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1.  CGKB: an annotation knowledge base for cowpea (Vigna unguiculata L.) methylation filtered genomic genespace sequences 
BMC Bioinformatics  2007;8:129.
Background
Cowpea [Vigna unguiculata (L.) Walp.] is one of the most important food and forage legumes in the semi-arid tropics because of its ability to tolerate drought and grow on poor soils. It is cultivated mostly by poor farmers in developing countries, with 80% of production taking place in the dry savannah of tropical West and Central Africa. Cowpea is largely an underexploited crop with relatively little genomic information available for use in applied plant breeding. The goal of the Cowpea Genomics Initiative (CGI), funded by the Kirkhouse Trust, a UK-based charitable organization, is to leverage modern molecular genetic tools for gene discovery and cowpea improvement. One aspect of the initiative is the sequencing of the gene-rich region of the cowpea genome (termed the genespace) recovered using methylation filtration technology and providing annotation and analysis of the sequence data.
Description
CGKB, Cowpea Genespace/Genomics Knowledge Base, is an annotation knowledge base developed under the CGI. The database is based on information derived from 298,848 cowpea genespace sequences (GSS) isolated by methylation filtering of genomic DNA. The CGKB consists of three knowledge bases: GSS annotation and comparative genomics knowledge base, GSS enzyme and metabolic pathway knowledge base, and GSS simple sequence repeats (SSRs) knowledge base for molecular marker discovery. A homology-based approach was applied for annotations of the GSS, mainly using BLASTX against four public FASTA formatted protein databases (NCBI GenBank Proteins, UniProtKB-Swiss-Prot, UniprotKB-PIR (Protein Information Resource), and UniProtKB-TrEMBL). Comparative genome analysis was done by BLASTX searches of the cowpea GSS against four plant proteomes from Arabidopsis thaliana, Oryza sativa, Medicago truncatula, and Populus trichocarpa. The possible exons and introns on each cowpea GSS were predicted using the HMM-based Genscan gene predication program and the potential domains on annotated GSS were analyzed using the HMMER package against the Pfam database. The annotated GSS were also assigned with Gene Ontology annotation terms and integrated with 228 curated plant metabolic pathways from the Arabidopsis Information Resource (TAIR) knowledge base. The UniProtKB-Swiss-Prot ENZYME database was used to assign putative enzymatic function to each GSS. Each GSS was also analyzed with the Tandem Repeat Finder (TRF) program in order to identify potential SSRs for molecular marker discovery. The raw sequence data, processed annotation, and SSR results were stored in relational tables designed in key-value pair fashion using a PostgreSQL relational database management system. The biological knowledge derived from the sequence data and processed results are represented as views or materialized views in the relational database management system. All materialized views are indexed for quick data access and retrieval. Data processing and analysis pipelines were implemented using the Perl programming language. The web interface was implemented in JavaScript and Perl CGI running on an Apache web server. The CPU intensive data processing and analysis pipelines were run on a computer cluster of more than 30 dual-processor Apple XServes. A job management system called Vela was created as a robust way to submit large numbers of jobs to the Portable Batch System (PBS).
Conclusion
CGKB is an integrated and annotated resource for cowpea GSS with features of homology-based and HMM-based annotations, enzyme and pathway annotations, GO term annotation, toolkits, and a large number of other facilities to perform complex queries. The cowpea GSS, chloroplast sequences, mitochondrial sequences, retroelements, and SSR sequences are available as FASTA formatted files and downloadable at CGKB. This database and web interface are publicly accessible at .
doi:10.1186/1471-2105-8-129
PMCID: PMC1868039  PMID: 17445272
2.  OntologyWidget – a reusable, embeddable widget for easily locating ontology terms 
BMC Bioinformatics  2007;8:338.
Background
Biomedical ontologies are being widely used to annotate biological data in a computer-accessible, consistent and well-defined manner. However, due to their size and complexity, annotating data with appropriate terms from an ontology is often challenging for experts and non-experts alike, because there exist few tools that allow one to quickly find relevant ontology terms to easily populate a web form.
Results
We have produced a tool, OntologyWidget, which allows users to rapidly search for and browse ontology terms. OntologyWidget can easily be embedded in other web-based applications. OntologyWidget is written using AJAX (Asynchronous JavaScript and XML) and has two related elements. The first is a dynamic auto-complete ontology search feature. As a user enters characters into the search box, the appropriate ontology is queried remotely for terms that match the typed-in text, and the query results populate a drop-down list with all potential matches. Upon selection of a term from the list, the user can locate this term within a generic and dynamic ontology browser, which comprises the second element of the tool. The ontology browser shows the paths from a selected term to the root as well as parent/child tree hierarchies. We have implemented web services at the Stanford Microarray Database (SMD), which provide the OntologyWidget with access to over 40 ontologies from the Open Biological Ontology (OBO) website [1]. Each ontology is updated weekly. Adopters of the OntologyWidget can either use SMD's web services, or elect to rely on their own. Deploying the OntologyWidget can be accomplished in three simple steps: (1) install Apache Tomcat [2] on one's web server, (2) download and install the OntologyWidget servlet stub that provides access to the SMD ontology web services, and (3) create an html (HyperText Markup Language) file that refers to the OntologyWidget using a simple, well-defined format.
