Gene Ontology Causal Activity Modeling (GO-CAM) moves beyond GO annotations to structured descriptions of biological functions and systems

Abstract

To increase the utility of Gene Ontology annotations for interpretation of genome-wide experimental data, we have developed GO-CAM, a structured framework for linking multiple GO annotations into an integrated model of a biological system. We expect that GO-CAM will enable new applications in pathway and network analysis as well as improving standard GO annotations for traditional GO-based applications.

Figure 1.. Standard GO annotations vs. GO-CAM model.

The same biological model (how NEDD4 represses RNA transcription in response to UV-induced DNA damage as elucidated in (5)) is depicted in a) as a set of disconnected GO annotations, each covering a partial description of the overall function; and in b) as a GO-CAM model, linking together GO annotations into a structured model of NEDD4 functions, including the effect of NEDD4’s activity on the activity of a macromolecular complex, RNA polymerase II. GO molecular functions are shown in white boxes, cellular components in green, and biological processes in light blue. Gene products or complexes are shown in brown if they execute an activity (e.g. NEDD4), and in dark blue if they are acted upon by an activity (e.g. RNA polymerase II in the left part of panel b). The causal relationship representing how the activity of NEDD4 negatively regulates the activity of RNA polymerase II, which is captured indirectly in the last annotation in panel a, is shown as a red arrow in panel b. Coloring conventions are retained in Figures 2 and 3 below.

Figure 2.. An overview of the structured representation defined by GO-CAM.

Arrows are relations from the Relations Ontology, and all boxes must refer to a class from an ontology (or other stable object identifier) as described in Table 1. The core of the model is a Molecular Activity, which is carried out (enabled) by a specific gene product or macromolecular complex (Active Entity, brown) and may act on a specific Target Entity (dark blue). An activity occurs in a specific Location (green), is part of a specific Biological Program (light blue), and may occur during a specific Biological Phase (gray). In addition, the activity may have causal effects on other activities (red arrow). Curved part of arrows indicate that smaller processes can be nested as modules inside larger processes (blue), or that an activity is known to occur in a specific cell type or anatomical structure (green, e.g. nucleus part of neuron). More detail on the GO-CAM specification can be found at http://geneontology.org/go-cam/docs.

Figure 3.. GO-CAM model of initial steps in the canonical Wnt signaling pathway.

This diagram is a screenshot of the interface of the web-based curation platform (Noctua) for GO-CAM models. In this view, each molecular activity is represented by a box, and some of the properties in Figure 2 (the active entity, the location and the target entity) are “folded” into that box. The beta-catenin destruction complex is not folded into its activity box, so that the constituent gene products (e.g. AXIN1) are visible. Noctua is available at http://noctua.geneontology.org (the URL for this model is http://model.geneontology.org/596ef51500000088).