MecCog: a knowledge representation framework for genetic disease mechanism

Abstract

Motivation: Experimental findings on genetic disease mechanisms are scattered throughout the literature and represented in many ways, including unstructured text, cartoons, pathway diagrams and network graphs. Integration and structuring of such mechanistic information greatly enhances its utility.

Results: MecCog is a graphical framework for building integrated representations (mechanism schemas) of mechanisms by which a genetic variant causes a disease phenotype. A MecCog mechanism schema displays the propagation of system perturbations across stages of biological organization, using graphical notations to symbolize perturbed entities and activities, hyperlinked evidence tagging, a mechanism ontology and depiction of knowledge gaps, ambiguities and uncertainties. The web platform enables a user to construct, store, publish, browse, query and comment on schemas. MecCog facilitates the identification of potential biomarkers, therapeutic intervention sites and critical future experiments.

Availability and implementation: The MecCog framework is freely available at http://www.meccog.org.

Supplementary information: Supplementary data are available at Bioinformatics online.

Fig. 1.

Principles of a mechanism schema. Each SSP represents a perturbed biological entity and each MM represents a productive activity (or a group of entities and activities) that produce an output SSP. MM: mechanism module; SSP: substate perturbation

Fig. 2.

MecCog web application architecture. HTTP: hypertext transfer protocol; JSON: JavaScript Object Notation; ORM: object-relational mapping; REST API: representational state transfer application programming interface; SQL: structured query language

Fig. 3.

Graphical notations for components in a mechanism schema

Fig. 4.

Data model of mechanism schema and component annotations. Text in parentheses indicates the data type. ‘#’ represents an integer number denoting the order of the schema component (e.g. SSP1, MM3, BM1, TT2)

Fig. 5.

NOD2 mechanism schema entry in MecCog. This schema describes the known mechanisms by which a frameshift mutation (rs2066847) in the NOD2 gene causes an increased risk for CD. (A) Part of the landing page of the NOD2 schema, displaying the meta-information in tabular format. This page includes the collection of thumbnails of PMC figures selected to illustrate aspects of the mechanism and the list of references with PubMed IDs from which evidence was derived (the list is truncated here—there are 26 references). (B) The schema visualizer GUI used for interactive navigation of the schema. For this schema, four possible submechanisms with varying levels of evidence (indicated by the confidence colors—red: low, orange: medium and green: high) are included. The example yellow pop-up box displays hyperlinked evidence for the associated MM. The comment button on the top can be used to open a modal box, allowing a user to view and add comments. Details of the mechanism are described in the text