SUMMARY: Statistical dependencies are present in a variety of sequence data, but are not discernible from traditional sequence logos. Here, we present the R package DepLogo for visualizing inter-position dependencies in aligned sequence data as dependency logos. Dependency logos make dependency structures, which correspond to regular co-occurrences of symbols at dependent positions, visually perceptible. To this end, sequences are partitioned based on their symbols at highly dependent positions as measured by mutual information, and each partition obtains its own visual representation. We illustrate the utility of the DepLogo package in several use cases generating dependency logos from DNA, RNA and protein sequences. AVAILABILITY AND IMPLEMENTATION: The DepLogo R package is available from CRAN and its source code is available at https://github.com/Jstacs/DepLogo. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: Genome annotation is of key importance in many research questions. The identification of protein-coding genes is often based on transcriptome sequencing data, ab-initio or homology-based prediction. Recently, it was demonstrated that intron position conservation improves homology-based gene prediction, and that experimental data improves ab-initio gene prediction. RESULTS: Here, we present an extension of the gene prediction program GeMoMa that utilizes amino acid sequence conservation, intron position conservation and optionally RNA-seq data for homology-based gene prediction. We show on published benchmark data for plants, animals and fungi that GeMoMa performs better than the gene prediction programs BRAKER1, MAKER2, and CodingQuarry, and purely RNA-seq-based pipelines for transcript identification. In addition, we demonstrate that using multiple reference organisms may help to further improve the performance of GeMoMa. Finally, we apply GeMoMa to four nematode species and to the recently published barley reference genome indicating that current annotations of protein-coding genes may be refined using GeMoMa predictions. CONCLUSIONS: GeMoMa might be of great utility for annotating newly sequenced genomes but also for finding homologs of a specific gene or gene family. GeMoMa has been published under GNU GPL3 and is freely available at http://www.jstacs.de/index.php/GeMoMa .

Abstract Summary: Precision-recall (PR) and receiver operating characteristic (ROC) curves are valuable measures of classifier performance. Here, we present the R-package PRROC, which allows for computing and visualizing both PR and ROC curves. In contrast to available R-packages, PRROC allows for computing PR and ROC curves and areas under these curves for soft-labeled data using a continuous interpolation between the points of PR curves. In addition, PRROC provides a generic plot function for generating publication-quality graphics of PR and ROC curves. Availability and implementation: PRROC is available from CRAN and is licensed under GPL 3. Contact: [email protected]

BACKGROUND: For three decades, sequence logos are the de facto standard for the visualization of sequence motifs in biology and bioinformatics. Reasons for this success story are their simplicity and clarity. The number of inferred and published motifs grows with the number of data sets and motif extraction algorithms. Hence, it becomes more and more important to perceive differences between motifs. However, motif differences are hard to detect from individual sequence logos in case of multiple motifs for one transcription factor, highly similar binding motifs of different transcription factors, or multiple motifs for one protein domain. RESULTS: Here, we present DiffLogo, a freely available, extensible, and user-friendly R package for visualizing motif differences. DiffLogo is capable of showing differences between DNA motifs as well as protein motifs in a pair-wise manner resulting in publication-ready figures. In case of more than two motifs, DiffLogo is capable of visualizing pair-wise differences in a tabular form. Here, the motifs are ordered by similarity, and the difference logos are colored for clarity. We demonstrate the benefit of DiffLogo on CTCF motifs from different human cell lines, on E-box motifs of three basic helix-loop-helix transcription factors as examples for comparison of DNA motifs, and on F-box domains from three different families as example for comparison of protein motifs. CONCLUSIONS: DiffLogo provides an intuitive visualization of motif differences. It enables the illustration and investigation of differences between highly similar motifs such as binding patterns of transcription factors for different cell types, treatments, and algorithmic approaches.

In this paper we introduce an extension of the Traveling Salesman Problem (TSP), which is motivated by an important application in bioinformatics. In contrast to the TSP the costs do not only depend on each pair of two nodes traversed in succession in a cycle but on each triple of nodes traversed in succession. This problem can be formulated as optimizing a quadratic objective function over the traveling salesman polytope, so we call the combinatorial optimization problem quadratic TSP (QTSP). Besides its application in bioinformatics, the QTSP is a generalization of the Angular-Metric TSP and the TSP with reload costs. Apart from the TSP with quadratic cost structure we also consider the related Cycle Cover Problem with quadratic objective function (QCCP). In this work we present three exact solution approaches and several heuristics for the QTSP. The first exact approach is based on a polynomial transformation to a TSP, which is then solved by standard software. The second one is a branch-and-bound algorithm that relies on combinatorial bounds. The best exact algorithm is a branch-and-cut approach based on an integer programming formulation with problem-specific cutting planes. All heuristical approaches are extensions of classic heuristics for the TSP. Finally, we compare all algorithms on real-world instances from bioinformatics and on randomly generated instances. In these tests, the branch-and-cut approach turned out to be superior for solving the real-world instances from bioinformatics. Instances with up to 100 nodes could be solved to optimality in about ten minutes.

