Transcription factor target prediction using multiple short expression time series from Arabidopsis thaliana

BACKGROUND: The central role of transcription factors (TFs) in higher eukaryotes has led to much interest in deciphering transcriptional regulatory interactions. Even in the best case, experimental identification of TF target genes is error prone, and has been shown to be improved by considering additional forms of evidence such as expression data. Previous expression based methods have not explicitly tried to associate TFs with their targets and therefore largely ignored the treatment specific and time dependent nature of transcription regulation. RESULTS: In this study we introduce CERMT, Covariance based Extraction of Regulatory targets using Multiple Time series. Using simulated and real data we show that using multiple expression time series, selecting treatments in which the TF responds, allowing time shifts between TFs and their targets and using covariance to identify highly responding genes appear to be a good strategy. We applied our method to published TF - target gene relationships determined using expression profiling on TF mutants and show that in most cases we obtain significant target gene enrichment and in half of the cases this is sufficient to deliver a usable list of high-confidence target genes. CONCLUSION: CERMT could be immediately useful in refining possible target genes of candidate TFs using publicly available data, particularly for organisms lacking comprehensive TF binding data. In the future, we believe its incorporation with other forms of evidence may improve integrative genome-wide predictions of transcriptional networks

Homoeologs: What Are They and How Do We Infer Them?

The evolutionary history of nearly all flowering plants includes a polyploidization event. Homologous genes resulting from allopolyploidy are commonly referred to as 'homoeologs', although this term has not always been used precisely or consistently in the literature. With several allopolyploid genome sequencing projects under way, there is a pressing need for computational methods for homoeology inference. Here we review the definition of homoeology in historical and modern contexts and propose a precise and testable definition highlighting the connection between homoeologs and orthologs. In the second part, we survey experimental and computational methods of homoeolog inference, considering the strengths and limitations of each approach. Establishing a precise and evolutionarily meaningful definition of homoeology is essential for understanding the evolutionary consequences of polyploidization

Prioritising candidate genes causing QTL using hierarchical orthologous groups.

A key goal in plant biotechnology applications is the identification of genes associated to particular phenotypic traits (for example: yield, fruit size, root length). Quantitative Trait Loci (QTL) studies identify genomic regions associated with a trait of interest. However, to infer potential causal genes in these regions, each of which can contain hundreds of genes, these data are usually intersected with prior functional knowledge of the genes. This process is however laborious, particularly if the experiment is performed in a non-model species, and the statistical significance of the inferred candidates is typically unknown. This paper introduces QTLSearch, a method and software tool to search for candidate causal genes in QTL studies by combining Gene Ontology annotations across many species, leveraging hierarchical orthologous groups. The usefulness of this approach is demonstrated by re-analysing two metabolic QTL studies: one in Arabidopsis thaliana, the other in Oryza sativa subsp. indica. Even after controlling for statistical significance, QTLSearch inferred potential causal genes for more QTL than BLAST-based functional propagation against UniProtKB/Swiss-Prot, and for more QTL than in the original studies. QTLSearch is distributed under the LGPLv3 license. It is available to install from the Python Package Index (as qtlsearch), with the source available from https://bitbucket.org/alex-warwickvesztrocy/qtlsearch. Supplementary data are available at Bioinformatics online

pcaMethods - a bioconductor package providing PCA methods for incomplete data

pcaMethods is a Bioconductor compliant library for computing principal component analysis (PCA) on incomplete data sets. The results can be analyzed directly or used to estimate missing values to enable the use of missing value sensitive statistical methods. The package was mainly developed with microarray and metabolite data sets in mind, but can be applied to any other incomplete data set as well

Prioritising candidate genes causing QTL using hierarchical orthologous groups

Motivation: A key goal in plant biotechnology applications is the identification of genes associated to particular phenotypic traits (for example: yield, fruit size, root length). Quantitative Trait Loci (QTL) studies identify genomic regions associated with a trait of interest. However, to infer potential causal genes in these regions, each of which can contain hundreds of genes, these data are usually intersected with prior functional knowledge of the genes. This process is however laborious, particularly if the experiment is performed in a non-model species, and the statistical significance of the inferred candidates is typically unknown. // Results: This paper introduces QTLSearch, a method and software tool to search for candidate causal genes in QTL studies by combining Gene Ontology annotations across many species, leveraging hierarchical orthologous groups. The usefulness of this approach is demonstrated by re-analysing two metabolic QTL studies: one in Arabidopsis thaliana, the other in Oryza sativa subsp. indica. Even after controlling for statistical significance, QTLSearch inferred potential causal genes for more QTL than BLAST-based functional propagation against UniProtKB/Swiss-Prot, and for more QTL than in the original studies. // Availability and implementation: QTLSearch is distributed under the LGPLv3 license. It is available to install from the Python Package Index (as qtlsearch), with the source available from https://bitbucket.org/alex-warwickvesztrocy/qtlsearch

TargetSearch - a Bioconductor package for the efficient preprocessing of GC-MS metabolite profiling data

