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Characterization of the dog Agouti gene and a nonagoutimutation in German Shepherd Dogs

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Abstract

The interaction between two genes, Agouti and Melanocortin-1 receptor (Mc1r), produces diverse pigment patterns in mammals by regulating the type, amount, and distribution pattern of the two pigment types found in mammalian hair: eumelanin (brown/black) and pheomelanin (yellow/red). In domestic dogs (Canis familiaris), there is a tremendous variation in coat color patterns between and within breeds; however, previous studies suggest that the molecular genetics of pigment-type switching in dogs may differ from that of other mammals. Here we report the identification and characterization of the Agouti gene from domestic dogs, predicted to encode a 131-amino-acid secreted protein 98% identical to the fox homolog, and which maps to chromosome CFA24 in a region of conserved linkage. Comparative analysis of the Doberman Pinscher Agouti cDNA, the fox cDNA, and 180 kb of Doberman Pinscher genomic DNA suggests that, as with laboratory mice, different pigment-type-switching patterns in the canine family are controlled by alternative usage of different promoters and untranslated first exons. A small survey of Labrador Retrievers, Greyhounds, Australian Shepherds, and German Shepherd Dogs did not uncover any polymorphisms, but we identified a single nucleotide variant in black German Shepherd Dogs predicted to cause an Arg-to-Cys substitution at codon 96, which is likely to account for recessive inheritance of a uniform black coat.

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References

  • GS Barsh (1996) ArticleTitleThe genetics of pigmentation: from fancy genes to complex traits Trends Genet 12 299–305 Occurrence Handle10.1016/0168-9525(96)10031-7 Occurrence Handle1:CAS:528:DyaK28XkvV2rs74%3D Occurrence Handle8783939

    Article  CAS  PubMed  Google Scholar 

  • KA Bolin DJ Anderson JA Trulson DA Thompson J Wilken et al. (1999) ArticleTitleNMR structure of a minimized human agouti related protein prepared by total chemical synthesis FEBS Lett 451 125–131 Occurrence Handle10.1016/S0014-5793(99)00553-0 Occurrence Handle1:CAS:528:DyaK1MXjsVSjtLg%3D Occurrence Handle10371151

    Article  CAS  PubMed  Google Scholar 

  • M Breen R Thomas MM Binns NP Carter CF Langford (1999) ArticleTitleReciprocal chromosome painting reveals detailed regions of conserved synteny between the karyotypes of the domestic dog (Canis familiaris) and human Genomics 61 145–155 Occurrence Handle10.1006/geno.1999.5947 Occurrence Handle1:CAS:528:DyaK1MXmslyitrk%3D Occurrence Handle10534400

    Article  CAS  PubMed  Google Scholar 

  • SJ Bultman EJ Michaud RP Woychik (1992) ArticleTitleMolecular characterization of the mouse agouti locus Cell 71 1195–1204 Occurrence Handle1:CAS:528:DyaK3sXlslGjsLo%3D Occurrence Handle1473152

    CAS  PubMed  Google Scholar 

  • SJ Bultman ML Klebig EJ Michaud HO Sweet MT Davisson et al. (1994) ArticleTitleMolecular analysis of reverse mutations from nonagouti (A) to Black-and-Tan (A(T)) and White-Bellied agouti (A(W)) reveals alternative forms of agouti transcripts Gene Dev 8 481–490 Occurrence Handle1:CAS:528:DyaK2cXis1aksLs%3D Occurrence Handle8125260

    CAS  PubMed  Google Scholar 

  • M Burns MN Fraser (1966) Genetics of the Dog. The basis of successful breeding Oliver and Boyd Edinburgh, Scotland

    Google Scholar 

  • SI Candille CD Raamsdonk C Chen S Kuijper Y Chen–Tsai et al. (2004) ArticleTitleDorsoventral patterning of the mouse coat by Tbx15 PLoS Biol 2 30–42 Occurrence Handle10.1371/journal.pbio.0020003 Occurrence Handle1:CAS:528:DC%2BD2cXht1Krtrs%3D

    Article  CAS  Google Scholar 

  • EA Carver (1984) ArticleTitleCoat color genetics of the German Shepherd Dog J Hered 75 247–252

