He, Bin Z.Ludwig, Michael Z.Dickerson, Desiree A.Barse, LeviArun, BharathVilhjálmsson, Bjarni JJiang, PengyaoPark, Soo-YoungTamarina, Natalia A.Selleck, Scott B.Wittkopp, Patricia J.Bell, Graeme I.Kreitman, Martin2014-03-112014He, B. Z., M. Z. Ludwig, D. A. Dickerson, L. Barse, B. Arun, B. J. Vilhjálmsson, P. Jiang, et al. 2014. “Effect of Genetic Variation in a Drosophila Model of Diabetes-Associated Misfolded Human Proinsulin.” Genetics 196 (2): 557-567. doi:10.1534/genetics.113.157800. http://dx.doi.org/10.1534/genetics.113.157800.0016-6731http://nrs.harvard.edu/urn-3:HUL.InstRepos:11879803The identification and validation of gene–gene interactions is a major challenge in human studies. Here, we explore an approach for studying epistasis in humans using a Drosophila melanogaster model of neonatal diabetes mellitus. Expression of the mutant preproinsulin (hINSC96Y) in the eye imaginal disc mimics the human disease: it activates conserved stress-response pathways and leads to cell death (reduction in eye area). Dominant-acting variants in wild-derived inbred lines from the Drosophila Genetics Reference Panel produce a continuous, highly heritable distribution of eye-degeneration phenotypes in a hINSC96Y background. A genome-wide association study (GWAS) in 154 sequenced lines identified a sharp peak on chromosome 3L, which mapped to a 400-bp linkage block within an intron of the gene sulfateless (sfl). RNAi knockdown of sfl enhanced the eye-degeneration phenotype in a mutant-hINS-dependent manner. RNAi against two additional genes in the heparan sulfate (HS) biosynthetic pathway (ttv and botv), in which sfl acts, also modified the eye phenotype in a hINSC96Y-dependent manner, strongly suggesting a novel link between HS-modified proteins and cellular responses to misfolded proteins. Finally, we evaluated allele-specific expression difference between the two major sfl-intronic haplotypes in heterozygtes. The results showed significant heterogeneity in marker-associated gene expression, thereby leaving the causal mutation(s) and its mechanism unidentified. In conclusion, the ability to create a model of human genetic disease, map a QTL by GWAS to a specific gene, and validate its contribution to disease with available genetic resources and the potential to experimentally link the variant to a molecular mechanism demonstrate the many advantages Drosophila holds in determining the genetic underpinnings of human disease.en-USGenetics of Complex Traitsmutant insulingenome-wide association studyheparan sulfate proteoglycansulfatelessJournal Article2014-03-1110.1534/genetics.113.157800