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The insulin-like growth factor 1 receptor (IGF1R) contributes to reduced size in dogs

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Abstract

Domestic dog breeds have undergone intense selection for a variety of morphologic features, including size. Among small-dog breeds, defined as those averaging less than ~15 in. at the withers, there remains still considerable variation in body size. Yet essentially all such dogs are fixed for the same allele at the insulin-like growth factor 1 gene, which we and others previously found to be a size locus of large effect. In this study we sought to identify additional genes that contribute to tiny size in dogs using an association scan with the single nucleotide polymorphism (SNP) dataset CanMap, in which 915 purebred dogs were genotyped at 60,968 SNP markers. Our strongest association for tiny size (defined as breed-average height not more than 10 in. at the withers) was on canine chromosome 3 (p = 1.9 × 10−70). Fine mapping revealed a nonsynonymous SNP at chr3:44,706,389 that changes a highly conserved arginine at amino acid 204 to histidine in the insulin-like growth factor 1 receptor (IGF1R). This mutation is predicted to prevent formation of several hydrogen bonds within the cysteine-rich domain of the receptor’s ligand-binding extracellular subunit. Nine of 13 tiny dog breeds carry the mutation and many dogs are homozygous for it. This work underscores the central importance of the IGF1 pathway in controlling the tremendous size diversity of dogs.

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References

  • Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249

    Article  PubMed  CAS  Google Scholar 

  • Akey JM, Ruhe AL, Akey DT, Wong AK, Connelly CF, Madeoy J, Nicholas TJ, Neff MW (2010) Tracking footprints of artificial selection in the dog genome. Proc Natl Acad Sci USA 107:1160–1165

    Article  PubMed  CAS  Google Scholar 

  • American Kennel Club (AKC) (1998) The complete dog book, 19th edn. Howell Book House, New York

    Google Scholar 

  • Aulchenko YS, Struchalin MV, Belonogova NM, Axenovich TI, Weedon MN, Hofman A, Uitterlinden AG, Kayser M, Oostra BA, van Duijn CM, Janssens AC, Borodin PM (2009) Predicting human height by Victorian and genomic methods. Eur J Hum Genet 17:1070–1075

    Article  PubMed  CAS  Google Scholar 

  • Bannasch D, Young A, Myers J, Truve K, Dickinson P, Gregg J, Davis R, Bongcam-Rudloff E, Webster MT, Lindblad-Toh K, Pedersen N (2010) Localization of canine brachycephaly using an across breed mapping approach. PLoS ONE 5:e9632

    Article  PubMed  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  PubMed  CAS  Google Scholar 

  • Bokov AF, Garg N, Ikeno Y, Thakur S, Musi N, DeFronzo RA, Zhang N, Erickson RC, Gelfond J, Hubbard GB, Adamo ML, Richardson A (2011) Does reduced IGF1R signaling in Igf1r+/− mice alter aging? PLoS ONE 6(11):e26891

    Article  PubMed  CAS  Google Scholar 

  • Boyko AR, Quignon P, Li L, Schoenebeck JJ, Degenhardt JD, Lohmueller KE, Zhao K, Brisbin A, Parker HG, vonHoldt BM, Cargill M, Auton A, Reynolds A, Elkahloun AG, Castelhano M, Mosher DS, Sutter NB, Johnson GS, Novembre J, Hubisz MJ, Siepel A, Wayne RK, Bustamante CD, Ostrander EA (2010) A simple genetic architecture underlies morphological variation in dogs. PLoS Biol 8:e1000451

    Article  PubMed  Google Scholar 

  • Cadieu E, Neff MW, Quignon P, Walsh K, Chase K, Parker HG, vonHoldt BM, Rhue A, Boyko A, Byers A, Wong A, Mosher DS, Elkahloun AG, Spady TC, Andre C, Lark KG, Cargill M, Bustamante CD, Wayne RK, Ostrander EA (2009) Coat variation in the domestic dog is governed by variants in three genes. Science 326:150–153

    Article  PubMed  CAS  Google Scholar 

  • Chase K, Carrier DR, Adler FR, Jarvik T, Ostrander EA, Lorentzen TD, Lark KG (2002) Genetic basis for systems of skeletal quantitative traits: principal component analysis of the canid skeleton. Proc Natl Acad Sci USA 99:9930–9935

