Visualization of automatically combined disease maps and pathway diagrams for rare diseases

Abstract

Introduction: Investigation of molecular mechanisms of human disorders, especially rare diseases, require exploration of various knowledge repositories for building precise hypotheses and complex data interpretation. Recently, increasingly more resources offer diagrammatic representation of such mechanisms, including disease-dedicated schematics in pathway databases and disease maps. However, collection of knowledge across them is challenging, especially for research projects with limited manpower. Methods: In this article we present an automated workflow for construction of maps of molecular mechanisms for rare diseases. The workflow requires a standardized definition of a disease using Orphanet or HPO identifiers to collect relevant genes and variants, and to assemble a functional, visual repository of related mechanisms, including data overlays. The diagrams composing the final map are unified to a common systems biology format from CellDesigner SBML, GPML and SBML+layout+render. The constructed resource contains disease-relevant genes and variants as data overlays for immediate visual exploration, including embedded genetic variant browser and protein structure viewer. Results: We demonstrate the functionality of our workflow on two examples of rare diseases: Kawasaki disease and retinitis pigmentosa. Two maps are constructed based on their corresponding identifiers. Moreover, for the retinitis pigmentosa use-case, we include a list of differentially expressed genes to demonstrate how to tailor the workflow using omics datasets. Discussion: In summary, our work allows for an ad-hoc construction of molecular diagrams combined from different sources, preserving their layout and graphical style, but integrating them into a single resource. This allows to reduce time consuming tasks of prototyping of a molecular disease map, enabling visual exploration, hypothesis building, data visualization and further refinement. The code of the workflow is open and accessible at https://gitlab.lcsb.uni.lu/minerva/automap/.

Keywords: disease maps; gene-disease association; pathway diagrams; rare diseases (RD); systems biomedicine.

FIGURE 1

A workflow for ad-hoc map building for rare diseases.

FIGURE 2

An overview of the ad-hoc map for the Kawasaki disease. The map includes three diagrams from two disease maps (two from the COVID-19 Disease Map (Ostaszewski et al., 2021), one from the Asthma Map (Mazein et al., 2021)), 192 interactions from text mining, and 5 pathways from both WikiPathways and Reactome databases. See https://pathwaylab.elixir-luxembourg.org/minerva/?id=adhoc_ORPHA2331.

FIGURE 3

A view of the ad-hoc map with the visualized data overlays. One of disease-related variants in the FCGR2A gene is shown in the embedded pileup.js browser (Vanderkam et al., 2016) (top box). Disease-related genes, highlighted in blue, are shown as another visual overlay on top of the map (bottom box).

FIGURE 4

Protein structure view offered by MolArt visualization tool. MolArt (Hoksza et al., 2018) is integrated with the MINERVA Platform and available in the contextual menu for all proteins having UniProt annotation. Here, MolArt visualizes FCGR2A protein together with the position and context of the protein-coding mutation retrieved by the ad-hoc map building workflow.

FIGURE 5

Visualization of differential gene expression in a fragment of the ad-hoc map. Multiple proteins and complexes of the “Cell surface interactions at the vascular wall” pathway (Reactome, R-HSA-202733) are differentially expressed in the RP dataset, indicating potentially dysregulated mechanisms.