    Google Scholar 

  • RE Eizirik N Yuhki WE Johnson M Menotti–Raymond SS Hannah et al. (2003) ArticleTitleMolecular genetics and evolution of melanism in the cat family Curr Biol 13 448–453 Occurrence Handle10.1016/S0960-9822(03)00128-3 Occurrence Handle1:CAS:528:DC%2BD3sXhvFaiurk%3D Occurrence Handle12620197

    Article  CAS  PubMed  Google Scholar 

  • RE Everts J Rothuizen BA Oost Particlevan (2000) ArticleTitleIdentification of a premature stop codon in the melanocyte-stimulating hormone receptor gene (MC1R) in Labrador and Golden retrievers with yellow coat colour Anim Genet 31 194–199 Occurrence Handle10.1046/j.1365-2052.2000.00639.x Occurrence Handle1:CAS:528:DC%2BD3cXkvFOgtL8%3D Occurrence Handle10895310

    Article  CAS  PubMed  Google Scholar 

  • T Ha L Naysmith K Waterston C Oh R Weller et al. (2003) ArticleTitleDefining the quantitative contribution of the melanocortin 1 receptor (MC1R) to variation in pigmentary phenotype Ann NY Acad Sci 994 339–347 Occurrence Handle1:CAS:528:DC%2BD3sXmtVCktbo%3D Occurrence Handle12851334

    CAS  PubMed  Google Scholar 

  • CM Hustad WL Perry LD Siracusa C Rasberry L Cobb et al. (1995) ArticleTitleMolecular genetic characterization of six recessive viable alleles of the mouse agouti locus Genetics 140 255–265 Occurrence Handle1:CAS:528:DyaK28Xht1Cgu78%3D Occurrence Handle7635290

    CAS  PubMed  Google Scholar 

  • NA Iljin (1941) ArticleTitleWolf-Dog Genetics J Genet 42 359–427

    Google Scholar 

  • IJ Jackson (1994) ArticleTitleMolecular and developmental genetics of mouse coat color Annu Rev of Genet 28 189–217 Occurrence Handle10.1146/annurev.ge.28.120194.001201 Occurrence Handle1:CAS:528:DyaK2MXislWmu74%3D

    Article  CAS  Google Scholar 

  • H Joerg HR Fries E Meijerink GF Stranzinger (1996) ArticleTitleRed coat color in Holstein cattle is associated with a deletion in the MSHR gene Mamm Genome 7 317–318 Occurrence Handle10.1007/s003359900090 Occurrence Handle1:CAS:528:DyaK28Xjt1Wrtbs%3D Occurrence Handle8661706

    Article  CAS  PubMed  Google Scholar 

  • SA Jordan IJ Jackson (1998) ArticleTitleMelanocortin receptors and antagonists regulate pigmentation and body weight Bioessays 20 603–606 Occurrence Handle10.1002/(SICI)1521-1878(199808)20:8<603::AID-BIES1>3.0.CO;2-J Occurrence Handle1:STN:280:DyaK1cvlsVWiug%3D%3D Occurrence Handle9780833

    Article  CAS  PubMed  Google Scholar 

  • JA Kerns M Olivier G Lust GS Barsh (2003) ArticleTitleExclusion of melanocortin-1 receptor (mc1r) and agouti as candidates for dominant black in dogs J Hered 94 75–79 Occurrence Handle1:CAS:528:DC%2BD3sXktVWhu7k%3D Occurrence Handle12692166

    CAS  PubMed  Google Scholar 

  • LL Kiefer ORR Ittoop K Bunce AT Truesdale DH Willard et al. (1997) ArticleTitleMutations in the carboxyl terminus of the agouti protein decrease agouti inhibition of ligand binding to the melanocortin receptors Biochemistry 36 2084–2090 Occurrence Handle10.1021/bi962647v Occurrence Handle1:CAS:528:DyaK2sXhs1Cqsrg%3D Occurrence Handle9047307

    Article  CAS  PubMed  Google Scholar 

  • JM Kijas R Wales A Tornsten P Chardon M Moller et al. (1998) ArticleTitleMelanocortin receptor 1 (MC1R) mutations and coat color in pigs Genetics 150 1177–1185 Occurrence Handle1:CAS:528:DyaK1cXnsFCntb4%3D Occurrence Handle9799269