Conclusion
We have developed OntologyWidget, an easy-to-use ontology search and display tool that can be used on any web page by creating a simple html description. OntologyWidget provides a rapid auto-complete search function paired with an interactive tree display. We have developed a web service layer that communicates between the web page interface and a database of ontology terms. We currently store 40 of the ontologies from the OBO website [1], as well as a several others. These ontologies are automatically updated on a weekly basis. OntologyWidget can be used in any web-based application to take advantage of the ontologies we provide via web services or any other ontology that is provided elsewhere in the correct format. The full source code for the JavaScript and description of the OntologyWidget is available from .
doi:10.1186/1471-2105-8-338
PMCID: PMC2080642  PMID: 17854506
3.  TF-finder: A software package for identifying transcription factors involved in biological processes using microarray data and existing knowledge base 
BMC Bioinformatics  2010;11:425.
Background
Identification of transcription factors (TFs) involved in a biological process is the first step towards a better understanding of the underlying regulatory mechanisms. However, due to the involvement of a large number of genes and complicated interactions in a gene regulatory network (GRN), identification of the TFs involved in a biology process remains to be very challenging. In reality, the recognition of TFs for a given a biological process can be further complicated by the fact that most eukaryotic genomes encode thousands of TFs, which are organized in gene families of various sizes and in many cases with poor sequence conservation except for small conserved domains. This poses a significant challenge for identification of the exact TFs involved or ranking the importance of a set of TFs to a process of interest. Therefore, new methods for recognizing novel TFs are desperately needed. Although a plethora of methods have been developed to infer regulatory genes using microarray data, it is still rare to find the methods that use existing knowledge base in particular the validated genes known to be involved in a process to bait/guide discovery of novel TFs. Such methods can replace the sometimes-arbitrary process of selection of candidate genes for experimental validation and significantly advance our knowledge and understanding of the regulation of a process.
Results
We developed an automated software package called TF-finder for recognizing TFs involved in a biological process using microarray data and existing knowledge base. TF-finder contains two components, adaptive sparse canonical correlation analysis (ASCCA) and enrichment test, for TF recognition. ASCCA uses positive target genes to bait TFS from gene expression data while enrichment test examines the presence of positive TFs in the outcomes from ASCCA. Using microarray data from salt and water stress experiments, we showed TF-finder is very efficient in recognizing many important TFs involved in salt and drought tolerance as evidenced by the rediscovery of those TFs that have been experimentally validated. The efficiency of TF-finder in recognizing novel TFs was further confirmed by a thorough comparison with a method called Intersection of Coexpression (ICE).
Conclusions
TF-finder can be successfully used to infer novel TFs involved a biological process of interest using publicly available gene expression data and known positive genes from existing knowledge bases. The package for TF-finder includes an R script for ASCCA, a Perl controller, and several Perl scripts for parsing intermediate outputs. The package is available upon request (hairong@mtu.edu). The R code for standalone ASCCA is also available.
doi:10.1186/1471-2105-11-425
PMCID: PMC2930629  PMID: 20704747
4.  BIO::Phylo-phyloinformatic analysis using perl 
BMC Bioinformatics  2011;12:63.
Background
Phyloinformatic analyses involve large amounts of data and metadata of complex structure. Collecting, processing, analyzing, visualizing and summarizing these data and metadata should be done in steps that can be automated and reproduced. This requires flexible, modular toolkits that can represent, manipulate and persist phylogenetic data and metadata as objects with programmable interfaces.
Results
This paper presents Bio::Phylo, a Perl5 toolkit for phyloinformatic analysis. It implements classes and methods that are compatible with the well-known BioPerl toolkit, but is independent from it (making it easy to install) and features a richer API and a data model that is better able to manage the complex relationships between different fundamental data and metadata objects in phylogenetics. It supports commonly used file formats for phylogenetic data including the novel NeXML standard, which allows rich annotations of phylogenetic data to be stored and shared. Bio::Phylo can interact with BioPerl, thereby giving access to the file formats that BioPerl supports. Many methods for data simulation, transformation and manipulation, the analysis of tree shape, and tree visualization are provided.
Conclusions
Bio::Phylo is composed of 59 richly documented Perl5 modules. It has been deployed successfully on a variety of computer architectures (including various Linux distributions, Mac OS X versions, Windows, Cygwin and UNIX-like systems). It is available as open source (GPL) software from http://search.cpan.org/dist/Bio-Phylo
doi:10.1186/1471-2105-12-63
PMCID: PMC3056726  PMID: 21352572
5.  Integrating Diverse Datasets Improves Developmental Enhancer Prediction 
PLoS Computational Biology  2014;10(6):e1003677.
Gene-regulatory enhancers have been identified using various approaches, including evolutionary conservation, regulatory protein binding, chromatin modifications, and DNA sequence motifs. To integrate these different approaches, we developed EnhancerFinder, a two-step method for distinguishing developmental enhancers from the genomic background and then predicting their tissue specificity. EnhancerFinder uses a multiple kernel learning approach to integrate DNA sequence motifs, evolutionary patterns, and diverse functional genomics datasets from a variety of cell types. In contrast with prediction approaches that define enhancers based on histone marks or p300 sites from a single cell line, we trained EnhancerFinder on hundreds of experimentally verified human developmental enhancers from the VISTA Enhancer Browser. We comprehensively evaluated EnhancerFinder using cross validation and found that our integrative method improves the identification of enhancers over approaches that consider a single type of data, such as sequence motifs, evolutionary conservation, or the binding of enhancer-associated proteins. We find that VISTA enhancers active in embryonic heart are easier to identify than enhancers active in several other embryonic tissues, likely due to their uniquely high GC content. We applied EnhancerFinder to the entire human genome and predicted 84,301 developmental enhancers and their tissue specificity. These predictions provide specific functional annotations for large amounts of human non-coding DNA, and are significantly enriched near genes with annotated roles in their predicted tissues and lead SNPs from genome-wide association studies. We demonstrate the utility of EnhancerFinder predictions through in vivo validation of novel embryonic gene regulatory enhancers from three developmental transcription factor loci. Our genome-wide developmental enhancer predictions are freely available as a UCSC Genome Browser track, which we hope will enable researchers to further investigate questions in developmental biology.
