A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX

BMC Genomics

Volumn 14, Issue 1, 2013, Pages

  Pendse, Jay ^a   Ramachandran, Prasanna V ^b   Na, Jianbo ^a   Narisu, Narisu ^c   Fink, Jill L ^b   Cagan, Ross L ^a   Collins, Francis S ^c   Baranski, Thomas J ^b  

^a MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^b WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c NATIONAL HUMAN GENOME RESEARCH INSTITUTE   (United States)

Author keywords

Diabetes mellitus, type 2; Drosophila melanogaster; Dyslipidemias; Genome wide association study; HHEX protein, Human; High throughput screening assays; Hyperglycemia; Phylogeny; Reverse genetics

Indexed keywords

GLUCOSAMINE; GLUCOSE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DHHEX GENE; DIET; DROSOPHILA MELANOGASTER; ENVIRONMENTAL FACTOR; GENE; GENE ACTIVITY; GENE FUNCTION; GENE IDENTIFICATION; GENE INTERACTION; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC RISK; GENETIC TRAIT; HEMOLYMPH; HHEX GENE; HUMAN; HUMAN GENOME; INSULIN SENSITIVITY; KCNJ11; LETHALITY; METABOLIC DISORDER; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PHENOTYPE; PPARG GENE; RISK FACTOR; THADA GENE;

ANIMALS; DIABETES MELLITUS, TYPE 2; DROSOPHILA MELANOGASTER; DROSOPHILA PROTEINS; FAT BODY; GENETIC ASSOCIATION STUDIES; GENETIC PREDISPOSITION TO DISEASE; GENOME-WIDE ASSOCIATION STUDY; GLUCOSE; HOMEODOMAIN PROTEINS; HUMANS; INSULIN RESISTANCE; MUSCLE PROTEINS; ORGAN SPECIFICITY; PHENOTYPE; POLYMORPHISM, SINGLE NUCLEOTIDE; TRANSCRIPTION FACTORS;

DROSOPHILA MELANOGASTER;

EID: 84874255352     PISSN: None     EISSN: 14712164     Source Type: Journal    
DOI: 10.1186/1471-2164-14-136     Document Type: Article

References (55)