    CAS  PubMed  Google Scholar 

  • H Klungland DI Vage L Gomez–Raya S Adalsteinsson S Lien (1995) ArticleTitleThe role of melanocyte-stimulating hormone (MSH) receptor in bovine coat color determination Mamm Genome 6 636–639 Occurrence Handle10.1007/BF00352371 Occurrence Handle1:CAS:528:DyaK2MXoslKls7o%3D Occurrence Handle8535072

    Article  CAS  PubMed  Google Scholar 

  • T Kuramoto T Nomoto T Sugimura T Ushijima (2001) ArticleTitleCloning of the rat agouti gene and identification of the rat nonagouti mutation Mamm Genome 12 469–471 Occurrence Handle10.1007/s003350020010 Occurrence Handle1:CAS:528:DC%2BD3MXjs1Cnsrs%3D Occurrence Handle11353396

    Article  CAS  PubMed  Google Scholar 

  • R Li E Mignot J Faraco H Kadotani J Cantanese et al. (1999) ArticleTitleConstruction and characterization of an eightfold redundant dog genomic bacterial artificial chromosome library Genomics 58 9–17 Occurrence Handle10.1006/geno.1999.5772 Occurrence Handle1:CAS:528:DyaK1MXjtVymtbw%3D Occurrence Handle10331940

    Article  CAS  PubMed  Google Scholar 

  • MK Ling MC Lagerstrom R Fredriksson R Okimoto NI Mundy et al. (2003) ArticleTitleAssociation of feather colour with constitutively active melanocortin 1 receptors in chicken Eur J Biochem 270 1441–1449 Occurrence Handle1:CAS:528:DC%2BD3sXivFWnsb8%3D Occurrence Handle12653999

    CAS  PubMed  Google Scholar 

  • F Lingaas A Sorensen RK Juneja S Johansson M Fredholm et al. (1997) ArticleTitleTowards construction of a canine linkage map: establishment of 16 linkage groups Mamm Genome 8 218–221 Occurrence Handle10.1007/s003359900393 Occurrence Handle1:CAS:528:DyaK2sXit1aqu7k%3D Occurrence Handle9069125

    Article  CAS  PubMed  Google Scholar 

  • CC Little (1957) The inheritance of coat color in dogs Comstock Ithaca, N.Y.

    Google Scholar 

  • DS Lu D Willard IR Patel S Kadwell L Overton et al. (1994) ArticleTitleAgouti protein is an antagonist of the melanocyte-stimulating-hormone receptor Nature 371 799–802 Occurrence Handle10.1038/371799a0 Occurrence Handle1:CAS:528:DyaK2cXmvFeiu7o%3D Occurrence Handle7935841

    Article  CAS  PubMed  Google Scholar 

  • L Marklund MJ Moller K Sandberg L Andersson (1996) ArticleTitleA missense mutation in the gene for melanocyte-stimulating hormone receptor (MC1R) is associated with the chestnut coat color in horses Mamm Genome 7 895–899 Occurrence Handle10.1007/s003359900264 Occurrence Handle1:CAS:528:DyaK2sXnsVeqsw%3D%3D Occurrence Handle8995760

    Article  CAS  PubMed  Google Scholar 

  • JC McNulty DA Thompson KA Bolin J Wilken GS Barsh et al. (2001) ArticleTitleHigh-resolution NMR structure of the chemically-synthesized melanocortin receptor binding domain AGRP(87-132) of the agouti-related protein Biochemistry 40 15520–15527 Occurrence Handle10.1021/bi0117192 Occurrence Handle1:CAS:528:DC%2BD3MXos1CjsbY%3D Occurrence Handle11747427

    Article  CAS  PubMed  Google Scholar 

  • MW Miller DMJ Duhl H Vrieling SP Cordes MM Ollmann et al. (1993) ArticleTitleCloning of the mouse agouti gene predicts a secreted protein ubiquitously expressed in mice carrying the Lethal-Yellow mutation Genes Dev 7 454–467 Occurrence Handle1:CAS:528:DyaK3sXit1Oiu7c%3D Occurrence Handle8449404

    CAS  PubMed  Google Scholar 

  • RJ Miltenberger K Wakamatsu S Ito RP Woychik LB Russell et al. (2002) ArticleTitleMolecular and phenotypic analysis of 25 recessive, homozygous-viable alleles at the mouse agouti locus Genetics 160 659–674 Occurrence Handle1:CAS:528:DC%2BD38XitlWrsL4%3D Occurrence Handle11861569