Author Summary
The human genome contains an immense amount of non-protein-coding DNA with unknown function. Some of this DNA regulates when, where, and at what levels genes are active during development. Enhancers, one type of regulatory element, are short stretches of DNA that can act as “switches” to turn a gene on or off at specific times in specific cells or tissues. Understanding where in the genome enhancers are located can provide insight into the genetic basis of development and disease. Enhancers are hard to identify, but clues about their locations are found in different types of data including DNA sequence, evolutionary history, and where proteins bind to DNA. Here, we introduce a new tool, called EnhancerFinder, which combines these data to predict the location and activity of enhancers during embryonic development. We trained EnhancerFinder on a large set of functionally validated human enhancers, and it proved to be very accurate. We used EnhancerFinder to predict tens of thousands of enhancers in the human genome and validated several of the predictions near three important developmental genes in mouse or zebrafish. EnhancerFinder's predictions will be useful in understanding functional regions hidden in the vast amounts of human non-coding DNA.
doi:10.1371/journal.pcbi.1003677
PMCID: PMC4072507  PMID: 24967590
6.  The Bio-Community Perl toolkit for microbial ecology 
Bioinformatics  2014;30(13):1926-1927.
Summary: The development of bioinformatic solutions for microbial ecology in Perl is limited by the lack of modules to represent and manipulate microbial community profiles from amplicon and meta-omics studies. Here we introduce Bio-Community, an open-source, collaborative toolkit that extends BioPerl. Bio-Community interfaces with commonly used programs using various file formats, including BIOM, and provides operations such as rarefaction and taxonomic summaries. Bio-Community will help bioinformaticians to quickly piece together custom analysis pipelines and develop novel software.
Availability an implementation: Bio-Community is cross-platform Perl code available from http://search.cpan.org/dist/Bio-Community under the Perl license. A readme file describes software installation and how to contribute.
Contact: f.angly@uq.edu.au
Supplementary information: Supplementary data are available at Bioinformatics online
doi:10.1093/bioinformatics/btu130
PMCID: PMC4071200  PMID: 24618462
7.  trieFinder: an efficient program for annotating Digital Gene Expression (DGE) tags 
BMC Bioinformatics  2014;15(1):329.
Background
Quantification of a transcriptional profile is a useful way to evaluate the activity of a cell at a given point in time. Although RNA-Seq has revolutionized transcriptional profiling, the costs of RNA-Seq are still significantly higher than microarrays, and often the depth of data delivered from RNA-Seq is in excess of what is needed for simple transcript quantification. Digital Gene Expression (DGE) is a cost-effective, sequence-based approach for simple transcript quantification: by sequencing one read per molecule of RNA, this technique can be used to efficiently count transcripts while obviating the need for transcript-length normalization and reducing the total numbers of reads necessary for accurate quantification. Here, we present trieFinder, a program specifically designed to rapidly map, parse, and annotate DGE tags of various lengths against cDNA and/or genomic sequence databases.
Results
The trieFinder algorithm maps DGE tags in a two-step process. First, it scans FASTA files of RefSeq, UniGene, and genomic DNA sequences to create a database of all tags that can be derived from a predefined restriction site. Next, it compares the experimental DGE tags to this tag database, taking advantage of the fact that the tags are stored as a prefix tree, or “trie”, which allows for linear-time searches for exact matches. DGE tags with mismatches are analyzed by recursive calls in the data structure. We find that, in terms of alignment speed, the mapping functionality of trieFinder compares favorably with Bowtie.
Conclusions
trieFinder can quickly provide the user an annotation of the DGE tags from three sources simultaneously, simplifying transcript quantification and novel transcript detection, delivering the data in a simple parsed format, obviating the need to post-process the alignment results. trieFinder is available at http://research.nhgri.nih.gov/software/trieFinder/.
doi:10.1186/1471-2105-15-329
PMCID: PMC4287429  PMID: 25311246
RNA-Seq; Transcriptional profiling; DGE; SAGE
8.  Identification of acquired antimicrobial resistance genes 
Journal of Antimicrobial Chemotherapy  2012;67(11):2640-2644.
Objectives
Identification of antimicrobial resistance genes is important for understanding the underlying mechanisms and the epidemiology of antimicrobial resistance. As the costs of whole-genome sequencing (WGS) continue to decline, it becomes increasingly available in routine diagnostic laboratories and is anticipated to substitute traditional methods for resistance gene identification. Thus, the current challenge is to extract the relevant information from the large amount of generated data.
Methods
We developed a web-based method, ResFinder that uses BLAST for identification of acquired antimicrobial resistance genes in whole-genome data. As input, the method can use both pre-assembled, complete or partial genomes, and short sequence reads from four different sequencing platforms. The method was evaluated on 1862 GenBank files containing 1411 different resistance genes, as well as on 23 de-novo-sequenced isolates.
Results
When testing the 1862 GenBank files, the method identified the resistance genes with an ID = 100% (100% identity) to the genes in ResFinder. Agreement between in silico predictions and phenotypic testing was found when the method was further tested on 23 isolates of five different bacterial species, with available phenotypes. Furthermore, ResFinder was evaluated on WGS chromosomes and plasmids of 30 isolates. Seven of these isolates were annotated to have antimicrobial resistance, and in all cases, annotations were compatible with the ResFinder results.