    Article  PubMed  CAS  Google Scholar 

  • Eigenmann JE, Patterson DF, Froesch ER (1984) Body size parallels insulin-like growth factor I levels but not growth hormone secretory capacity. Acta Endocrinol (Copenh) 106:448–453

    CAS  Google Scholar 

  • Farias FH, Johnson GS, Taylor JF, Giuliano E, Katz ML, Sanders DN, Schnabel RD, McKay SD, Khan S, Gharahkhani P, O’Leary CA, Pettitt L, Forman OP, Boursnell M, McLaughlin B, Ahonen S, Lohi H, Hernandez-Merino E, Gould DJ, Sargan DR, Mellersh C (2010) An ADAMTS17 splice donor site mutation in dogs with primary lens luxation. Investig Ophthalmol Vis Sci 51:4716–4721

    Article  Google Scholar 

  • Forbes BE (2011) Molecular mechanisms underlying insulin-like growth factor action: how mutations in the GH: IGF axis lead to short stature. Pediatr Endocrinol Rev 8:374–381

    PubMed  Google Scholar 

  • Garrett TP, McKern NM, Lou M, Frenkel MJ, Bentley JD, Lovrecz GO, Elleman TC, Cosgrove LJ, Ward CW (1998) Crystal structure of the first three domains of the type-1 insulin-like growth factor receptor. Nature 394:395–399

    Article  PubMed  CAS  Google Scholar 

  • Gould D, Pettitt L, McLaughlin B, Holmes N, Forman O, Thomas A, Ahonen S, Lohi H, O’Leary C, Sargan D, Mellersh C (2011) ADAMTS17 mutation associated with primary lens luxation is widespread among breeds. Vet Ophthalmol 14:378–384

    Article  PubMed  CAS  Google Scholar 

  • Gray MM, Sutter NB, Ostrander EA, Wayne RK (2010) The IGF1 small dog haplotype is derived from Middle Eastern grey wolves. BMC Biol 8:16

    Article  PubMed  Google Scholar 

  • Gudbjartsson DF, Walters GB, Thorleifsson G, Stefansson H, Halldorsson BV, Zusmanovich P, Sulem P, Thorlacius S, Gylfason A, Steinberg S, Helgadottir A, Ingason A, Steinthorsdottir V, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Pedersen O, Aben KK, Witjes JA, Swinkels DW, den Heijer M, Franke B, Verbeek AL, Becker DM, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Gulcher J, Kiemeney LA, Kong A, Thorsteinsdottir U, Stefansson K (2008) Many sequence variants affecting diversity of adult human height. Nat Genet 40:609–615

    Article  PubMed  CAS  Google Scholar 

  • Hirschhorn JN, Gajdos ZK (2011) Genome-wide association studies: results from the first few years and potential implications for clinical medicine. Annu Rev Med 62:11–24

    Article  PubMed  CAS  Google Scholar 

  • Jones P, Chase K, Martin A, Davern P, Ostrander EA, Lark KG (2008) Single-nucleotide-polymorphism-based association mapping of dog stereotypes. Genetics 179:1033–1044

    Article  PubMed  CAS  Google Scholar 

  • Kappeler L, De Magalhaes Filho C, Dupont J, Leneuve P, Cervera P, Perin L, Loudes C, Blaise A, Klein R, Epelbaum J, Le Bouc Y, Holzenberger M (2008) Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS Biol 6(10):e254

    Article  PubMed  Google Scholar 

  • Karlsson EK, Baranowska I, Wade CM, Salmon Hillbertz NH, Zody MC, Anderson N, Biagi TM, Patterson N, Pielberg GR, Kulbokas EJ III, Comstock KE, Keller ET, Mesirov JP, von Euler H, Kampe O, Hedhammar A, Lander ES, Andersson G, Andersson L, Lindblad-Toh K (2007) Efficient mapping of Mendelian traits in dogs through genome-wide association. Nat Genet 39:1321–1328

    Article  PubMed  CAS  Google Scholar 

  • Kawashima Y, Higaki K, Fukushima T, Hakuno F, Nagaishi J, Hanaki K, Nanba E, Takahashi S, Kanzaki S (2012) Novel missense mutation in the IGF-1 receptor L2 domain results in intrauterine and postnatal growth retardation. Clin Endocrinol 77(2):246–254

