Edgotype: a fundamental link between genotype and phenotype

Abstract

Classical 'one-gene/one-disease' models cannot fully reconcile with the increasingly appreciated prevalence of complicated genotype-to-phenotype associations in human disease. Genes and gene products function not in isolation but as components of intricate networks of macromolecules (DNA, RNA, or proteins) and metabolites linked through biochemical or physical interactions, represented in 'interactome' network models as 'nodes' and 'edges', respectively. Accordingly, mechanistic understanding of human disease will require understanding of how disease-causing mutations affect systems or interactome properties. The study of 'edgetics' uncovers specific loss or gain of interactions (edges) to interpret genotype-to-phenotype relationships. We review how distinct genetic variants, the genotype, lead to distinct phenotypic outcomes, the phenotype, through edgetic perturbations in interactome networks altogether representing the 'edgotype'.

Figure 1

Genetic variant-induced perturbations in network properties give rise to altered phenotypes, such as disease. Distinct genetic variants of the same gene can exhibit different interaction profiles, ranging from loss of all interactions (node removal), to loss of some interactions (edgetic), to no loss of interactions (pseudo-wildtype), to gain-of-interaction. Nodes represent macromolecules, and edges represent biochemical or biophysical interactions between them. The stars denote a disease-associated variant or mutation. The profile of edgetic perturbations defines the edgotype, providing the explanatory connections between genotype and phenotype.

Figure 2

Human genetic variations (the variome) and pathogenic viral proteins (the virome) similarly influence local and global properties of networks to induce disease states.

Figure 3

Forward and reverse edgetics to functionally characterize genomic variants. Forward edgetics studies the underlying edgotype for a given phenotype (disease), introducing known disease-causing mutations to study mutation-mediated loss or maintenance of known protein interactions and to relate the corresponding edgotype to a disease phenotype. Reverse edgetics introduces novel mutations into proteins of interest, finding those mutations that cause loss or maintenance of interactions against known interactors. The obtained mutations can then be introduced in vivo to characterize the resulting phenotype.

Figure 4

Edgetics can apply to all types of biomolecular interaction networks, including but not limited to protein-protein, protein-DNA, protein-RNA, and protein-metabolite interactions. Perturbations of these distinct types of interactions have been shown to be a factor in human disease.