1. Zimmet P, Alberti KGMM, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001, 414:782-787. 10.1038/414782a, 11742409.
2. Roglic G, Unwin N. Mortality attributable to diabetes: estimates for the year 2010. Diabetes Res Clin Pract 2010, 87:15-19. 10.1016/j.diabres.2009.10.006, 19914728.
3. Alwan A, MacLean DR, Riley LM, d'Espaignet ET, Mathers CD, Stevens GA, Bettcher D. Monitoring and surveillance of chronic non-communicable diseases: progress and capacity in high-burden countries. Lancet 2010, 376:1861-1868. 10.1016/S0140-6736(10)61853-3, 21074258.
4. McCarthy MI. Genomics, type 2 diabetes, and obesity. N Engl J Med 2010, 363:2339-2350. 10.1056/NEJMra0906948, 21142536.
5. Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A 2009, 106:9362-9367. 10.1073/pnas.0903103106, 2687147, 19474294.
6. Lettice LA, Heaney SJH, Purdie LA, Li L, De Beer P, Oostra BA, Goode D, Elgar G, Hill RE, De Graaff E. A long-range shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet 2003, 12:1725-1735. 10.1093/hmg/ddg180, 12837695.
7. Spilianakis CG, Lalioti MD, Town T, Lee GR, Flavell RA. Interchromosomal associations between alternatively expressed loci. Nature 2005, 435:637-645. 10.1038/nature03574, 15880101.
8. Cox RD, Church CD. Mouse models and the interpretation of human GWAS in type 2 diabetes and obesity. Dis Model Mech 2011, 4:155-164. 10.1242/dmm.000414, 3046087, 21324932.
9. Baker KD, Thummel CS. Diabetic larvae and obese flies-emerging studies of metabolism in drosophila. Cell Metab 2007, 6:257-266. 10.1016/j.cmet.2007.09.002, 2231808, 17908555.
10. Palanker Musselman L, Fink JL, Narzinski K, Ramachandran PV, Sukumar Hathiramani S, Cagan RL, Baranski TJ. A high-sugar diet produces obesity and insulin resistance in wild-type Drosophila. Dis Model Mech 2011, 4:842-849. 10.1242/dmm.007948, 3209653, 21719444.
11. Shulman JM, Chipendo P, Chibnik LB, Aubin C, Tran D, Keenan BT, Kramer PL, Schneider JA, Bennett DA, Feany MB, De Jager PL. Functional screening of Alzheimer pathology genome-wide association signals in Drosophila. Am J Hum Genet 2011, 88:232-238. 10.1016/j.ajhg.2011.01.006, 3035702, 21295279.
12. Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S, Balkau B, Heude B, Charpentier G, Hudson TJ, Montpetit A, Pshezhetsky AV, Prentki M, Posner BI, Balding DJ, Meyre D, Polychronakos C, Froguel P. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2007, 445:881-885. 10.1038/nature05616, 17293876.
13. Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU, Prokunina-Olsson L, Ding C-J, Swift AJ, Narisu N, Hu T, Pruim R, Xiao R, Li X-Y, Conneely KN, Riebow NL, Sprau AG, Tong M, White PP, Hetrick KN, Barnhart MW, Bark CW, Goldstein JL, Watkins L, Xiang F, Saramies J. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007, 316:1341-1345. 10.1126/science.1142382, 3214617, 17463248.
14. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JRB, Rayner NW, Freathy RM, Barrett JC, Shields B, Morris AP, Ellard S, Groves CJ, Harries LW, Marchini JL, Owen KR, Knight B, Cardon LR, Walker M, Hitman GA, Morris AD, Doney ASF, McCarthy MI, Hattersley AT. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007, 316:1336-1341. 10.1126/science.1142364, 17463249.
15. Chen W-M, Erdos MR, Jackson AU, Saxena R, Sanna S, Silver KD, Timpson NJ, Hansen T, Orrù M, Grazia Piras M, Bonnycastle LL, Willer CJ, Lyssenko V, Shen H, Kuusisto J, Ebrahim S, Sestu N, Duren WL, Spada MC, Stringham HM, Scott LJ, Olla N, Swift AJ, Najjar S, Mitchell BD, Lawlor DA, Smith GD, Ben-Shlomo Y, Andersen G, Borch-Johnsen K. Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels. J Clin Invest 2008, 118:2620-2628. 2398737, 18521185.
16. Dupuis J, Langenberg C, Prokopenko I. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 2010, 42:105-116. 10.1038/ng.520, 3018764, 20081858.
17. Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, Heath SC, Timpson NJ, Najjar SS, Stringham HM, Strait J, Duren WL, Maschio A, Busonero F, Mulas A, Albai G, Swift AJ, Morken MA, Narisu N, Bennett D, Parish S, Shen H, Galan P, Meneton P, Hercberg S, Zelenika D, Chen W-M, Li Y, Scott LJ, Scheet PA. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008, 40:161-169. 10.1038/ng.76, 18193043.
18. Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, Wahlstrand B, Hedner T, Corella D, Tai ES, Ordovas JM, Berglund G, Vartiainen E, Jousilahti P, Hedblad B, Taskinen M-R, Newton-Cheh C, Salomaa V, Peltonen L, Groop L, Altshuler DM, Orho-Melander M. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008, 40:189-197. 10.1038/ng.75, 2682493, 18193044.
19. Kooner JS, Chambers JC, Aguilar-Salinas CA, Hinds DA, Hyde CL, Warnes GR, Pérez FJG, Frazer KA, Elliott P, Scott J, Milos PM, Cox DR, Thompson JF. Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides. Nat Genet 2008, 40:149-151. 10.1038/ng.2007.61, 18193046.
20. Hubbard TJP, Aken BL, Ayling S, Ballester B, Beal K, Bragin E, Brent S, Chen Y, Clapham P, Clarke L, Coates G, Fairley S, Fitzgerald S, Fernandez-Banet J, Gordon L, Graf S, Haider S, Hammond M, Holland R, Howe K, Jenkinson A, Johnson N, Kahari A, Keefe D, Keenan S, Kinsella R, Kokocinski F, Kulesha E, Lawson D, Longden I. Ensembl 2009. Nucleic Acids Res 2009, 37:D690-D697. 10.1093/nar/gkn828, 2686571, 19033362.
21. Vilella AJ, Severin J, Ureta-Vidal A, Heng L, Durbin R, Birney E. EnsemblCompara GeneTrees: complete, duplication-aware phylogenetic trees in vertebrates. Genome Res 2009, 19:327-335. 2652215, 19029536.
22. Pasco MY, Léopold P. High Sugar-induced insulin resistance in Drosophila relies on the lipocalin neural lazarillo. PLoS One 2012, 7:e36583. 10.1371/journal.pone.0036583, 3342234, 22567167.
23. del Valle RA, Didiano D, Desplan C. Power tools for gene expression and clonal analysis in Drosophila. Nat Methods 2012, 9:47-55.
24. Dietzl G, Chen D, Schnorrer F, Su K-C, Barinova Y, Fellner M, Gasser B, Kinsey K, Oppel S, Scheiblauer S, Couto A, Marra V, Keleman K, Dickson BJ. A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 2007, 448:151-156. 10.1038/nature05954, 17625558.
25. Bennett EP, Weghuis DO, Merkx G, van Kessel AG, Eiberg H, Clausen H. Genomic organization and chromosomal localization of three members of the UDP-N-acetylgalactosamine: polypeptide N-acetylgalactosaminyltransferase family. Glycobiology 1998, 8:547-555. 10.1093/glycob/8.6.547, 9592121.
26. Steinthorsdottir V, Thorleifsson G, Reynisdottir I, Benediktsson R, Jonsdottir T, Walters GB, Styrkarsdottir U, Gretarsdottir S, Emilsson V, Ghosh S, Baker A, Snorradottir S, Bjarnason H, Ng MCY, Hansen T, Bagger Y, Wilensky RL, Reilly MP, Adeyemo A, Chen Y, Zhou J, Gudnason V, Chen G, Huang H, Lashley K, Doumatey A, So W-Y, Ma RCY, Andersen G, Borch-Johnsen K. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 2007, 39:770-775. 10.1038/ng2043, 17460697.
27. Vionnet N, Stoffel M, Takeda J, Yasuda K, Bell GI, Zouali H, Lesage S, Velho G, Iris F, Passa P. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature 1992, 356:721-722. 10.1038/356721a0, 1570017.
28. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PIW, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, Altshuler D, Almgren P, Florez JC, Meyer J, Ardlie K, Bengtsson Boström K, Isomaa B, Lettre G, Lindblad U, Lyon HN, Melander O, Newton-Cheh C, Nilsson P, Orho-Melander M, Råstam L, Speliotes EK, Taskinen M-R, Tuomi T. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007, 316:1331-1336.
29. Voight BF, Scott LJ, Steinthorsdottir V. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 2010, 42:579-589. 10.1038/ng.609, 3080658, 20581827.
30. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A 2003, 100:4162-4167. 10.1073/pnas.0230450100, 153065, 12634421.
31. Abdul-Hay SO, Kang D, McBride M, Li L, Zhao J, Leissring MA. Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance. PLoS One 2011, 6:e20818. 10.1371/journal.pone.0020818, 3111440, 21695259.
32. Chauvière M, Kress C, Kress M. Disruption of the mitotic kinesin Eg5 gene (Knsl1) results in early embryonic lethality. Biochem Biophys Res Commun 2008, 372:513-519. 10.1016/j.bbrc.2008.04.177, 18474226.
33. Hanover JA, Lai Z, Lee G, Lubas WA, Sato SM. Elevated O-linked N-acetylglucosamine metabolism in pancreatic beta-cells. Arch Biochem Biophys 1999, 362:38-45. 10.1006/abbi.1998.1016, 9917327.
34. Na J, Musselman LP, Pendse J, Baranski TJ, Bodmer R, Ocorr K, Cagan R. A Drosophila model of high sugar diet-induced cardiomyopathy. PLoS Genet 2013, 9:e1003175. 10.1371/journal.pgen.1003175, 3542070, 23326243.
