8,490 research outputs found
Mutual Enrichment in Ranked Lists and the Statistical Assessment of Position Weight Matrix Motifs
Statistics in ranked lists is important in analyzing molecular biology
measurement data, such as ChIP-seq, which yields ranked lists of genomic
sequences. State of the art methods study fixed motifs in ranked lists. More
flexible models such as position weight matrix (PWM) motifs are not addressed
in this context. To assess the enrichment of a PWM motif in a ranked list we
use a PWM induced second ranking on the same set of elements. Possible orders
of one ranked list relative to the other are modeled by permutations. Due to
sample space complexity, it is difficult to characterize tail distributions in
the group of permutations. In this paper we develop tight upper bounds on tail
distributions of the size of the intersection of the top of two uniformly and
independently drawn permutations and demonstrate advantages of this approach
using our software implementation, mmHG-Finder, to study PWMs in several
datasets.Comment: Peer-reviewed and presented as part of the 13th Workshop on
Algorithms in Bioinformatics (WABI2013
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
POIMs: positional oligomer importance matrices—understanding support vector machine-based signal detectors
Motivation: At the heart of many important bioinformatics problems, such as gene finding and function prediction, is the classification of biological sequences. Frequently the most accurate classifiers are obtained by training support vector machines (SVMs) with complex sequence kernels. However, a cumbersome shortcoming of SVMs is that their learned decision rules are very hard to understand for humans and cannot easily be related to biological facts
Motif Discovery through Predictive Modeling of Gene Regulation
We present MEDUSA, an integrative method for learning motif models of
transcription factor binding sites by incorporating promoter sequence and gene
expression data. We use a modern large-margin machine learning approach, based
on boosting, to enable feature selection from the high-dimensional search space
of candidate binding sequences while avoiding overfitting. At each iteration of
the algorithm, MEDUSA builds a motif model whose presence in the promoter
region of a gene, coupled with activity of a regulator in an experiment, is
predictive of differential expression. In this way, we learn motifs that are
functional and predictive of regulatory response rather than motifs that are
simply overrepresented in promoter sequences. Moreover, MEDUSA produces a model
of the transcriptional control logic that can predict the expression of any
gene in the organism, given the sequence of the promoter region of the target
gene and the expression state of a set of known or putative transcription
factors and signaling molecules. Each motif model is either a -length
sequence, a dimer, or a PSSM that is built by agglomerative probabilistic
clustering of sequences with similar boosting loss. By applying MEDUSA to a set
of environmental stress response expression data in yeast, we learn motifs
whose ability to predict differential expression of target genes outperforms
motifs from the TRANSFAC dataset and from a previously published candidate set
of PSSMs. We also show that MEDUSA retrieves many experimentally confirmed
binding sites associated with environmental stress response from the
literature.Comment: RECOMB 200
Automatic detection of exonic splicing enhancers (ESEs) using SVMs
<p>Abstract</p> <p>Background</p> <p>Exonic splicing enhancers (ESEs) activate nearby splice sites and promote the inclusion (vs. exclusion) of exons in which they reside, while being a binding site for SR proteins. To study the impact of ESEs on alternative splicing it would be useful to have a possibility to detect them in exons. Identifying SR protein-binding sites in human DNA sequences by machine learning techniques is a formidable task, since the exon sequences are also constrained by their functional role in coding for proteins.</p> <p>Results</p> <p>The choice of training examples needed for machine learning approaches is difficult since there are only few exact locations of human ESEs described in the literature which could be considered as positive examples. Additionally, it is unclear which sequences are suitable as negative examples. Therefore, we developed a motif-oriented data-extraction method that extracts exon sequences around experimentally or theoretically determined ESE patterns. Positive examples are restricted by heuristics based on known properties of ESEs, e.g. location in the vicinity of a splice site, whereas negative examples are taken in the same way from the middle of long exons. We show that a suitably chosen SVM using optimized sequence kernels (e.g., combined oligo kernel) can extract meaningful properties from these training examples. Once the classifier is trained, every potential ESE sequence can be passed to the SVM for verification. Using SVMs with the combined oligo kernel yields a high accuracy of about 90 percent and well interpretable parameters.</p> <p>Conclusion</p> <p>The motif-oriented data-extraction method seems to produce consistent training and test data leading to good classification rates and thus allows verification of potential ESE motifs. The best results were obtained using an SVM with the combined oligo kernel, while oligo kernels with oligomers of a certain length could be used to extract relevant features.</p
Improved benchmarks for computational motif discovery
Background
An important step in annotation of sequenced genomes is the identification of transcription factor binding sites. More than a hundred different computational methods have been proposed, and it is difficult to make an informed choice. Therefore, robust assessment of motif discovery methods becomes important, both for validation of existing tools and for identification of promising directions for future research.
