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GADEM: a genetic algorithm guided formation of spaced dyads coupled with an EM algorithm for motif discovery.

ABSTRACT: Genome-wide analyses of protein binding sites generate large amounts of data; a ChIP dataset might contain 10,000 sites. Unbiased motif discovery in such datasets is not generally feasible using current methods that employ probabilistic models. We propose an efficient method, GADEM, which combines spaced dyads and an expectation-maximization (EM) algorithm. Candidate words (four to six nucleotides) for constructing spaced dyads are prioritized by their degree of overrepresentation in the input sequence data. Spaced dyads are converted into starting position weight matrices (PWMs). GADEM then employs a genetic algorithm (GA), with an embedded EM algorithm to improve starting PWMs, to guide the evolution of a population of spaced dyads toward one whose entropy scores are more statistically significant. Spaced dyads whose entropy scores reach a pre-specified significance threshold are declared motifs. GADEM performed comparably with MEME on 500 sets of simulated "ChIP" sequences with embedded known P53 binding sites. The major advantage of GADEM is its computational efficiency on large ChIP datasets compared to competitors. We applied GADEM to six genome-wide ChIP datasets. Approximately, 15 to 30 motifs of various lengths were identified in each dataset. Remarkably, without any prior motif information, the expected known motif (e.g., P53 in P53 data) was identified every time. GADEM discovered motifs of various lengths (6-40 bp) and characteristics in these datasets containing from 0.5 to >13 million nucleotides with run times of 5 to 96 h. GADEM can be viewed as an extension of the well-known MEME algorithm and is an efficient tool for de novo motif discovery in large-scale genome-wide data. The GADEM software is available at (www.niehs.nih.gov/research/resources/software/GADEM/).

SUBMITTER: Li L

PROVIDER: S-EPMC2756050 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:MOTIVATION:Most de novo motif identification methods optimize the motif model first and then separately test the statistical significance of the motif score. In the first stage, a motif abundance parameter needs to be specified or modeled. In the second stage, a Z-score or P-value is used as the test statistic. Error rates under multiple comparisons are not fully considered. METHODOLOGY:We propose a simple but novel approach, fdrMotif, that selects as many binding sites as possible while controlling a user-specified false discovery rate (FDR). Unlike existing iterative methods, fdrMotif combines model optimization [e.g. position weight matrix (PWM)] and significance testing at each step. By monitoring the proportion of binding sites selected in many sets of background sequences, fdrMotif controls the FDR in the original data. The model is then updated using an expectation (E)- and maximization (M)-like procedure. We propose a new normalization procedure in the E-step for updating the model. This process is repeated until either the model converges or the number of iterations exceeds a maximum. RESULTS:Simulation studies suggest that our normalization procedure assigns larger weights to the binding sites than do two other commonly used normalization procedures. Furthermore, fdrMotif requires only a user-specified FDR and an initial PWM. When tested on 542 high confidence experimental p53 binding loci, fdrMotif identified 569 p53 binding sites in 505 (93.2%) sequences. In comparison, MEME identified more binding sites but in fewer ChIP sequences than fdrMotif. When tested on 500 sets of simulated 'ChIP' sequences with embedded known p53 binding sites, fdrMotif, compared to MEME, has higher sensitivity with similar positive predictive value. Furthermore, fdrMotif is robust to noise: it selected nearly identical binding sites in data adulterated with 50% added background sequences and the unadulterated data. We suggest that fdrMotif represents an improvement over MEME. AVAILABILITY:C code can be found at: http://www.niehs.nih.gov/research/resources/software/fdrMotif/.

Project description:BackgroundMotif discovery aims to detect short, highly conserved patterns in a collection of unaligned DNA or protein sequences. Discriminative motif finding algorithms aim to increase the sensitivity and selectivity of motif discovery by utilizing a second set of sequences, and searching only for patterns that can differentiate the two sets of sequences. Potential applications of discriminative motif discovery include discovering transcription factor binding site motifs in ChIP-chip data and finding protein motifs involved in thermal stability using sets of orthologous proteins from thermophilic and mesophilic organisms.ResultsWe describe DEME, a discriminative motif discovery algorithm for use with protein and DNA sequences. Input to DEME is two sets of sequences; a "positive" set and a "negative" set. DEME represents motifs using a probabilistic model, and uses a novel combination of global and local search to find the motif that optimally discriminates between the two sets of sequences. DEME is unique among discriminative motif finders in that it uses an informative Bayesian prior on protein motif columns, allowing it to incorporate prior knowledge of residue characteristics. We also introduce four, synthetic, discriminative motif discovery problems that are designed for evaluating discriminative motif finders in various biologically motivated contexts. We test DEME using these synthetic problems and on two biological problems: finding yeast transcription factor binding motifs in ChIP-chip data, and finding motifs that discriminate between groups of thermophilic and mesophilic orthologous proteins.ConclusionUsing artificial data, we show that DEME is more effective than a non-discriminative approach when there are "decoy" motifs or when a variant of the motif is present in the "negative" sequences. With real data, we show that DEME is as good, but not better than non-discriminative algorithms at discovering yeast transcription factor binding motifs. We also show that DEME can find highly informative thermal-stability protein motifs. Binaries for the stand-alone program DEME is free for academic use and is available at http://bioinformatics.org.au/deme/

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GADEM: a genetic algorithm guided formation of spaced dyads coupled with an EM algorithm for motif discovery.

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