12,737 research outputs found
Formation of regulatory modules by local sequence duplication
Turnover of regulatory sequence and function is an important part of
molecular evolution. But what are the modes of sequence evolution leading to
rapid formation and loss of regulatory sites? Here, we show that a large
fraction of neighboring transcription factor binding sites in the fly genome
have formed from a common sequence origin by local duplications. This mode of
evolution is found to produce regulatory information: duplications can seed new
sites in the neighborhood of existing sites. Duplicate seeds evolve
subsequently by point mutations, often towards binding a different factor than
their ancestral neighbor sites. These results are based on a statistical
analysis of 346 cis-regulatory modules in the Drosophila melanogaster genome,
and a comparison set of intergenic regulatory sequence in Saccharomyces
cerevisiae. In fly regulatory modules, pairs of binding sites show
significantly enhanced sequence similarity up to distances of about 50 bp. We
analyze these data in terms of an evolutionary model with two distinct modes of
site formation: (i) evolution from independent sequence origin and (ii)
divergent evolution following duplication of a common ancestor sequence. Our
results suggest that pervasive formation of binding sites by local sequence
duplications distinguishes the complex regulatory architecture of higher
eukaryotes from the simpler architecture of unicellular organisms
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
Inference of Markovian Properties of Molecular Sequences from NGS Data and Applications to Comparative Genomics
Next Generation Sequencing (NGS) technologies generate large amounts of short
read data for many different organisms. The fact that NGS reads are generally
short makes it challenging to assemble the reads and reconstruct the original
genome sequence. For clustering genomes using such NGS data, word-count based
alignment-free sequence comparison is a promising approach, but for this
approach, the underlying expected word counts are essential.
A plausible model for this underlying distribution of word counts is given
through modelling the DNA sequence as a Markov chain (MC). For single long
sequences, efficient statistics are available to estimate the order of MCs and
the transition probability matrix for the sequences. As NGS data do not provide
a single long sequence, inference methods on Markovian properties of sequences
based on single long sequences cannot be directly used for NGS short read data.
Here we derive a normal approximation for such word counts. We also show that
the traditional Chi-square statistic has an approximate gamma distribution,
using the Lander-Waterman model for physical mapping. We propose several
methods to estimate the order of the MC based on NGS reads and evaluate them
using simulations. We illustrate the applications of our results by clustering
genomic sequences of several vertebrate and tree species based on NGS reads
using alignment-free sequence dissimilarity measures. We find that the
estimated order of the MC has a considerable effect on the clustering results,
and that the clustering results that use a MC of the estimated order give a
plausible clustering of the species.Comment: accepted by RECOMB-SEQ 201
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
Regulatory motif discovery using a population clustering evolutionary algorithm
This paper describes a novel evolutionary algorithm for regulatory motif discovery in DNA promoter sequences. The algorithm uses data clustering to logically distribute the evolving population across the search space. Mating then takes place within local regions of the population, promoting overall solution diversity and encouraging discovery of multiple solutions. Experiments using synthetic data sets have demonstrated the algorithm's capacity to find position frequency matrix models of known regulatory motifs in relatively long promoter sequences. These experiments have also shown the algorithm's ability to maintain diversity during search and discover multiple motifs within a single population. The utility of the algorithm for discovering motifs in real biological data is demonstrated by its ability to find meaningful motifs within muscle-specific regulatory sequences
A temporal switch model for estimating transcriptional activity in gene expression
Motivation: The analysis and mechanistic modelling of time series gene expression data provided by techniques such as microarrays, NanoString, reverse transcription–polymerase chain reaction and advanced sequencing are invaluable for developing an understanding of the variation in key biological processes. We address this by proposing the estimation of a flexible dynamic model, which decouples temporal synthesis and degradation of mRNA and, hence, allows for transcriptional activity to switch between different states.