Results
We use a machine learning perspective to analyze collections of transcription factors with known binding sites. Algorithms are presented for finding position weight matrices (PWMs), IUPAC-type motifs and mismatch motifs with optimal discrimination of binding sites from remaining sequence. We show that for many data sets in a recently proposed benchmark suite for motif discovery, none of the common motif models can accurately discriminate the binding sites from remaining sequence. This may obscure the distinction between the potential performance of the motif discovery tool itself versus the intrinsic complexity of the problem we are trying to solve. Synthetic data sets may avoid this problem, but we show on some previously proposed benchmarks that there may be a strong bias towards a presupposed motif model. We also propose a new approach to benchmark data set construction. This approach is based on collections of binding site fragments that are ranked according to the optimal level of discrimination achieved with our algorithms. This allows us to select subsets with specific properties. We present one benchmark suite with data sets that allow good discrimination between positive and negative instances with the common motif models. These data sets are suitable for evaluating algorithms for motif discovery that rely on these models. We present another benchmark suite where PWM, IUPAC and mismatch motif models are not able to discriminate reliably between positive and negative instances. This suite could be used for evaluating more powerful motif models.
Conclusion
Our improved benchmark suites have been designed to differentiate between the performance of motif discovery algorithms and the power of motif models. We provide a web server where users can download our benchmark suites, submit predictions and visualize scores on the benchmarks
Extracting Functional Modules from Biological Pathways
It has been proposed that functional modules are the fundamental units of cellular function. Methods to identify these modules have thus far relied on gene expression data or protein-protein interaction (PPI) data, but have a few limitations. We propose a new method, using biological pathway data to identify functional modules, that can potentially overcome these limitations. We also construct a network of these modules using functionally relevant PPI data. This network displays the flow and integration of information between modules and can be used to map cellular function
Probabilistic Clustering of Sequences: Inferring new bacterial regulons by comparative genomics
Genome wide comparisons between enteric bacteria yield large sets of
conserved putative regulatory sites on a gene by gene basis that need to be
clustered into regulons. Using the assumption that regulatory sites can be
represented as samples from weight matrices we derive a unique probability
distribution for assignments of sites into clusters. Our algorithm, 'PROCSE'
(probabilistic clustering of sequences), uses Monte-Carlo sampling of this
distribution to partition and align thousands of short DNA sequences into
clusters. The algorithm internally determines the number of clusters from the
data, and assigns significance to the resulting clusters. We place theoretical
limits on the ability of any algorithm to correctly cluster sequences drawn
from weight matrices (WMs) when these WMs are unknown. Our analysis suggests
that the set of all putative sites for a single genome (e.g. E. coli) is
largely inadequate for clustering. When sites from different genomes are
combined and all the homologous sites from the various species are used as a
block, clustering becomes feasible. We predict 50-100 new regulons as well as
many new members of existing regulons, potentially doubling the number of known
regulatory sites in E. coli.Comment: 27 pages including 9 figures and 3 table
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PATTERNA: transcriptome-wide search for functional RNA elements via structural data signatures.
Establishing a link between RNA structure and function remains a great challenge in RNA biology. The emergence of high-throughput structure profiling experiments is revolutionizing our ability to decipher structure, yet principled approaches for extracting information on structural elements directly from these data sets are lacking. We present PATTERNA, an unsupervised pattern recognition algorithm that rapidly mines RNA structure motifs from profiling data. We demonstrate that PATTERNA detects motifs with an accuracy comparable to commonly used thermodynamic models and highlight its utility in automating data-directed structure modeling from large data sets. PATTERNA is versatile and compatible with diverse profiling techniques and experimental conditions
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