Conclusions
A web server providing a convenient way of identifying acquired antimicrobial resistance genes in completely sequenced isolates was created. ResFinder can be accessed at www.genomicepidemiology.org. ResFinder will continuously be updated as new resistance genes are identified.
doi:10.1093/jac/dks261
PMCID: PMC3468078  PMID: 22782487
antibiotic resistance; genotype; ResFinder; resistance gene identification
9.  M-Finder: Uncovering functionally associated proteins from interactome data integrated with GO annotations 
Proteome Science  2013;11(Suppl 1):S3.
Background
Protein-protein interactions (PPIs) play a key role in understanding the mechanisms of cellular processes. The availability of interactome data has catalyzed the development of computational approaches to elucidate functional behaviors of proteins on a system level. Gene Ontology (GO) and its annotations are a significant resource for functional characterization of proteins. Because of wide coverage, GO data have often been adopted as a benchmark for protein function prediction on the genomic scale.
Results
We propose a computational approach, called M-Finder, for functional association pattern mining. This method employs semantic analytics to integrate the genome-wide PPIs with GO data. We also introduce an interactive web application tool that visualizes a functional association network linked to a protein specified by a user. The proposed approach comprises two major components. First, the PPIs that have been generated by high-throughput methods are weighted in terms of their functional consistency using GO and its annotations. We assess two advanced semantic similarity metrics which quantify the functional association level of each interacting protein pair. We demonstrate that these measures outperform the other existing methods by evaluating their agreement to other biological features, such as sequence similarity, the presence of common Pfam domains, and core PPIs. Second, the information flow-based algorithm is employed to discover a set of proteins functionally associated with the protein in a query and their links efficiently. This algorithm reconstructs a functional association network of the query protein. The output network size can be flexibly determined by parameters.
Conclusions
M-Finder provides a useful framework to investigate functional association patterns with any protein. This software will also allow users to perform further systematic analysis of a set of proteins for any specific function. It is available online at http://bionet.ecs.baylor.edu/mfinder
doi:10.1186/1477-5956-11-S1-S3
PMCID: PMC3909039  PMID: 24565382
10.  ThioFinder: A Web-Based Tool for the Identification of Thiopeptide Gene Clusters in DNA Sequences 
PLoS ONE  2012;7(9):e45878.
Thiopeptides are a growing class of sulfur-rich, highly modified heterocyclic peptides that are mainly active against Gram-positive bacteria including various drug-resistant pathogens. Recent studies also reveal that many thiopeptides inhibit the proliferation of human cancer cells, further expanding their application potentials for clinical use. Thiopeptide biosynthesis shares a common paradigm, featuring a ribosomally synthesized precursor peptide and conserved posttranslational modifications, to afford a characteristic core system, but differs in tailoring to furnish individual members. Identification of new thiopeptide gene clusters, by taking advantage of increasing information of DNA sequences from bacteria, may facilitate new thiopeptide discovery and enrichment of the unique biosynthetic elements to produce novel drug leads by applying the principle of combinatorial biosynthesis. In this study, we have developed a web-based tool ThioFinder to rapidly identify thiopeptide biosynthetic gene cluster from DNA sequence using a profile Hidden Markov Model approach. Fifty-four new putative thiopeptide biosynthetic gene clusters were found in the sequenced bacterial genomes of previously unknown producing microorganisms. ThioFinder is fully supported by an open-access database ThioBase, which contains the sufficient information of the 99 known thiopeptides regarding the chemical structure, biological activity, producing organism, and biosynthetic gene (cluster) along with the associated genome if available. The ThioFinder website offers researchers a unique resource and great flexibility for sequence analysis of thiopeptide biosynthetic gene clusters. ThioFinder is freely available at http://db-mml.sjtu.edu.cn/ThioFinder/.
doi:10.1371/journal.pone.0045878
PMCID: PMC3454323  PMID: 23029291
11.  MutationFinder: a high-performance system for extracting point mutation mentions from text 
Bioinformatics (Oxford, England)  2007;23(14):1862-1865.
Summary
Discussion of point mutations is ubiquitous in biomedical literature, and manually compiling databases or literature on mutations in specific genes or proteins is tedious. We present an open-source, rule-based system, MutationFinder, for extracting point mutation mentions from text. On blind test data, it achieves nearly perfect precision and a markedly improved recall over a baseline.
Availability
MutationFinder, along with a high-quality gold standard data set, and a scoring script for mutation extraction systems have been made publicly available. Implementations, source code and unit tests are available in Python, Perl and Java. MutationFinder can be used as a stand-alone script, or imported by other applications.
Project URL
http://bionlp.sourceforge.net
Contact
gregcaporaso@gmail.com
doi:10.1093/bioinformatics/btm235
PMCID: PMC2516306  PMID: 17495998
12.  GOLEM: an interactive graph-based gene-ontology navigation and analysis tool 
BMC Bioinformatics  2006;7:443.
Background
The Gene Ontology has become an extremely useful tool for the analysis of genomic data and structuring of biological knowledge. Several excellent software tools for navigating the gene ontology have been developed. However, no existing system provides an interactively expandable graph-based view of the gene ontology hierarchy. Furthermore, most existing tools are web-based or require an Internet connection, will not load local annotations files, and provide either analysis or visualization functionality, but not both.
Results
To address the above limitations, we have developed GOLEM (Gene Ontology Local Exploration Map), a visualization and analysis tool for focused exploration of the gene ontology graph. GOLEM allows the user to dynamically expand and focus the local graph structure of the gene ontology hierarchy in the neighborhood of any chosen term. It also supports rapid analysis of an input list of genes to find enriched gene ontology terms. The GOLEM application permits the user either to utilize local gene ontology and annotations files in the absence of an Internet connection, or to access the most recent ontology and annotation information from the gene ontology webpage. GOLEM supports global and organism-specific searches by gene ontology term name, gene ontology id and gene name.