Transcription factors are a main component of gene regulation as they activate or repress gene expression by binding to specific binding sites in promoters. The de-novo discovery of transcription factor binding sites in target regions obtained by wet-lab experiments is a challenging problem in computational biology, which has not been fully solved yet. Here, we present a de-novo motif discovery tool called Dispom for finding differentially abundant transcription factor binding sites that models existing positional preferences of binding sites and adjusts the length of the motif in the learning process. Evaluating Dispom, we find that its prediction performance is superior to existing tools for de-novo motif discovery for 18 benchmark data sets with planted binding sites, and for a metazoan compendium based on experimental data from micro-array, ChIP-chip, ChIP-DSL, and DamID as well as Gene Ontology data. Finally, we apply Dispom to find binding sites differentially abundant in promoters of auxin-responsive genes extracted from Arabidopsis thaliana microarray data, and we find a motif that can be interpreted as a refined auxin responsive element predominately positioned in the 250-bp region upstream of the transcription start site. Using an independent data set of auxin-responsive genes, we find in genome-wide predictions that the refined motif is more specific for auxin-responsive genes than the canonical auxin-responsive element. In general, Dispom can be used to find differentially abundant motifs in sequences of any origin. However, the positional distribution learned by Dispom is especially beneficial if all sequences are aligned to some anchor point like the transcription start site in case of promoter sequences. We demonstrate that the combination of searching for differentially abundant motifs and inferring a position distribution from the data is beneficial for de-novo motif discovery. Hence, we make the tool freely available as a component of the open-source Java framework Jstacs and as a stand-alone application at http://www.jstacs.de/index.php/Dispom.

BACKGROUND: One of the challenges of bioinformatics remains the recognition of short signal sequences in genomic DNA such as donor or acceptor splice sites, splicing enhancers or silencers, translation initiation sites, transcription start sites, transcription factor binding sites, nucleosome binding sites, miRNA binding sites, or insulator binding sites. During the last decade, a wealth of algorithms for the recognition of such DNA sequences has been developed and compared with the goal of improving their performance and to deepen our understanding of the underlying cellular processes. Most of these algorithms are based on statistical models belonging to the family of Markov random fields such as position weight matrix models, weight array matrix models, Markov models of higher order, or moral Bayesian networks. While in many comparative studies different learning principles or different statistical models have been compared, the influence of choosing different prior distributions for the model parameters when using different learning principles has been overlooked, and possibly lead to questionable conclusions. RESULTS: With the goal of allowing direct comparisons of different learning principles for models from the family of Markov random fields based on the same a-priori information, we derive a generalization of the commonly-used product-Dirichlet prior. We find that the derived prior behaves like a Gaussian prior close to the maximum and like a Laplace prior in the far tails. In two case studies, we illustrate the utility of the derived prior for a direct comparison of different learning principles with different models for the recognition of binding sites of the transcription factor Sp1 and human donor splice sites. CONCLUSIONS: We find that comparisons of different learning principles using the same a-priori information can lead to conclusions different from those of previous studies in which the effect resulting from different priors has been neglected. We implement the derived prior is implemented in the open-source library Jstacs to enable an easy application to comparative studies of different learning principles in the field of sequence analysis.

BACKGROUND: The recognition of functional binding sites in genomic DNA remains one of the fundamental challenges of genome research. During the last decades, a plethora of different and well-adapted models has been developed, but only little attention has been payed to the development of different and similarly well-adapted learning principles. Only recently it was noticed that discriminative learning principles can be superior over generative ones in diverse bioinformatics applications, too. RESULTS: Here, we propose a generalization of generative and discriminative learning principles containing the maximum likelihood, maximum a posteriori, maximum conditional likelihood, maximum supervised posterior, generative-discriminative trade-off, and penalized generative-discriminative trade-off learning principles as special cases, and we illustrate its efficacy for the recognition of vertebrate transcription factor binding sites. CONCLUSIONS: We find that the proposed learning principle helps to improve the recognition of transcription factor binding sites, enabling better computational approaches for extracting as much information as possible from valuable wet-lab data. We make all implementations available in the open-source library Jstacs so that this learning principle can be easily applied to other classification problems in the field of genome and epigenome analysis.

MOTIVATION: Array-based analysis of chromatin immunoprecipitation (ChIP-chip) data is a powerful technique for identifying DNA target regions of individual transcription factors. The identification of these target regions from comprehensive promoter array ChIP-chip data is challenging. Here, three approaches for the identification of transcription factor target genes from promoter array ChIP-chip data are presented. We compare (i) a standard log-fold-change analysis (LFC); (ii) a basic method based on a Hidden Markov Model (HMM); and (iii) a new extension of the HMM approach to an HMM with scaled transition matrices (SHMM) that incorporates information about the relative orientation of adjacent gene pairs on DNA. RESULTS: All three methods are applied to different promoter array ChIP-chip datasets of the yeast Saccharomyces cerevisiae and the important model plant Arabidopsis thaliana to compare the prediction of transcription factor target genes. In the context of the yeast cell cycle, common target genes bound by the transcription factors ACE2 and SWI5, and ACE2 and FKH2 are identified and evaluated using the Saccharomyces Genome Database. Regarding A.thaliana, target genes of the seed-specific transcription factor ABI3 are predicted and evaluate based on publicly available gene expression profiles and transient assays performed in the wet laboratory experiments. The application of the novel SHMM to these two different promoter array ChIP-chip datasets leads to an improved identification of transcription factor target genes in comparison to the two standard approaches LFC and HMM. AVAILABILITY: The software of LFC, HMM and SHMM, the ABI3 ChIP-chip dataset, and Supplementary Material can be downloaded from http://dig.ipk-gatersleben.de/SHMMs/ChIPchip/ChIPchip.html.