Results: The model is flexible enough to capture a variety of observed transcriptional dynamics, including oscillatory behaviour, in a way that is compatible with the demands imposed by the quality, time-resolution and quantity of the data. We show that the timing and number of switch events in transcriptional activity can be estimated alongside individual gene mRNA stability with the help of a Bayesian reversible jump Markov chain Monte Carlo algorithm. To demonstrate the methodology, we focus on modelling the wild-type behaviour of a selection of 200 circadian genes of the model plant Arabidopsis thaliana. The results support the idea that using a mechanistic model to identify transcriptional switch points is likely to strongly contribute to efforts in elucidating and understanding key biological processes, such as transcription and degradation
Natural similarity measures between position frequency matrices with an application to clustering
Motivation: Transcription factors (TFs) play a key role in gene regulation by binding to target sequences. In silico prediction of potential binding of a TF to a binding site is a well-studied problem in computational biology. The binding sites for one TF are represented by a position frequency matrix (PFM). The discovery of new PFMs requires the comparison to known PFMs to avoid redundancies. In general, two PFMs are similar if they occur at overlapping positions under a null model. Still, most existing methods compute similarity according to probabilistic distances of the PFMs. Here we propose a natural similarity measure based on the asymptotic covariance between the number of PFM hits incorporating both strands. Furthermore, we introduce a second measure based on the same idea to cluster a set of the Jaspar PFMs. Results: We show that the asymptotic covariance can be efficiently computed by a two dimensional convolution of the score distributions. The asymptotic covariance approach shows strong correlation with simulated data. It outperforms three alternative methods. The Jaspar clustering yields distinct groups of TFs of the same class. Furthermore, a representative PFM is given for each class. In contrast to most other clustering methods, PFMs with low similarity automatically remain singletons. Availability: A website to compute the similarity and to perform clustering, the source code and Supplementary Material are available at http://mosta.molgen.mpg.d
Application of regulatory sequence analysis and metabolic network analysis to the interpretation of gene expression data
We present two complementary approaches for the interpretation of clusters of
co-regulated genes, such as those obtained from DNA chips and related methods.
Starting from a cluster of genes with similar expression profiles, two basic
questions can be asked:
1. Which mechanism is responsible for the coordinated transcriptional response
of the genes? This question is approached by extracting motifs that are shared
between the upstream sequences of these genes. The motifs extracted are putative
cis-acting regulatory elements.
2. What is the physiological meaning for the cell to express together these
genes? One way to answer the question is to search for potential metabolic
pathways that could be catalyzed by the products of the genes. This can be
done by selecting the genes from the cluster that code for enzymes, and trying
to assemble the catalyzed reactions to form metabolic pathways.
We present tools to answer these two questions, and we illustrate their use with
selected examples in the yeast Saccharomyces cerevisiae. The tools are available
on the web (http://ucmb.ulb.ac.be/bioinformatics/rsa-tools/;
http://www.ebi.ac.uk/research/pfbp/; http://www.soi.city.ac.uk/~msch/)
DNA Familial Binding Profiles Made Easy: Comparison of Various Motif Alignment and Clustering Strategies
Transcription factor (TF) proteins recognize a small number of DNA sequences with high specificity and control the expression of neighbouring genes. The evolution of TF binding preference has been the subject of a number of recent studies, in which generalized binding profiles have been introduced and used to improve the prediction of new target sites. Generalized profiles are generated by aligning and merging the individual profiles of related TFs. However, the distance metrics and alignment algorithms used to compare the binding profiles have not yet been fully explored or optimized. As a result, binding profiles depend on TF structural information and sometimes may ignore important distinctions between subfamilies. Prediction of the identity or the structural class of a protein that binds to a given DNA pattern will enhance the analysis of microarray and ChIP–chip data where frequently multiple putative targets of usually unknown TFs are predicted. Various comparison metrics and alignment algorithms are evaluated (a total of 105 combinations). We find that local alignments are generally better than global alignments at detecting eukaryotic DNA motif similarities, especially when combined with the sum of squared distances or Pearson's correlation coefficient comparison metrics. In addition, multiple-alignment strategies for binding profiles and tree-building methods are tested for their efficiency in constructing generalized binding models. A new method for automatic determination of the optimal number of clusters is developed and applied in the construction of a new set of familial binding profiles which improves upon TF classification accuracy. A software tool, STAMP, is developed to host all tested methods and make them publicly available. This work provides a high quality reference set of familial binding profiles and the first comprehensive platform for analysis of DNA profiles. Detecting similarities between DNA motifs is a key step in the comparative study of transcriptional regulation, and the work presented here will form the basis for tool and method development for future transcriptional modeling studies
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