{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T17:52:18Z","timestamp":1783101138708,"version":"3.54.6"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2014,2,1]],"date-time":"2014-02-01T00:00:00Z","timestamp":1391212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The identification and validation of gene\u2013gene 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.<\/jats:p>","DOI":"10.1534\/genetics.113.157800","type":"journal-article","created":{"date-parts":[[2013,11,27]],"date-time":"2013-11-27T03:08:42Z","timestamp":1385521722000},"page":"557-567","source":"Crossref","is-referenced-by-count":51,"title":["Effect of Genetic Variation in a <i>Drosophila<\/i> Model of Diabetes-Associated Misfolded Human Proinsulin"],"prefix":"10.1093","volume":"196","author":[{"given":"Bin Z","family":"He","sequence":"first","affiliation":[{"name":"Department of Ecology and Evolution , The University of Chicago, Chicago, Illinois 60637"},{"name":"Department of Ecology and Evolution , The University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Z","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , The University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desiree A","family":"Dickerson","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , The University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levi","family":"Barse","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , The University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bharath","family":"Arun","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , The University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bjarni J","family":"Vilhj\u00e1lmsson","sequence":"additional","affiliation":[{"name":"Department of Epidemiology , and Department of Biostatistics, Harvard School of Public Health, Harvard University, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , The University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo-Young","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Medicine , The University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia A","family":"Tamarina","sequence":"additional","affiliation":[{"name":"Department of Medicine , The University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott B","family":"Selleck","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology , The Pennsylvania State University, University Park, Pennsylvania 16802"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia J","family":"Wittkopp","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolutionary Biology , and Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme I","family":"Bell","sequence":"additional","affiliation":[{"name":"Department of Medicine , The University of Chicago, Chicago, Illinois 60637"},{"name":"Department of Human Genetics , The University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Kreitman","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , The University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,2,1]]},"reference":[{"key":"2023042007210344100_bib1","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nature08800","article-title":"Genome-wide association study of 107 phenotypes in Arabidopsis thaliana inbred lines","volume":"465","author":"Atwell","year":"2010","journal-title":"Nature"},{"key":"2023042007210344100_bib2","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1146\/annurev.genet.39.110304.095804","article-title":"Drosophila as a model for human neurodegenerative disease.","volume":"39","author":"Bilen","year":"2005","journal-title":"Annu. 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