Conclusion
GOLEM is a useful software tool for biologists interested in visualizing the local directed acyclic graph structure of the gene ontology hierarchy and searching for gene ontology terms enriched in genes of interest. It is freely available both as an application and as an applet at .
doi:10.1186/1471-2105-7-443
PMCID: PMC1618863  PMID: 17032457
13.  Evaluating measures of semantic similarity and relatedness to disambiguate terms in biomedical text 
Journal of biomedical informatics  2013;46(6):10.1016/j.jbi.2013.08.008.
Introduction
In this article, we evaluate a knowledge-based word sense disambiguation method that determines the intended concept associated with an ambiguous word in biomedical text using semantic similarity and relatedness measures. These measures quantify the degree of similarity or relatedness between concepts in the Unified Medical Language System (UMLS). The objective of this work is to develop a method that can disambiguate terms in biomedical text by exploiting similarity and relatedness information extracted from biomedical resources and to evaluate the efficacy of these measure on WSD.
Method
We evaluate our method on a biomedical dataset (MSH-WSD) that contains 203 ambiguous terms and acronyms.
Results
We show that information content-based measures derived from either a corpus or taxonomy obtain a higher disambiguation accuracy than path-based measures or relatedness measures on the MSH-WSD dataset.
Availability
The WSD system is open source and freely available from http://search.cpan.org/dist/UMLS-SenseRelate/. The MSH-WSD dataset is available from the National Library of Medicine http://wsd.nlm.nih.gov.
doi:10.1016/j.jbi.2013.08.008
PMCID: PMC3864022  PMID: 24012881
Natural Language Processing; NLP; Word Sense Disambiguation; WSD; semantic similarity and relatedness; biomedical documents
14.  GO2MSIG, an automated GO based multi-species gene set generator for gene set enrichment analysis 
BMC Bioinformatics  2014;15:146.
Background
Despite the widespread use of high throughput expression platforms and the availability of a desktop implementation of Gene Set Enrichment Analysis (GSEA) that enables non-experts to perform gene set based analyses, the availability of the necessary precompiled gene sets is rare for species other than human.
Results
A software tool (GO2MSIG) was implemented that combines data from various publicly available sources and uses the Gene Ontology (GO) project term relationships to produce GSEA compatible hierarchical GO based gene sets for all species for which association data is available. Annotation sources include the GO association database (which contains data for over 200000 species), the Entrez gene2go table, and various manufacturers’ array annotation files. This enables the creation of gene sets from the most up-to-date annotation data available. Additional features include the ability to restrict by evidence code, to remap gene descriptors, to filter by set size and to speed up repeat queries by caching the GO term hierarchy. Synonymous GO terms are remapped to the version preferred by the GO ontology supplied. The tool can be used in standalone form, or via a web interface. Prebuilt gene set collections constructed from the September 2013 GO release are also available for common species including human. In contrast human GO based sets available from the Broad Institute itself date from 2008.
Conclusions
GO2MSIG enables the bioinformatician and non-bioinformatician alike to generate gene sets required for GSEA analysis for almost any organism for which GO term association data exists. The output gene sets may be used directly within GSEA and do not require knowledge of programming languages such as Perl, R or Python. The output sets can also be used with other analysis software such as ErmineJ that accept gene sets in the same format. Source code can be downloaded and installed locally from http://www.bioinformatics.org/go2msig/releases/ or used via the web interface at http://www.go2msig.org/cgi-bin/go2msig.cgi.
doi:10.1186/1471-2105-15-146
PMCID: PMC4038065  PMID: 24884810
Gene set enrichment analysis (GSEA); GO ontology; Gene set collection; ErmineJ
15.  Simulate_PCR for amplicon prediction and annotation from multiplex, degenerate primers and probes 
BMC Bioinformatics  2014;15:237.
Background
Pairing up primers to amplify desired targets and avoid undesired cross reactions can be a combinatorial challenge. Effective prediction of specificity and inclusivity from multiplexed primers and TaqMan®/Luminex® probes is a critical step in PCR design.
Results
Code is described to identify all primer and probe combinations from a list of unpaired, unordered candidates that should produce a product. It predicts and extracts all amplicon sequences in a large sequence database from a list of primers and probes, allowing degenerate bases and user-specified levels of primer-target mismatch tolerance. Amplicons hit by TaqMan®/Luminex® probes are indicated, and products may be annotated with gene information from NCBI. Fragment length distributions are calculated to predict electrophoretic gel banding patterns.
Conclusions
Simulate_PCR is the only freely available software that can be run from the command line for high throughput applications which can calculate all products from large lists of primers and probes compared to a large sequence database such as nt. It requires no prior knowledge of how primers should be paired. Degenerate bases are allowed and entire amplicon sequences are extracted and annotated with gene information. Examples are provided for sets of TaqMan®/Luminex® PCR signatures predicted to amplify all HIV-1 genomes, all Coronaviridae genomes, and a group of antibiotic resistance genes. The software is a command line perl script freely available as open source.
doi:10.1186/1471-2105-15-237
PMCID: PMC4226945  PMID: 25005023
PCR target prediction software; HIV 1; Coronaviridae; Multiplex PCR; Amplicon prediction; Degenerate PCR; Consensus PCR
16.  nGASP – the nematode genome annotation assessment project 
BMC Bioinformatics  2008;9:549.
