Journal article
Effect of genetic variation in a Drosophila model of diabetes-associated misfolded human proinsulin
Genetics (Austin), Vol.196(2), pp.557-567
02/2014
DOI: 10.1534/genetics.113.157800
PMCID: PMC3914626
PMID: 24281155
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 (hINS(C96Y)) 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 hINS(C96Y) 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 hINS(C96Y)-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.
Details
- Title: Subtitle
- Effect of genetic variation in a Drosophila model of diabetes-associated misfolded human proinsulin
- Creators
- Bin Z He - Department of Ecology and Evolution, The University of Chicago, Chicago, Illinois 60637Michael Z LudwigDesiree A DickersonLevi BarseBharath Arun - University of ChicagoBjarni J VilhjálmssonPengyao JiangSoo-Young ParkNatalia A TamarinaScott B SelleckPatricia J WittkoppGraeme I BellMartin Kreitman
- Resource Type
- Journal article
- Publication Details
- Genetics (Austin), Vol.196(2), pp.557-567
- Publisher
- United States
- DOI
- 10.1534/genetics.113.157800
- PMID
- 24281155
- PMCID
- PMC3914626
- ISSN
- 0016-6731
- eISSN
- 1943-2631
- Grant note
- P50 GM081892 / NIGMS NIH HHS P60 DK020595 / NIDDK NIH HHS GM081892 / NIGMS NIH HHS R01 DK013914 / NIDDK NIH HHS R01 GM054832 / NIGMS NIH HHS P30 DK020595 / NIDDK NIH HHS GM054832 / NIGMS NIH HHS
- Language
- English
- Date published
- 02/2014
- Academic Unit
- Anatomy and Cell Biology; Biology
- Record Identifier
- 9983992000202771
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