    Article  CAS  Google Scholar 

  • Keyhanfar M, Booker GW, Whittaker J, Wallace JC, Forbes BE (2007) Precise mapping of an IGF-I-binding site on the IGF-1R. Biochem J 401:269–277

    Article  PubMed  CAS  Google Scholar 

  • Kim JJ, Lee HI, Park T, Kim K, Lee JE, Cho NH, Shin C, Cho YS, Lee JY, Han BG, Yoo HW, Lee JK (2010) Identification of 15 loci influencing height in a Korean population. J Hum Genet 55:27–31

    Article  PubMed  Google Scholar 

  • Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081

    Article  PubMed  CAS  Google Scholar 

  • Lango Allen H, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, Willer CJ, Jackson AU, Vedantam S, Raychaudhuri S, Ferreira T, Wood AR, Weyant RJ, Segre AV, Speliotes EK, Wheeler E, Soranzo N, Park JH, Yang J, Gudbjartsson D, Heard-Costa NL, Randall JC, Qi L, Vernon Smith A, Magi R, Pastinen T, Liang L, Heid IM, Luan J, Thorleifsson G, Winkler TW, Goddard ME, Sin Lo K, Palmer C, Workalemahu T, Aulchenko YS, Johansson A, Zillikens MC, Feitosa MF, Esko T, Johnson T, Ketkar S, Kraft P, Mangino M, Prokopenko I, Absher D, Albrecht E, Ernst F, Glazer NL, Hayward C, Hottenga JJ, Jacobs KB, Knowles JW, Kutalik Z, Monda KL, Polasek O, Preuss M, Rayner NW, Robertson NR, Steinthorsdottir V, Tyrer JP, Voight BF, Wiklund F, Xu J, Zhao JH, Nyholt DR, Pellikka N, Perola M, Perry JR, Surakka I, Tammesoo ML, Altmaier EL, Amin N, Aspelund T, Bhangale T, Boucher G, Chasman DI, Chen C, Coin L, Cooper MN, Dixon AL, Gibson Q, Grundberg E, Hao K, Juhani Junttila M, Kaplan LM, Kettunen J, Konig IR, Kwan T, Lawrence RW, Levinson DF, Lorentzon M, McKnight B, Morris AP, Muller M, Suh Ngwa J, Purcell S, Rafelt S, Salem RM, Salvi E, Sanna S, Shi J, Sovio U, Thompson JR, Turchin MC, Vandenput L, Verlaan DJ, Vitart V, White CC, Ziegler A, Almgren P, Balmforth AJ, Campbell H, Citterio L, De Grandi A, Dominiczak A, Duan J, Elliott P, Elosua R, Eriksson JG, Freimer NB, Geus EJ, Glorioso N, Haiqing S, Hartikainen AL, Havulinna AS, Hicks AA, Hui J, Igl W, Illig T, Jula A, Kajantie E, Kilpelainen TO, Koiranen M, Kolcic I, Koskinen S, Kovacs P, Laitinen J, Liu J, Lokki ML, Marusic A, Maschio A, Meitinger T, Mulas A, Pare G, Parker AN, Peden JF, Petersmann A, Pichler I, Pietilainen KH, Pouta A, Ridderstrale M, Rotter JI, Sambrook JG, Sanders AR, Schmidt CO, Sinisalo J, Smit JH, Stringham HM, Bragi Walters G, Widen E, Wild SH, Willemsen G, Zagato L, Zgaga L, Zitting P, Alavere H, Farrall M, McArdle WL, Nelis M, Peters MJ, Ripatti S, van Meurs JB, Aben KK, Ardlie KG, Beckmann JS, Beilby JP, Bergman RN, Bergmann S, Collins FS, Cusi D, den Heijer M, Eiriksdottir G, Gejman PV, Hall AS, Hamsten A, Huikuri HV, Iribarren C, Kahonen M, Kaprio J, Kathiresan S, Kiemeney L, Kocher T, Launer LJ, Lehtimaki T, Melander O, Mosley TH Jr, Musk AW, Nieminen MS, O’Donnell CJ, Ohlsson C, Oostra B, Palmer LJ, Raitakari O, Ridker PM, Rioux JD, Rissanen A, Rivolta C, Schunkert H, Shuldiner AR, Siscovick DS, Stumvoll M, Tonjes A, Tuomilehto J, van Ommen GJ, Viikari J, Heath AC, Martin NG, Montgomery GW, Province MA, Kayser M, Arnold AM, Atwood LD, Boerwinkle E, Chanock SJ, Deloukas P, Gieger C, Gronberg H, Hall P, Hattersley AT, Hengstenberg C, Hoffman W, Lathrop GM, Salomaa V, Schreiber S, Uda M, Waterworth D, Wright AF, Assimes TL, Barroso I, Hofman A, Mohlke KL, Boomsma DI, Caulfield MJ, Cupples LA, Erdmann J, Fox CS, Gudnason V, Gyllensten U, Harris TB, Hayes RB, Jarvelin MR, Mooser V, Munroe PB, Ouwehand WH, Penninx BW, Pramstaller PP, Quertermous T, Rudan I, Samani NJ, Spector TD, Volzke H, Watkins H, Wilson JF, Groop LC, Haritunians T, Hu FB, Kaplan RC, Metspalu A, North KE, Schlessinger D, Wareham NJ, Hunter DJ, O’Connell JR, Strachan DP, Wichmann HE, Borecki IB, van Duijn CM, Schadt EE, Thorsteinsdottir U, Peltonen L, Uitterlinden AG, Visscher PM, Chatterjee N, Loos RJ, Boehnke M, McCarthy MI, Ingelsson E, Lindgren CM, Abecasis GR, Stefansson K, Frayling TM, Hirschhorn JN (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467:832–838