Background: Metabolite profiling, the simultaneous quantification of multiple metabolites in an experiment, is becoming increasingly popular, particularly with the rise of systems-level biology. The workhorse in this field is gas-chromatography hyphenated with mass spectrometry (GC-MS). The high-throughput of this technology coupled with a demand for large experiments has led to data pre-processing, i.e. the quantification of metabolites across samples, becoming a major bottleneck. Existing software has several limitations, including restricted maximum sample size, systematic errors and low flexibility. However, the biggest limitation is that the resulting data usually require extensive hand-curation, which is subjective and can typically take several days to weeks. Results: We introduce the TargetSearch package, an open source tool which is a flexible and accurate method for pre-processing even very large numbers of GC-MS samples within hours. We developed a novel strategy to iteratively correct and update retention time indices for searching and identifying metabolites. The package is written in the R programming language with computationally intensive functions written in C for speed and performance. The package includes a graphical user interface to allow easy use by those unfamiliar with R. Conclusions: TargetSearch allows fast and accurate data pre-processing for GC-MS experiments and overcomes the sample number limitations and manual curation requirements of existing software. We validate our method by carrying out an analysis against both a set of known chemical standard mixtures and of a biological experiment. In addition we demonstrate its capabilities and speed by comparing it with other GC-MS pre-processing tools. We believe this package will greatly ease current bottlenecks and facilitate the analysis of metabolic profiling data

Phylogenetic approaches to identifying fragments of the same gene, with application to the wheat genome.

As the time and cost of sequencing decrease, the number of available genomes and transcriptomes rapidly increases. Yet the quality of the assemblies and the gene annotations varies considerably and often remains poor, affecting downstream analyses. This is particularly true when fragments of the same gene are annotated as distinct genes, which may cause them to be mistaken as paralogs. In this study, we introduce two novel phylogenetic tests to infer non-overlapping or partially overlapping genes that are in fact parts of the same gene. One approach collapses branches with low bootstrap support and the other computes a likelihood ratio test. We extensively validated these methods by (i) introducing and recovering fragmentation on the bread wheat, Triticum aestivum cv. Chinese Spring, chromosome 3B; (ii) by applying the methods to the low-quality 3B assembly and validating predictions against the high-quality 3B assembly; and (iii) by comparing the performance of the proposed methods to the performance of existing methods, namely Ensembl Compara and ESPRIT. Application of this combination to a draft shotgun assembly of the entire bread wheat genome revealed 1221 pairs of genes that are highly likely to be fragments of the same gene. Our approach demonstrates the power of fine-grained evolutionary inferences across multiple species to improving genome assemblies and annotations. An open source software tool is available at https://github.com/DessimozLab/esprit2. Supplementary data are available at Bioinformatics online

The OMA orthology database in 2015: function predictions, better plant support, synteny view and other improvements

The Orthologous Matrix (OMA) project is a method and associated database inferring evolutionary relationships amongst currently 1706 complete proteomes (i.e. the protein sequence associated for every protein-coding gene in all genomes). In this update article, we present six major new developments in OMA: (i) a new web interface; (ii) Gene Ontology function predictions as part of the OMA pipeline; (iii) better support for plant genomes and in particular homeologs in the wheat genome; (iv) a new synteny viewer providing the genomic context of orthologs; (v) statically computed hierarchical orthologous groups subsets downloadable in OrthoXML format; and (vi) possibility to export parts of the all-against-all computations and to combine them with custom data for ‘client-side' orthology prediction. OMA can be accessed through the OMA Browser and various programmatic interfaces at http://omabrowser.or

The OMA orthology database in 2018: retrieving evolutionary relationships among all domains of life through richer web and programmatic interfaces.

The Orthologous Matrix (OMA) is a leading resource to relate genes across many species from all of life. In this update paper, we review the recent algorithmic improvements in the OMA pipeline, describe increases in species coverage (particularly in plants and early-branching eukaryotes) and introduce several new features in the OMA web browser. Notable improvements include: (i) a scalable, interactive viewer for hierarchical orthologous groups; (ii) protein domain annotations and domain-based links between orthologous groups; (iii) functionality to retrieve phylogenetic marker genes for a subset of species of interest; (iv) a new synteny dot plot viewer; and (v) an overhaul of the programmatic access (REST API and semantic web), which will facilitate incorporation of OMA analyses in computational pipelines and integration with other bioinformatic resources. OMA can be freely accessed at https://omabrowser.org

Consolidating metabolite identifiers to enable contextual and multi-platform metabolomics data analysis

<p>Abstract</p> <p>Background</p> <p>Analysis of data from high-throughput experiments depends on the availability of well-structured data that describe the assayed biomolecules. Procedures for obtaining and organizing such meta-data on genes, transcripts and proteins have been streamlined in many data analysis packages, but are still lacking for metabolites. Chemical identifiers are notoriously incoherent, encompassing a wide range of different referencing schemes with varying scope and coverage. Online chemical databases use multiple types of identifiers in parallel but lack a common primary key for reliable database consolidation. Connecting identifiers of analytes found in experimental data with the identifiers of their parent metabolites in public databases can therefore be very laborious.</p> <p>Results</p> <p>Here we present a strategy and a software tool for integrating metabolite identifiers from local reference libraries and public databases that do not depend on a single common primary identifier. The program constructs groups of interconnected identifiers of analytes and metabolites to obtain a local metabolite-centric SQLite database. The created database can be used to map in-house identifiers and synonyms to external resources such as the KEGG database. New identifiers can be imported and directly integrated with existing data. Queries can be performed in a flexible way, both from the command line and from the statistical programming environment R, to obtain data set tailored identifier mappings.</p> <p>Conclusions</p> <p>Efficient cross-referencing of metabolite identifiers is a key technology for metabolomics data analysis. We provide a practical and flexible solution to this task and an open-source program, the metabolite masking tool (MetMask), available at <url>http://metmask.sourceforge.net</url>, that implements our ideas.</p