Large-scale Edgetic Profiling

Genes and gene products do not act in isolation. They rather interact with each other within intricate and dynamic ‘interactome’ networks, depicted as nodes and edges representing individual molecules and their mutual interactions, respectively. In network representations, a genotypic variation can be modeled either as knockout or knockdown of gene function, leading to removal of a node and all of its edges. Alternatively, a genotypic variation can be modeled as interaction-specific ‘edgetic’ perturbation, leading to the removal or addition of specific interactions while other edges remain unperturbed (Figure 1). Edgetic network perturbation models, which emphasize the disruption of specific edges, complement and extend classic gene-centric paradigms, which assess the effects of deleting or overexpressing genes, but generally neglect the influence of genetic variation.

The term edgetic promotes a subtle yet meaningful archetype shift from conventional gene-centric approaches towards interaction-centric systems approaches. Edgetic models can help make sense of confounding genetic heterogeneity, put forth direct mechanistic connections from genotype to phenotype, and are emerging as a powerful strategy for interpretation of genotype-to-phenotype relationships (Edgotype: a fundamental link between genotype and phenotype).

In the course of this CEGS we will systematically characterize protein-protein interactions that are altered by disease-associated missense mutations in targeted disease genes. Starting from known mutations associated with human disease phenotypes, we will systematically investigate interaction profile changes, the edgotype, in proteins constructed to contain these known mutations (Figure). Disease-associated mutations can be readily introduced by high-throughput technologies of recombinational DNA cloning and site-directed mutagenesis. Such technologies have now advanced to the point where thousands of alleles and hundreds of interactors can readily be tested for allelic perturbations

The diseases and associated mutations selected for systematic edgotyping in the course of this CEGS will be settled upon by members of the Edgotyping Initiative.

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