    Article  PubMed  CAS  Google Scholar 

  • Lettre G (2011) Recent progress in the study of the genetics of height. Hum Genet 129:465–472

    Article  PubMed  Google Scholar 

  • Lindblad-Toh K, Wade CM, Mikkelsen TS, Karlsson EK, Jaffe DB, Kamal M, Clamp M, Chang JL, Kulbokas EJ III, Zody MC, Mauceli E, Xie X, Breen M, Wayne RK, Ostrander EA, Ponting CP, Galibert F, Smith DR, DeJong PJ, Kirkness E, Alvarez P, Biagi T, Brockman W, Butler J, Chin CW, Cook A, Cuff J, Daly MJ, DeCaprio D, Gnerre S, Grabherr M, Kellis M, Kleber M, Bardeleben C, Goodstadt L, Heger A, Hitte C, Kim L, Koepfli KP, Parker HG, Pollinger JP, Searle SM, Sutter NB, Thomas R, Webber C, Baldwin J, Abebe A, Abouelleil A, Aftuck L, Ait-Zahra M, Aldredge T, Allen N, An P, Anderson S, Antoine C, Arachchi H, Aslam A, Ayotte L, Bachantsang P, Barry A, Bayul T, Benamara M, Berlin A, Bessette D, Blitshteyn B, Bloom T, Blye J, Boguslavskiy L, Bonnet C, Boukhgalter B, Brown A, Cahill P, Calixte N, Camarata J, Cheshatsang Y, Chu J, Citroen M, Collymore A, Cooke P, Dawoe T, Daza R, Decktor K, DeGray S, Dhargay N, Dooley K, Dorje P, Dorjee K, Dorris L, Duffey N, Dupes A, Egbiremolen O, Elong R, Falk J, Farina A, Faro S, Ferguson D, Ferreira P, Fisher S, FitzGerald M, Foley K, Foley C, Franke A, Friedrich D, Gage D, Garber M, Gearin G, Giannoukos G, Goode T, Goyette A, Graham J, Grandbois E, Gyaltsen K, Hafez N, Hagopian D, Hagos B, Hall J, Healy C, Hegarty R, Honan T, Horn A, Houde N, Hughes L, Hunnicutt L, Husby M, Jester B, Jones C, Kamat A, Kanga B, Kells C, Khazanovich D, Kieu AC, Kisner P, Kumar M, Lance K, Landers T, Lara M, Lee W, Leger JP, Lennon N, Leuper L, LeVine S, Liu J, Liu X, Lokyitsang Y, Lokyitsang T, Lui A, Macdonald J, Major J, Marabella R, Maru K, Matthews C, McDonough S, Mehta T, Meldrim J, Melnikov A, Meneus L, Mihalev A, Mihova T, Miller K, Mittelman R, Mlenga V, Mulrain L, Munson G, Navidi A, Naylor J, Nguyen T, Nguyen N, Nguyen C, Nicol R, Norbu N, Norbu C, Novod N, Nyima T, Olandt P, O’Neill B, O’Neill K, Osman S, Oyono L, Patti C, Perrin D, Phunkhang P, Pierre F, Priest M, Rachupka A, Raghuraman S, Rameau R, Ray V, Raymond C, Rege F, Rise C, Rogers J, Rogov P, Sahalie J, Settipalli S, Sharpe T, Shea T, Sheehan M, Sherpa N, Shi J, Shih D, Sloan J, Smith C, Sparrow T, Stalker J, Stange-Thomann N, Stavropoulos S, Stone C, Stone S, Sykes S, Tchuinga P, Tenzing P, Tesfaye S, Thoulutsang D, Thoulutsang Y, Topham K, Topping I, Tsamla T, Vassiliev H, Venkataraman V, Vo A, Wangchuk T, Wangdi T, Weiand M, Wilkinson J, Wilson A, Yadav S, Yang S, Yang X, Young G, Yu Q, Zainoun J, Zembek L, Zimmer A, Lander ES (2005) Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438:803–819

