Induced mutant analyses in C. elegans wild type Bristol N2 have been widely studied for understanding signaling pathways. However induced mutations in a single genetic background do not reveal genome-wide allelic effects that segregate in natural populations and contribute to phenotypic variation. For this reason there is a scanty knowledge of what the phenotypic effect of a mutation is in strains other than Bristol N2. This touches upon fundamental aspects if we want to understand the natural genetic architecture of complex phenotypic traits. Furthermore single mutations induced in C. elegans are of limited value in the approach of complex human disease pathways, for which C. elegans is an important model species, due to the complexity of most of disease pathways and their natural variation. To address this question for the Wnt/b-catenin signaling pathway we investigated the phenotypic effects of
bar-1(
ga80) in a population of different genotypes. Each genotype carries the
bar-1 mutation in a genetic mosaic background of N2 and CB4856 alleles. We measured vulva development index, gonad migration and genome-wide gene expression across all genotypes, and identified loci on chromosome I and II associated with these phenotypes. We confirmed these QTLs in
bar-1 induced mutant introgression lines (these are Bristol N2 genotypes which carry the mutation together with a CB4856 locus). Concretely the QTL on chromosome I spanned a region of 300 Kbp harbouring 100 genes approximately. Experiments are ongoing to identify and characterize the causal modifier gene(s). By applying forward genetics in different genotypes we have revealed hidden genetic modifiers affecting Wnt/b-catenin signaling. Importantly we show that natural genetic variation provides means to study the cryptic variation harboring new players in Wnt signaling. This study was funded by EU FP7 contract nr 222936 PANACEA.