cross species database (Tompa et al., 2005) we match the best performer without much human intervention. It also improved the performance on mammalian TFs. The ensemble can integrate orthogonal information from different weak learners (potentially using entirely different types of features) into a machine learner that can perform consistently better for more TFs. The TF gene target identification component (problem 1 above) is useful in constructing a transcriptional regulatory network from known TF-target associations. The ensemble is easily extendable to include more tools as well as future PWM-based information.Comment: 33 page