    Article  PubMed  CAS  Google Scholar 

  • Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75:59–72

    PubMed  CAS  Google Scholar 

  • Liu JZ, Medland SE, Wright MJ, Henders AK, Heath AC, Madden PA, Duncan A, Montgomery GW, Martin NG, McRae AF (2010) Genome-wide association study of height and body mass index in Australian twin families. Twin Res Hum Genet 13:179–193

    Article  PubMed  Google Scholar 

  • Netchine I, Azzi S, Houang M, Seurin D, Perin L, Ricort JM, Daubas C, Legay C, Mester J, Herich R, Godeau F, Le Bouc Y (2009) Partial primary deficiency of insulin-like growth factor (IGF)-I activity associated with IGF1 mutation demonstrates its critical role in growth and brain development. J Clin Endocrinol Metab 94:3913–3921

    Article  PubMed  CAS  Google Scholar 

  • Netchine I, Azzi S, Le Bouc Y, Savage MO (2011) IGF1 molecular anomalies demonstrate its critical role in fetal, postnatal growth and brain development. Best Pract Res Clin Endocrinol Metab 25:181–190

    Article  PubMed  CAS  Google Scholar 

  • Okada Y, Kamatani Y, Takahashi A, Matsuda K, Hosono N, Ohmiya H, Daigo Y, Yamamoto K, Kubo M, Nakamura Y, Kamatani N (2010) A genome-wide association study in 19,633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci. Hum Mol Genet 19:2303–2312

    Article  PubMed  CAS  Google Scholar 

  • Olsson M, Meadows JR, Truve K, Rosengren Pielberg G, Puppo F, Mauceli E, Quilez J, Tonomura N, Zanna G, Docampo MJ, Bassols A, Avery AC, Karlsson EK, Thomas A, Kastner DL, Bongcam-Rudloff E, Webster MT, Sanchez A, Hedhammar A, Remmers EF, Andersson L, Ferrer L, Tintle L, Lindblad-Toh K (2011) A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs. PLoS Genet 7:e1001332

    Article  PubMed  CAS  Google Scholar 

  • Ostrander EA, Wayne RK (2005) The canine genome. Genome Res 15:1706–1716

    Article  PubMed  CAS  Google Scholar 

  • Parker HG, vonHoldt BM, Quignon P, Margulies EH, Shao S, Mosher DS, Spady TC, Elkahloun A, Cargill M, Jones PG, Maslen CL, Acland GM, Sutter NB, Kuroki K, Bustamante CD, Wayne RK, Ostrander EA (2009) An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs. Science 325:995–998

    Article  PubMed  CAS  Google Scholar 

  • Parker HG, Shearin AL, Ostrander EA (2010) Man’s best friend becomes biology’s best in show: genome analyses in the domestic dog. Annu Rev Genet 44:309–336