Background
While the C. elegans genome is extensively annotated, relatively little information is available for other Caenorhabditis species. The nematode genome annotation assessment project (nGASP) was launched to objectively assess the accuracy of protein-coding gene prediction software in C. elegans, and to apply this knowledge to the annotation of the genomes of four additional Caenorhabditis species and other nematodes. Seventeen groups worldwide participated in nGASP, and submitted 47 prediction sets across 10 Mb of the C. elegans genome. Predictions were compared to reference gene sets consisting of confirmed or manually curated gene models from WormBase.
Results
The most accurate gene-finders were 'combiner' algorithms, which made use of transcript- and protein-alignments and multi-genome alignments, as well as gene predictions from other gene-finders. Gene-finders that used alignments of ESTs, mRNAs and proteins came in second. There was a tie for third place between gene-finders that used multi-genome alignments and ab initio gene-finders. The median gene level sensitivity of combiners was 78% and their specificity was 42%, which is nearly the same accuracy reported for combiners in the human genome. C. elegans genes with exons of unusual hexamer content, as well as those with unusually many exons, short exons, long introns, a weak translation start signal, weak splice sites, or poorly conserved orthologs posed the greatest difficulty for gene-finders.
Conclusion
This experiment establishes a baseline of gene prediction accuracy in Caenorhabditis genomes, and has guided the choice of gene-finders for the annotation of newly sequenced genomes of Caenorhabditis and other nematode species. We have created new gene sets for C. briggsae, C. remanei, C. brenneri, C. japonica, and Brugia malayi using some of the best-performing gene-finders.
doi:10.1186/1471-2105-9-549
PMCID: PMC2651883  PMID: 19099578
17.  Resources for comparing the speed and performance of medical autocoders 
Background
Concept indexing is a popular method for characterizing medical text, and is one of the most important early steps in many data mining efforts. Concept indexing differs from simple word or phrase indexing because concepts are typically represented by a nomenclature code that binds a medical concept to all equivalent representations. A concept search on the term renal cell carcinoma would be expected to find occurrences of hypernephroma, and renal carcinoma (concept equivalents). The purpose of this study is to provide freely available resources to compare speed and performance among different autocoders. These tools consist of: 1) a public domain autocoder written in Perl (a free and open source programming language that installs on any operating system); 2) a nomenclature database derived from the unencumbered subset of the publicly available Unified Medical Language System; 3) a large corpus of autocoded output derived from a publicly available medical text.
Methods
A simple lexical autocoder was written that parses plain-text into a listing of all 1,2,3, and 4-word strings contained in text, assigning a nomenclature code for text strings that match terms in the nomenclature. The nomenclature used is the unencumbered subset of the 2003 Unified Medical Language System (UMLS). The unencumbered subset of UMLS was reduced to exclude homonymous one-word terms and proper names, resulting in a term/code data dictionary containing about a half million medical terms. The Online Mendelian Inheritance in Man (OMIM), a 92+ Megabyte publicly available medical opus, was used as sample medical text for the autocoder.
Results
The autocoding Perl script is remarkably short, consisting of just 38 command lines. The 92+ Megabyte OMIM file was completely autocoded in 869 seconds on a 2.4 GHz processor (less than 10 seconds per Megabyte of text). The autocoded output file (9,540,442 bytes) contains 367,963 coded terms from OMIM and is distributed with this manuscript.
Conclusions
A public domain Perl script is provided that can parse through plain-text files of any length, matching concepts against an external nomenclature. The script and associated files can be used freely to compare the speed and performance of autocoding software.
doi:10.1186/1472-6947-4-8
PMCID: PMC441395  PMID: 15198804
18.  FusionFinder: A Software Tool to Identify Expressed Gene Fusion Candidates from RNA-Seq Data 
PLoS ONE  2012;7(6):e39987.
The hallmarks of many haematological malignancies and solid tumours are chromosomal translocations, which may lead to gene fusions. Recently, next-generation sequencing techniques at the transcriptome level (RNA-Seq) have been used to verify known and discover novel transcribed gene fusions. We present FusionFinder, a Perl-based software designed to automate the discovery of candidate gene fusion partners from single-end (SE) or paired-end (PE) RNA-Seq read data. FusionFinder was applied to data from a previously published analysis of the K562 chronic myeloid leukaemia (CML) cell line. Using FusionFinder we successfully replicated the findings of this study and detected additional previously unreported fusion genes in their dataset, which were confirmed experimentally. These included two isoforms of a fusion involving the genes BRK1 and VHL, whose co-deletion has previously been associated with the prevalence and severity of renal-cell carcinoma. FusionFinder is made freely available for non-commercial use and can be downloaded from the project website (http://bioinformatics.childhealthresearch.org.au/software/fusionfinder/).
doi:10.1371/journal.pone.0039987
PMCID: PMC3384600  PMID: 22761941
19.  TOBFAC: the database of tobacco transcription factors 
BMC Bioinformatics  2008;9:53.
Background
Regulation of gene expression at the level of transcription is a major control point in many biological processes. Transcription factors (TFs) can activate and/or repress the transcriptional rate of target genes and vascular plant genomes devote approximately 7% of their coding capacity to TFs. Global analysis of TFs has only been performed for three complete higher plant genomes – Arabidopsis (Arabidopsis thaliana), poplar (Populus trichocarpa) and rice (Oryza sativa). Presently, no large-scale analysis of TFs has been made from a member of the Solanaceae, one of the most important families of vascular plants. To fill this void, we have analysed tobacco (Nicotiana tabacum) TFs using a dataset of 1,159,022 gene-space sequence reads (GSRs) obtained by methylation filtering of the tobacco genome. An analytical pipeline was developed to isolate TF sequences from the GSR data set. This involved multiple (typically 10–15) independent searches with different versions of the TF family-defining domain(s) (normally the DNA-binding domain) followed by assembly into contigs and verification. Our analysis revealed that tobacco contains a minimum of 2,513 TFs representing all of the 64 well-characterised plant TF families. The number of TFs in tobacco is higher than previously reported for Arabidopsis and rice.