35. Bort R, Martinez-Barbera JP, Beddington RSP, Zaret KS. Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas. Development 2004, 131:797-806. 10.1242/dev.00965, 14736744.
36. Bort R, Signore M, Tremblay K, Martinez Barbera JP, Zaret KS. Hex homeobox gene controls the transition of the endoderm to a pseudostratified, cell emergent epithelium for liver bud development. Dev Biol 2006, 290:44-56. 10.1016/j.ydbio.2005.11.006, 16364283.
37. Hallaq H, Pinter E, Enciso J, McGrath J, Zeiss C, Brueckner M, Madri J, Jacobs HC, Wilson CM, Vasavada H, Jiang X, Bogue CW. A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels. Development 2004, 131:5197-5209. 10.1242/dev.01393, 15459110.
38. Martinez Barbera JP, Clements M, Thomas P, Rodriguez T, Meloy D, Kioussis D, Beddington RS. The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation. Development 2000, 127:2433-2445.
39. Paz H, Lynch MR, Bogue CW, Gasson JC. The homeobox gene Hhex regulates the earliest stages of definitive hematopoiesis. Blood 2010, 116:1254-1262. 10.1182/blood-2009-11-254383, 2938236, 20472829.
40. Chen C, Jack J, Garofalo RS. The Drosophila insulin receptor is required for normal growth. Endocrinology 1996, 137:846-856. 10.1210/en.137.3.846, 8603594.
41. Brogiolo W, Stocker H, Ikeya T, Rintelen F, Fernandez R, Hafen E. An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr Biol 2001, 11:213-221. 10.1016/S0960-9822(01)00068-9, 11250149.
42. Shingleton AW, Das J, Vinicius L, Stern DL. The temporal requirements for insulin signaling during development in Drosophila. PLoS Biol 2005, 3:e289. 10.1371/journal.pbio.0030289, 1184592, 16086608.
43. Listenberger LL, Han X, Lewis SE, Cases S, Farese RV, Ory DS, Schaffer JE. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A 2003, 100:3077-3082. 10.1073/pnas.0630588100, 152249, 12629214.
44. Lee T, Luo L. Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 1999, 22:451-461. 10.1016/S0896-6273(00)80701-1, 10197526.
45. Asha H, Nagy I, Kovacs G, Stetson D, Ando I, Dearolf CR. Analysis of Ras-induced overproliferation in Drosophila hemocytes. Genetics 2003, 163:203-215. 1462399, 12586708.
46. Rulifson EJ, Kim SK, Nusse R. Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science 2002, 296:1118-1120. 10.1126/science.1070058, 12004130.
47. Kimbrell DA, Hice C, Bolduc C, Kleinhesselink K, Beckingham K. The Dorothy enhancer has Tinman binding sites and drives hopscotch-induced tumor formation. Genesis 2002, 34:23-28. 10.1002/gene.10134, 12324942.
48. Yi P, Han Z, Li X, Olson EN. The mevalonate pathway controls heart formation in Drosophila by isoprenylation of Ggamma1. Science 2006, 313:1301-1303. 10.1126/science.1127704, 16857902.
49. Wessells RJ, Fitzgerald E, Cypser JR, Tatar M, Bodmer R. Insulin regulation of heart function in aging fruit flies. Nat Genet 2004, 36:1275-1281. 10.1038/ng1476, 15565107.
50. Zhuang S, Shao H, Guo F, Trimble R, Pearce E, Abmayr SM. Sns and Kirre, the Drosophila orthologs of Nephrin and Neph1, direct adhesion, fusion and formation of a slit diaphragm-like structure in insect nephrocytes. Development 2009, 136:2335-2344. 10.1242/dev.031609, 2729346, 19515699.
51. Brückner K, Kockel L, Duchek P, Luque CM, Rørth P, Perrimon N. The PDGF/VEGF receptor controls blood cell survival in Drosophila. Dev Cell 2004, 7:73-84. 10.1016/j.devcel.2004.06.007, 15239955.
52. Das D, Aradhya R, Ashoka D, Inamdar M. Post-embryonic pericardial cells of Drosophila are required for overcoming toxic stress but not for cardiac function or adult development. Cell Tissue Res 2007, 331:565-570.
53. Iwaki DD, Lengyel JA. A Delta-Notch signaling border regulated by Engrailed/Invected repression specifies boundary cells in the Drosophila hindgut. Mech Dev 2002, 114:71-84. 10.1016/S0925-4773(02)00061-8, 12175491.
54. Takashima S, Mkrtchyan M, Younossi-Hartenstein A, Merriam JR, Hartenstein V. The behaviour of Drosophila adult hindgut stem cells is controlled by Wnt and Hh signalling. Nature 2008, 454:651-655. 10.1038/nature07156, 18633350.
55. Backhaus B, Sulkowski E, Schlote FW. A semi-synthetic, general-purpose medium for D. melanogaster. D. I. S. (not peer-reviewed) 1984, 60:210-212.