    Article  PubMed  CAS  Google Scholar 

  • Perola M (2011) Genome-wide association approaches for identifying loci for human height genes. Best Pract Res Clin Endocrinol Metab 25:19–23

    Article  PubMed  CAS  Google Scholar 

  • Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575

    Article  PubMed  CAS  Google Scholar 

  • Romero CJ, Ng Y, Luque RM, Kineman RD, Koch L, Bruning JC, Radovick S (2010) Targeted deletion of somatotroph insulin-like growth factor-I signaling in a cell-specific knockout mouse model. Mol Endocrinol 24(5):1077–1089

    Article  PubMed  CAS  Google Scholar 

  • Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132:365–386

    PubMed  CAS  Google Scholar 

  • Salmon Hillbertz NH, Isaksson M, Karlsson EK, Hellmen E, Pielberg GR, Savolainen P, Wade CM, von Euler H, Gustafson U, Hedhammar A, Nilsson M, Lindblad-Toh K, Andersson L, Andersson G (2007) Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs. Nat Genet 39:1318–1320

    Article  PubMed  CAS  Google Scholar 

  • Sambrook J, Russell DW (2001) Molecular cloning, a laboratory manual, 3rd edn. Cold Spring Harbor Laboratory Press, Cold Spring Harbor

    Google Scholar 

  • Sanna S, Jackson AU, Nagaraja R, Willer CJ, Chen WM, Bonnycastle LL, Shen H, Timpson N, Lettre G, Usala G, Chines PS, Stringham HM, Scott LJ, Dei M, Lai S, Albai G, Crisponi L, Naitza S, Doheny KF, Pugh EW, Ben-Shlomo Y, Ebrahim S, Lawlor DA, Bergman RN, Watanabe RM, Uda M, Tuomilehto J, Coresh J, Hirschhorn JN, Shuldiner AR, Schlessinger D, Collins FS, Davey Smith G, Boerwinkle E, Cao A, Boehnke M, Abecasis GR, Mohlke KL (2008) Common variants in the GDF5-UQCC region are associated with variation in human height. Nat Genet 40:198–203

    Article  PubMed  CAS  Google Scholar 

  • Soranzo N, Rivadeneira F, Chinappen-Horsley U, Malkina I, Richards JB, Hammond N, Stolk L, Nica A, Inouye M, Hofman A, Stephens J, Wheeler E, Arp P, Gwilliam R, Jhamai PM, Potter S, Chaney A, Ghori MJ, Ravindrarajah R, Ermakov S, Estrada K, Pols HA, Williams FM, McArdle WL, van Meurs JB, Loos RJ, Dermitzakis ET, Ahmadi KR, Hart DJ, Ouwehand WH, Wareham NJ, Barroso I, Sandhu MS, Strachan DP, Livshits G, Spector TD, Uitterlinden AG, Deloukas P (2009) Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size. PLoS Genet 5:e1000445

    Article  PubMed  Google Scholar 

  • Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989

    Article  PubMed  CAS  Google Scholar 

  • Sutter NB, Eberle MA, Parker HG, Pullar BJ, Kirkness EF, Kruglyak L, Ostrander EA (2004) Extensive and breed-specific linkage disequilibrium in Canis familiaris. Genome Res 14:2388–2396

    Article  PubMed  CAS  Google Scholar 

  • Sutter NB, Bustamante CD, Chase K, Gray MM, Zhao K, Zhu L, Padhukasahasram B, Karlins E, Davis S, Jones PG, Quignon P, Johnson GS, Parker HG, Fretwell N, Mosher DS, Lawler DF, Satyaraj E, Nordborg M, Lark KG, Wayne RK, Ostrander EA (2007) A single IGF1 allele is a major determinant of small size in dogs. Science 316:112–115

    Article  PubMed  CAS  Google Scholar 

  • Sutter NB, Mosher DS, Gray MM, Ostrander EA (2008) Morphometrics within dog breeds are highly reproducible and dispute Rensch’s rule. Mamm Genome 19:713–723

