Effect of Genetic Variation in a Drosophila Model of Diabetes-Associated Misfolded Human Proinsulin

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Effect of Genetic Variation in a Drosophila Model of Diabetes-Associated Misfolded Human Proinsulin

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Title: Effect of Genetic Variation in a Drosophila Model of Diabetes-Associated Misfolded Human Proinsulin
Author: He, Bin Z.; Ludwig, Michael Z.; Dickerson, Desiree A.; Barse, Levi; Arun, Bharath; Vilhjálmsson, Bjarni J.; Jiang, Pengyao; Park, Soo-Young; Tamarina, Natalia A.; Selleck, Scott B.; Wittkopp, Patricia J.; Bell, Graeme I.; Kreitman, Martin

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Citation: He, 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.
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Abstract: The 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.
Published Version: doi:10.1534/genetics.113.157800
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914626/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:11879803
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