The pathway ontology - updates and applications

Abstract

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.

Figure 1

The pathway ontology main nodes and positions of selected terms. A. The five nodes of the Pathway Ontology. B. The term ‘lipid hormone signaling pathway’ in the ontology showing the parent, siblings and children terms. C. The term ‘insulin signaling pathway’ in the ontology showing the position of the term within the tree. ‘Insulin signaling pathway’ is in a part_of relationship to the ‘glucose’ and ‘energy homeostasis pathway’ terms within the regulatory node and in an is_a relationship to ‘peptide and protein hormone signaling pathway’ term within the signaling node.

Figure 2

Pancreatic cancer pathway diagram. The interactive pathway diagram page for the ‘pancreatic cancer pathway’. The altered pathways associated with the condition are shown as gray rectangles that link to the ontology report(s) for the those terms. Culprit genes within the pathways are shown color-coded (default is red). The icon for the microRNAs (miRNA) with potential roles in pancreatic cancer links to a page where several down- and up-regulated miRNAs are shown with some targets listed and with links to their report pages in RGD and the microRNA database (MiRBase). The icon for the condition links to the Cancer Disease Portal in RGD.

Figure 3

Pathway portal data access. A. Rat Genome Database homepage with the main entry points to its content; the “Pathways” and “Function” entry points described in the text, are circled. B. Accessing the “Pathways” entry point and entries within.

Figure 4

The anatomy of an interactive pathway diagram page. A. The top of the page shows the beginning of the description with the option of viewing the whole text and the diagram below it. B. The genes in the pathway are shown by species in a tabular form with various link options. C. Genes in the pathway that have disease annotations are shown in a table that can be toggled between diseases, alphabetically listed, with the associated genes shown to the right (default), and genes, alphabetically listed, with the associated diseases shown to the right. D. Genes in the pathway that have annotations to other pathways are shown in a table that can be toggled between pathways, alphabetically listed, with the associated genes shown to the right (default), and genes, alphabetically listed, with the associated pathways shown to the right. The last section of the diagram page has the reference list as well as a view of the ontology tree (not shown).

Figure 5

Hypoxia inducible factor pathway. A. The normal functioning of the ‘hypoxia inducible factor pathway’. B. The ‘altered’ version of the ‘hypoxia inducible factor pathway’.