8,937 research outputs found
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
The EM Algorithm and the Rise of Computational Biology
In the past decade computational biology has grown from a cottage industry
with a handful of researchers to an attractive interdisciplinary field,
catching the attention and imagination of many quantitatively-minded
scientists. Of interest to us is the key role played by the EM algorithm during
this transformation. We survey the use of the EM algorithm in a few important
computational biology problems surrounding the "central dogma"; of molecular
biology: from DNA to RNA and then to proteins. Topics of this article include
sequence motif discovery, protein sequence alignment, population genetics,
evolutionary models and mRNA expression microarray data analysis.Comment: Published in at http://dx.doi.org/10.1214/09-STS312 the Statistical
Science (http://www.imstat.org/sts/) by the Institute of Mathematical
Statistics (http://www.imstat.org
Beyond position weight matrices: nucleotide correlations in transcription factor binding sites and their description
The identification of transcription factor binding sites (TFBSs) on genomic
DNA is of crucial importance for understanding and predicting regulatory
elements in gene networks. TFBS motifs are commonly described by Position
Weight Matrices (PWMs), in which each DNA base pair independently contributes
to the transcription factor (TF) binding, despite mounting evidence of
interdependence between base pairs positions. The recent availability of
genome-wide data on TF-bound DNA regions offers the possibility to revisit this
question in detail for TF binding {\em in vivo}. Here, we use available fly and
mouse ChIPseq data, and show that the independent model generally does not
reproduce the observed statistics of TFBS, generalizing previous observations.
We further show that TFBS description and predictability can be systematically
improved by taking into account pairwise correlations in the TFBS via the
principle of maximum entropy. The resulting pairwise interaction model is
formally equivalent to the disordered Potts models of statistical mechanics and
it generalizes previous approaches to interdependent positions. Its structure
allows for co-variation of two or more base pairs, as well as secondary motifs.
Although models consisting of mixtures of PWMs also have this last feature, we
show that pairwise interaction models outperform them. The significant pairwise
interactions are found to be sparse and found dominantly between consecutive
base pairs. Finally, the use of a pairwise interaction model for the
identification of TFBSs is shown to give significantly different predictions
than a model based on independent positions
Measuring reproducibility of high-throughput experiments
Reproducibility is essential to reliable scientific discovery in
high-throughput experiments. In this work we propose a unified approach to
measure the reproducibility of findings identified from replicate experiments
and identify putative discoveries using reproducibility. Unlike the usual
scalar measures of reproducibility, our approach creates a curve, which
quantitatively assesses when the findings are no longer consistent across
replicates. Our curve is fitted by a copula mixture model, from which we derive
a quantitative reproducibility score, which we call the "irreproducible
discovery rate" (IDR) analogous to the FDR. This score can be computed at each
set of paired replicate ranks and permits the principled setting of thresholds
both for assessing reproducibility and combining replicates. Since our approach
permits an arbitrary scale for each replicate, it provides useful descriptive
measures in a wide variety of situations to be explored. We study the
performance of the algorithm using simulations and give a heuristic analysis of
its theoretical properties. We demonstrate the effectiveness of our method in a
ChIP-seq experiment.Comment: Published in at http://dx.doi.org/10.1214/11-AOAS466 the Annals of
Applied Statistics (http://www.imstat.org/aoas/) by the Institute of
Mathematical Statistics (http://www.imstat.org
Recommended from our members
SCALE method for single-cell ATAC-seq analysis via latent feature extraction.
Single-cell ATAC-seq (scATAC-seq) profiles the chromatin accessibility landscape at single cell level, thus revealing cell-to-cell variability in gene regulation. However, the high dimensionality and sparsity of scATAC-seq data often complicate the analysis. Here, we introduce a method for analyzing scATAC-seq data, called Single-Cell ATAC-seq analysis via Latent feature Extraction (SCALE). SCALE combines a deep generative framework and a probabilistic Gaussian Mixture Model to learn latent features that accurately characterize scATAC-seq data. We validate SCALE on datasets generated on different platforms with different protocols, and having different overall data qualities. SCALE substantially outperforms the other tools in all aspects of scATAC-seq data analysis, including visualization, clustering, and denoising and imputation. Importantly, SCALE also generates interpretable features that directly link to cell populations, and can potentially reveal batch effects in scATAC-seq experiments
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
- …