    Article  PubMed  Google Scholar 

  • Vaysse A, Ratnakumar A, Derrien T, Axelsson E, Rosengren Pielberg G, Sigurdsson S, Fall T, Seppala EH, Hansen MS, Lawley CT, Karlsson EK, The Lupa Consortium, Bannasch D, Vila C, Lohi H, Galibert F, Fredholm M, Haggstrom J, Hedhammar A, Andre C, Lindblad-Toh K, Hitte C, Webster MT (2011) Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping. PLoS Genet 7:e1002316

    Article  PubMed  CAS  Google Scholar 

  • vonHoldt BM, Pollinger JP, Lohmueller KE, Han E, Parker HG, Quignon P, Degenhardt JD, Boyko AR, Earl DA, Auton A, Reynolds A, Bryc K, Brisbin A, Knowles JC, Mosher DS, Spady TC, Elkahloun A, Geffen E, Pilot M, Jedrzejewski W, Greco C, Randi E, Bannasch D, Wilton A, Shearman J, Musiani M, Cargill M, Jones PG, Qian Z, Huang W, Ding ZL, Zhang YP, Bustamante CD, Ostrander EA, Novembre J, Wayne RK (2010) Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication. Nature 464:898–902

    Article  PubMed  CAS  Google Scholar 

  • Weedon MN, Lettre G, Freathy RM, Lindgren CM, Voight BF, Perry JR, Elliott KS, Hackett R, Guiducci C, Shields B, Zeggini E, Lango H, Lyssenko V, Timpson NJ, Burtt NP, Rayner NW, Saxena R, Ardlie K, Tobias JH, Ness AR, Ring SM, Palmer CN, Morris AD, Peltonen L, Salomaa V, The Diabetes Genetics Initiative, The Wellcome Trust Case Control Consortium, Davey Smith G, Groop LC, Hattersley AT, McCarthy MI, Hirschhorn JN, Frayling TM (2007) A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat Genet 39:1245–1250

    Article  PubMed  CAS  Google Scholar 

  • Weedon MN, Lango H, Lindgren CM, Wallace C, Evans DM, Mangino M, Freathy RM, Perry JR, Stevens S, Hall AS, Samani NJ, Shields B, Prokopenko I, Farrall M, Dominiczak A, The Diabetes Genetics Initiative, Wellcome Trust Case Control Consortium, Johnson T, Bergmann S, Beckmann JS, Vollenweider P, Waterworth DM, Mooser V, Palmer CN, Morris AD, Ouwehand WH, Cambridge GEM Consortium, Caulfield M, Munroe PB, Hattersley AT, McCarthy MI, Frayling TM (2008) Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet 40:575–583

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank members of the Ostrander and Sutter laboratories and the students of BCH. We thank Jeffrey Schoenebeck for helpful discussion and Roger Rowlett for assistance with IGF1R structure analysis. This research would not be possible without the generous support of dog owners who provided access to their animals. BCH carried out a majority of her portion of this work while on sabbatical in the Ostrander lab with support from the Colgate Research Council. This work was funded by the intramural program at NHGRI/NIH (EAO, MR, DL) and Cornell University internal funds (NBS).

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Authors and Affiliations

  1. Department of Biology, Colgate University, 13 Oak Drive, Hamilton, NY, 13346, USA

    Barbara C. Hoopes

  2. National Human Genome Research Institute, Building 50, Room 5349, 50 South Drive MSC 8000, Bethesda, MD, 20892, USA

    Maud Rimbault, David Liebers & Elaine A. Ostrander

  3. Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA

    Nathan B. Sutter

  4. C3-179 Vet Medical Center, Cornell University, Ithaca, NY, 14850, USA

    Nathan B. Sutter

Authors
  1. Barbara C. Hoopes
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  2. Maud Rimbault
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  3. David Liebers
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  4. Elaine A. Ostrander
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  5. Nathan B. Sutter
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Corresponding author

Correspondence to Nathan B. Sutter.

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Electronic supplementary material The online version of this article (doi: 10.1007/s00335-012-9417-z) contains supplementary material which is available to authorized users. (DOCX 3307 kb)

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Hoopes, B.C., Rimbault, M., Liebers, D. et al. The insulin-like growth factor 1 receptor (IGF1R) contributes to reduced size in dogs. Mamm Genome 23, 780–790 (2012). https://doi.org/10.1007/s00335-012-9417-z

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  • DOI: https://doi.org/10.1007/s00335-012-9417-z

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