Results
TOBFAC: the database of tobacco transcription factors, is an integrative database that provides a portal to sequence and phylogeny data for the identified TFs, together with a large quantity of other data concerning TFs in tobacco. The database contains an individual page dedicated to each of the 64 TF families. These contain background information, domain architecture via Pfam links, a list of all sequences and an assessment of the minimum number of TFs in this family in tobacco. Downloadable phylogenetic trees of the major families are provided along with detailed information on the bioinformatic pipeline that was used to find all family members. TOBFAC also contains EST data, a list of published tobacco TFs and a list of papers concerning tobacco TFs. The sequences and annotation data are stored in relational tables using a PostgrelSQL relational database management system. The data processing and analysis pipelines used the Perl programming language. The web interface was implemented in JavaScript and Perl CGI running on an Apache web server. The computationally intensive data processing and analysis pipelines were run on an Apple XServe cluster with more than 20 nodes.
Conclusion
TOBFAC is an expandable knowledgebase of tobacco TFs with data currently available for over 2,513 TFs from 64 gene families. TOBFAC integrates available sequence information, phylogenetic analysis, and EST data with published reports on tobacco TF function. The database provides a major resource for the study of gene expression in tobacco and the Solanaceae and helps to fill a current gap in studies of TF families across the plant kingdom. TOBFAC is publicly accessible at .
doi:10.1186/1471-2105-9-53
PMCID: PMC2246155  PMID: 18221524
20.  GeneXplorer: an interactive web application for microarray data visualization and analysis 
BMC Bioinformatics  2004;5:141.
Background
When publishing large-scale microarray datasets, it is of great value to create supplemental websites where either the full data, or selected subsets corresponding to figures within the paper, can be browsed. We set out to create a CGI application containing many of the features of some of the existing standalone software for the visualization of clustered microarray data.
Results
We present GeneXplorer, a web application for interactive microarray data visualization and analysis in a web environment. GeneXplorer allows users to browse a microarray dataset in an intuitive fashion. It provides simple access to microarray data over the Internet and uses only HTML and JavaScript to display graphic and annotation information. It provides radar and zoom views of the data, allows display of the nearest neighbors to a gene expression vector based on their Pearson correlations and provides the ability to search gene annotation fields.
Conclusions
The software is released under the permissive MIT Open Source license, and the complete documentation and the entire source code are freely available for download from CPAN .
doi:10.1186/1471-2105-5-141
PMCID: PMC523853  PMID: 15458579
21.  The pathway ontology – updates and applications 
Background
The Pathway Ontology (PW) developed at the Rat Genome Database (RGD), covers all types of biological pathways, including altered and disease pathways and captures the relationships between them within the hierarchical structure of a directed acyclic graph. The ontology allows for the standardized annotation of rat, and of human and mouse genes to pathway terms. It also constitutes a vehicle for easy navigation between gene and ontology report pages, between reports and interactive pathway diagrams, between pathways directly connected within a diagram and between those that are globally related in pathway suites and suite networks. Surveys of the literature and the development of the Pathway and Disease Portals are important sources for the ongoing development of the ontology. User requests and mapping of pathways in other databases to terms in the ontology further contribute to increasing its content. Recently built automated pipelines use the mapped terms to make available the annotations generated by other groups.
Results
The two released pipelines – the Pathway Interaction Database (PID) Annotation Import Pipeline and the Kyoto Encyclopedia of Genes and Genomes (KEGG) Annotation Import Pipeline, make available over 7,400 and 31,000 pathway gene annotations, respectively. Building the PID pipeline lead to the addition of new terms within the signaling node, also augmented by the release of the RGD “Immune and Inflammatory Disease Portal” at that time. Building the KEGG pipeline lead to a substantial increase in the number of disease pathway terms, such as those within the ‘infectious disease pathway’ parent term category. The ‘drug pathway’ node has also seen increases in the number of terms as well as a restructuring of the node. Literature surveys, disease portal deployments and user requests have contributed and continue to contribute additional new terms across the ontology. Since first presented, the content of PW has increased by over 75%.
Conclusions
Ongoing development of the Pathway Ontology and the implementation of pipelines promote an enriched provision of pathway data. The ontology is freely available for download and use from the RGD ftp site at ftp://rgd.mcw.edu/pub/ontology/pathway/ or from the National Center for Biomedical Ontology (NCBO) BioPortal website at http://bioportal.bioontology.org/ontologies/PW.
doi:10.1186/2041-1480-5-7
PMCID: PMC3922094  PMID: 24499703
Biological pathway; Ontology; Pipeline; Pathway annotations; Pathway diagrams
22.  Toward an automatic method for extracting cancer- and other disease-related point mutations from the biomedical literature 
Bioinformatics  2010;27(3):408-415.
Motivation: A major goal of biomedical research in personalized medicine is to find relationships between mutations and their corresponding disease phenotypes. However, most of the disease-related mutational data are currently buried in the biomedical literature in textual form and lack the necessary structure to allow easy retrieval and visualization. We introduce a high-throughput computational method for the identification of relevant disease mutations in PubMed abstracts applied to prostate (PCa) and breast cancer (BCa) mutations.
