Threshold trait architecture of Hsp90-buffered variation

Common genetic variants buffered by Hsp90 are candidates for human diseases of signaling such as cancer. Like cancer, morphological abnormalities buffered by Hsp90 are discrete threshold traits with a continuous underlying basis of liability determining their probability of occurrence. QTL and deletion maps for one of the most frequent Hsp90-dependent abnormalities in Drosophila, deformed eye (dfe), were replicated across three genetically related artificial selection lines using strategies dependent on proximity to the dfe threshold and the direction of genetic and environmental effects. Up to 17 dfe loci (QTL) linked by 7 interactions were detected based on the ability of small recombinant regions of an unaffected and completely homozygous control genotype to dominantly suppress or enhance dfe penetrance at its threshold in groups of isogenic recombinant flies, and over 20 deletions increased dfe penetrance from a low expected value in one or more line, identifying a complex network of genes responsible for the dfe phenotype. Replicated comparisons of these whole-genome mapping approaches identified several QTL regions narrowly defined by deletions and 4 candidate genes, with additional uncorrelated QTL and deletions highlighting differences between the approaches and the need for caution in attributing the effect of deletions directly to QTL genes.