The updated RGD Pathway Portal utilizes increased curation efficiency and provides expanded pathway information
© Hayman et al; licensee BioMed Central Ltd. 2013
Received: 17 August 2012
Accepted: 10 December 2012
Published: 5 February 2013
The RGD Pathway Portal provides pathway annotations for rat, human and mouse genes and pathway diagrams and suites, all interconnected via the pathway ontology. Diagram pages present the diagram and description, with diagram objects linked to additional resources. A newly-developed dual-functionality web application composes the diagram page. Curators input the description, diagram, references and additional pathway objects. The application combines these with tables of rat, human and mouse pathway genes, including genetic information, analysis tool and reference links, and disease, phenotype and other pathway annotations to pathway genes. The application increases the information content of diagram pages while expediting publication.
KeywordsCuration Databases Ontologies Pathways Tools
The laboratory rat (Rattus norvegicus) has been used as an animal model for over 150 years, with inbred strains used to study human physiology and many human diseases, such as autoimmune, cardiovascular, kidney, and pulmonary diseases, and metabolic, reproductive, and urogenital disorders . The Rat Genome Database (RGD; http://rgd.mcw.edu)  is the primary archive of rat genetic and genomic data, holding over 40,000 active rat gene records, plus human and mouse orthologs. In addition to protein-coding genes, these include RNA genes and pseudogenes. A recent analysis reported 17,733 unambiguous rat orthologs of human genes, occurring in many syntenic segments , further supporting the use of the rat as a model for human physiology and disease. Also housed at RGD is information on rat and human quantitative trait loci (QTLs) and rat strains accumulated by manual curation  using an advanced suite of curation tools  and automated pipelines. RGD uses over a dozen different ontologies to annotate gene, QTL, and strain information. It is one of the few databases that stores human QTL data.
The Pathway Portal project  at RGD aims to provide a dynamic platform where users can find pathway associations for human, rat, and mouse genes. Users can access interactive pathway diagram pages, suites of functionally related pathways, and suite networks illustrating broader interactions to explore the connections between these and across other available resources. Several entry points and tools accessible from the RGD home page allow the user to search for and access pathway data and navigate between the portal’s components and the other resources at RGD. Searching for a pathway ontology (PW) term in the RGD generic keyword search will bring up a link to the pathway report page. The RGD Disease Portals also provide links to the pathway report pages. Pathway curation for the Pathway Portal involves annotating human, rat, and mouse genes to terms in the PW, which was originated at and continues to evolve at RGD. Curated pathway data are derived largely from published scientific review literature, and the norm is to annotate to the human genes; corresponding annotations made to the rat and mouse orthologs are qualified with the evidence code ‘inferred from sequence similarity’ (ISS) to denote that the annotation is additionally predicted for the rodent genes based on shared sequence similarity with the human gene. It might be suggested that use of pathway terms in the biological process arm of the Gene Ontology (GO) would be adequate for pathway annotations. While there are overlapping terms between PW and GO, the latter uses the perspective of a unidirectional process whose reactions and interactions lead to an end result, while the PW perspective is one of sets of interacting molecules whose reactions and interactions underlie functioning networks. This pathway ontology has five major nodes: metabolic, regulatory, signaling, drug, and disease pathways, with terms for altered versions of pathways. Drug pathways are offered by PharmGKB (http://www.pharmgkb.org/) and the Small Molecule Pathway Database (http://www.smpdb.ca/) with the latter also having disease along with signaling and metabolic pathways. Disease pathways can be found at the Kyoto Encyclopedia of Genes and Genomes (KEGG; http://www.genome.jp/kegg/) and Reactome (http://www.reactome.org/ReactomeGWT/entrypoint.html). RGD’s PW is unique in having all pathway types including disease and altered (unique to PW) versions. The ontology allows for the standardized annotation of genes to pathway terms, provides a link to interactive pathway diagrams, and serves as a navigational tool between the various pathway data types. The generation of diagrams and interactive diagram pages are important components of the curation process for the Pathway Portal. The visualization of pathways aids the user in understanding the position of and relationships between gene functions within networks. An application has been developed both to increase the range of and accessibility to the biological information provided by pathway diagram pages, and to expedite their production.
The Molecular Pathway diagram pages web application
Pathway Image files created in the Ariadne Pathway Studio software tool (version 8.0) are uploaded with Jupload, an OpenSource applet distributed on SourceForge that allows multiple file uploads within a single directory. This applet is distributed under the Common Public License version 1.0: JUnit, GNU GPL (general public license) V3: JUpload project on SourceForge, and The Apache Software License version 2.0: Commons Lang, Jakarta Commons Net, Maven Plugin application programming interface (http://jupload.sourceforge.net/). The compiled JUpload applet, signed with the JUpload project certificate, is employed for upload of the pathway directories to the curation server. A Java class that inherits the Hypertext Markup Language (HTML) Parser and Node Visitor methods is used to replace links created by Pathway Studio with links to all of the RGD resources. Automatic regeneration of file structure ensures no manual intervention during upload of each new or updated pathway.
The architecture and capabilities of the Pathway Curation software may be of interest to the informatics community. However, because the pathway application software was designed specifically to fit the RGD database schema and uses the licensed Ariadne software, it would not be readily adaptable for use with other databases, so it has not been made publicly available.
Perspective and outlook
The RGD Pathway Portal continues to grow, as does the number of researchers using it. A data pipeline importing almost 24,000 pathway gene annotations, including over 8,000 for human genes, from the Pathway Interaction Database (http://pid.nci.nih.gov/) has been recently added. A similar pipeline importing pathway data from KEGG will be released shortly. There are presently over 9,400 pathway annotations and in excess of 100 interactive pathway pages published at RGD. These are of great interest to research community users as evidenced by the numbers of views the pages receive (43,333 total, 27,547 unique page views from August 01, 2011 to August 01, 2012), determined using Google Analytics, as well as by upgrades and new trends found at other data sources. These include new webinars introducing the pathway and network visualization and analysis tools at Reactome, and the new Reaction Modules at KEGG.
In the process of providing the dynamic platform or ‘landscape’ for exploration that the Pathway Portal strives to be, new approaches or views are developed, such as the pathway suites and suite networks. Each suite offers an instant snapshot of the broader picture that brings together several pathways. The suite networks interconnect related pathway suites, illustrating their complex, higher-order interactions. We look forward to continued growth in all of these areas. As the portal expands in depth and scope, other approaches and tools will be developed and added to enhance the pathway page collection at RGD and the value it offers to the research community.
common gateway interface
Chemical Entities of Biological Interest
hypertext markup language
Kyoto Encyclopedia of Genes and Genomes
Rat Genome Database.
We thank Jennifer R. Smith for assistance with preparation of the figures, and the RGD Team. This work was supported by the National Heart, Lung, and Blood Institute on behalf of the National Institutes of Health [HL64541].
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