Overview

Genomic Analysis of Network Perturbations in Human Disease
II. Edgetic Perturbations at Large Scale

The overriding principle behind all the CCSB CEGS efforts is that making sense of genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply the result of genomic variations considered individually.

Since the first phase of the CCSB CEGS grant initiated in 2006 there has been an explosion of sequencing data, leading to a flood of available genome, exome and transcriptome sequences. The planned second phase of the CCSB CEGS aims to exploit this tsunami of information in unaffected genomes and Mendelian and complex disorder genomes. The vast amount of sequence information coming to the fore will create a huge bottleneck. What to do once disease genes are identified? How to find causal variants? How to functionalize the disease gene variants?

The overall focus of the CCSB “Genomic Analysis of Network Perturbations in Human Disease” CEGS is accordingly shifting. No longer will we use viruses as surrogates to reveal network perturbations (CEGS I), but instead will directly contextualize disease genes and functionalize causal genome variants, by leveraging existing CCSB expertise, datasets and methodologies regarding interactome networks. Specifically, we are mapping out the network edges perturbed in human disease, so-called edgetic variants, by applying at large scale existing edgetics platforms. The sum of all edges perturbed by a particular genotype therefore represents the edgotype. And the central hypothesis behind this phase of our CEGS efforts is then that it is the edgotype that drives the phenotype (Edgotype: a fundamental link between genotype and phenotype).

Ongoing efforts

Profiling edgetic variants in human disease
Mutations can disrupt expression of a protein or perturb interactions with other proteins that are essential for function within the overall network. Using our genetic and biochemical approaches we aim to characterize protein-protein interactions that are altered by missense mutations in targeted disease-associated genes. More…
The Edgotyping Disease Initiative
Novel experimental technologies and network modeling strategies are being developed for two dozen diseases selected both because disease features make them good candidates for edgotyping, but also because they are the very disorders that invited members of the Edgotyping Initiative specialize in. More…

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