Results: We developed the extractor of mutations (EMU) tool to identify mutations and their associated genes. We benchmarked EMU against MutationFinder—a tool to extract point mutations from text. Our results show that both methods achieve comparable performance on two manually curated datasets. We also benchmarked EMU's performance for extracting the complete mutational information and phenotype. Remarkably, we show that one of the steps in our approach, a filter based on sequence analysis, increases the precision for that task from 0.34 to 0.59 (PCa) and from 0.39 to 0.61 (BCa). We also show that this high-throughput approach can be extended to other diseases.
Discussion: Our method improves the current status of disease-mutation databases by significantly increasing the number of annotated mutations. We found 51 and 128 mutations manually verified to be related to PCa and Bca, respectively, that are not currently annotated for these cancer types in the OMIM or Swiss-Prot databases. EMU's retrieval performance represents a 2-fold improvement in the number of annotated mutations for PCa and BCa. We further show that our method can benefit from full-text analysis once there is an increase in Open Access availability of full-text articles.
Availability: Freely available at: http://bioinf.umbc.edu/EMU/ftp.
Contact: mkann@umbc.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btq667
PMCID: PMC3031038  PMID: 21138947
23.  The Ontology Lookup Service, a lightweight cross-platform tool for controlled vocabulary queries 
BMC Bioinformatics  2006;7:97.
Background
With the vast amounts of biomedical data being generated by high-throughput analysis methods, controlled vocabularies and ontologies are becoming increasingly important to annotate units of information for ease of search and retrieval. Each scientific community tends to create its own locally available ontology. The interfaces to query these ontologies tend to vary from group to group. We saw the need for a centralized location to perform controlled vocabulary queries that would offer both a lightweight web-accessible user interface as well as a consistent, unified SOAP interface for automated queries.
Results
The Ontology Lookup Service (OLS) was created to integrate publicly available biomedical ontologies into a single database. All modified ontologies are updated daily. A list of currently loaded ontologies is available online. The database can be queried to obtain information on a single term or to browse a complete ontology using AJAX. Auto-completion provides a user-friendly search mechanism. An AJAX-based ontology viewer is available to browse a complete ontology or subsets of it. A programmatic interface is available to query the webservice using SOAP. The service is described by a WSDL descriptor file available online. A sample Java client to connect to the webservice using SOAP is available for download from SourceForge. All OLS source code is publicly available under the open source Apache Licence.
Conclusion
The OLS provides a user-friendly single entry point for publicly available ontologies in the Open Biomedical Ontology (OBO) format. It can be accessed interactively or programmatically at .
doi:10.1186/1471-2105-7-97
PMCID: PMC1420335  PMID: 16507094
24.  FISH Finder: a high-throughput tool for analyzing FISH images 
Bioinformatics  2011;27(7):933-938.
Motivation: Fluorescence in situ hybridization (FISH) is used to study the organization and the positioning of specific DNA sequences within the cell nucleus. Analyzing the data from FISH images is a tedious process that invokes an element of subjectivity. Automated FISH image analysis offers savings in time as well as gaining the benefit of objective data analysis. While several FISH image analysis software tools have been developed, they often use a threshold-based segmentation algorithm for nucleus segmentation. As fluorescence signal intensities can vary significantly from experiment to experiment, from cell to cell, and within a cell, threshold-based segmentation is inflexible and often insufficient for automatic image analysis, leading to additional manual segmentation and potential subjective bias. To overcome these problems, we developed a graphical software tool called FISH Finder to automatically analyze FISH images that vary significantly. By posing the nucleus segmentation as a classification problem, compound Bayesian classifier is employed so that contextual information is utilized, resulting in reliable classification and boundary extraction. This makes it possible to analyze FISH images efficiently and objectively without adjustment of input parameters. Additionally, FISH Finder was designed to analyze the distances between differentially stained FISH probes.
Availability: FISH Finder is a standalone MATLAB application and platform independent software. The program is freely available from: http://code.google.com/p/fishfinder/downloads/list
Contact: gilbert@bio.fsu.edu
doi:10.1093/bioinformatics/btr053
PMCID: PMC3065689  PMID: 21310746
25.  DynGO: a tool for visualizing and mining of Gene Ontology and its associations 
BMC Bioinformatics  2005;6:201.
Background
A large volume of data and information about genes and gene products has been stored in various molecular biology databases. A major challenge for knowledge discovery using these databases is to identify related genes and gene products in disparate databases. The development of Gene Ontology (GO) as a common vocabulary for annotation allows integrated queries across multiple databases and identification of semantically related genes and gene products (i.e., genes and gene products that have similar GO annotations). Meanwhile, dozens of tools have been developed for browsing, mining or editing GO terms, their hierarchical relationships, or their "associated" genes and gene products (i.e., genes and gene products annotated with GO terms). Tools that allow users to directly search and inspect relations among all GO terms and their associated genes and gene products from multiple databases are needed.
Results
We present a standalone package called DynGO, which provides several advanced functionalities in addition to the standard browsing capability of the official GO browsing tool (AmiGO). DynGO allows users to conduct batch retrieval of GO annotations for a list of genes and gene products, and semantic retrieval of genes and gene products sharing similar GO annotations. The result are shown in an association tree organized according to GO hierarchies and supported with many dynamic display options such as sorting tree nodes or changing orientation of the tree. For GO curators and frequent GO users, DynGO provides fast and convenient access to GO annotation data. DynGO is generally applicable to any data set where the records are annotated with GO terms, as illustrated by two examples.
Conclusion
We have presented a standalone package DynGO that provides functionalities to search and browse GO and its association databases as well as several additional functions such as batch retrieval and semantic retrieval. The complete documentation and software are freely available for download from the website .
doi:10.1186/1471-2105-6-201
PMCID: PMC1199584  PMID: 16091147

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