Combining Genetic Variation with Targeted Knock-downs to Construct Gene Networks of Complex Human Diseases in C. elegans

The nematode worm C. elegans has intensively been studied for complex human disease pathways. Within the EU FP7 funded PANACEA consortium we perform a quantitative pathway analysis of natural variation in complex disease signalling in C. elegans. Here, we present a robust approach for selecting candidate genes associated with the Notch, Wnt and RAS pathway using a combination of recombinant inbred lines (RILs), derived from a cross of the wildtypes N2 and CB4856, and RNAi. The consortium focuses on the transcriptome, proteome and cellular development. We tested 180 different RNAi’s targeted against genes within these three pathways in a set of 50 RILs. We highlight a case of this cryptic genetic variation in genome wide gene expression levels underlying a gld-1 knock-down (a gene involved in germline development) This revealed new candidate regulators of gld-1 affected gene expression. Furthermore we will show how mutations of the RAS pathway in different genetic backgrounds lead to the discovery of hidden modifiers affecting vulva-development, an important readout of cancer signalling pathways. All this (transcriptomics, proteomics and phenotypic) data will feed into a predictive model of vulva development which can be used to investigate the relative contributions of various recombinants.