    CAS  PubMed  Google Scholar 

  • NI Mundy J Kelly E Theron K Hawkins (2003) ArticleTitleEvolutionary genetics of the melanocortin-1 receptor in vertebrates Ann NY Acad Sci 994 307–312 Occurrence Handle1:CAS:528:DC%2BD3sXmtVCktb4%3D Occurrence Handle12851330

    CAS  PubMed  Google Scholar 

  • JM Newton AL Wilkie L He SA Jordan DL Metallinos et al. (2000) ArticleTitleMelanocortin 1 receptor variation in the domestic dog Mamm Genome 11 24–30 Occurrence Handle10.1007/s003350010005 Occurrence Handle1:CAS:528:DC%2BD3cXos12hsw%3D%3D Occurrence Handle10602988

    Article  CAS  PubMed  Google Scholar 

  • MM Ollmann BD Wilson YK Yang JA Kerns Y Chen et al. (1997) ArticleTitleAntagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein Science 278 135–138 Occurrence Handle10.1126/science.278.5335.135 Occurrence Handle1:CAS:528:DyaK2sXmsV2ltrw%3D Occurrence Handle9311920

    Article  CAS  PubMed  Google Scholar 

  • MM Ollmann ML Lamoreux BD Wilson GS Barsh (1998) ArticleTitleInteraction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo Genes Dev 12 316–330 Occurrence Handle1:CAS:528:DyaK1cXhtVOitL0%3D Occurrence Handle9450927

    CAS  PubMed  Google Scholar 

  • WL Perry CM Hustad DA Swing NA Jenkins NG Copeland (1995) ArticleTitleA transgenic mouse assay for agouti protein activity Genetics 140 267–274 Occurrence Handle1:CAS:528:DyaK28Xht1Cgu7w%3D Occurrence Handle7635291

    CAS  PubMed  Google Scholar 

  • S Rieder S Taourit D Mariat B Langlois G Guerin (2001) ArticleTitleMutations in the agouti (ASIP), the extension (MC1R), and the brown (TYRP1) loci and their association to coat color phenotypes in horses (Equus caballus) Mamm Genome 12 450–455 Occurrence Handle10.1007/s003350020017 Occurrence Handle1:CAS:528:DC%2BD3MXjs1Cnsr8%3D Occurrence Handle11353392

    Article  CAS  PubMed  Google Scholar 

  • K Ritland C Newton HD Marshall (2001) ArticleTitleInheritance and population structure of the white-phased “Kermode” black bear Curr Biol 11 1468–1472 Occurrence Handle10.1016/S0960-9822(01)00448-1 Occurrence Handle1:CAS:528:DC%2BD3MXntV2gt7g%3D Occurrence Handle11566108

    Article  CAS  PubMed  Google Scholar 

  • LS Robbins JH Nadeau KR Johnson MA Kelly L Rosellirehfuss et al. (1993) ArticleTitlePigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function Cell 72 827–834 Occurrence Handle10.1016/0092-8674(93)90572-8 Occurrence Handle1:CAS:528:DyaK3sXit1Ohsr4%3D Occurrence Handle8458079

    Article  CAS  PubMed  Google Scholar 

  • P Savolainen YP Zhang J Luo J Lundeberg T Leitner (2002) ArticleTitleGenetic evidence for an East Asian origin of domestic dogs Science 298 1610–1613 Occurrence Handle10.1126/science.1073906 Occurrence Handle1:CAS:528:DC%2BD38Xosl2ktbg%3D Occurrence Handle12446907

    Article  CAS  PubMed  Google Scholar 

  • SM Schmutz TG Berryere NM Ellinwood JA Kerns GS Barsh (2003) ArticleTitleMC1R studies in dogs with melanistic mask or brindle patterns J Hered 94 69–73 Occurrence Handle10.1093/jhered/esg014 Occurrence Handle1:CAS:528:DC%2BD3sXktVWhu7g%3D Occurrence Handle12692165

    Article  CAS  PubMed  Google Scholar 

  • AG Searle (1968) Comparative Genetics of Coat Color in Mammals Academic Press New York

    Google Scholar 

  • WK Silvers (1979) The Coat Colors of Mice: A Model for Mammalian Gene Action and Interaction Springer-Verlag New York

    Google Scholar 

  • RA Sturm DL Duffy NF Box RA Newton AG Shepherd et al. (2003) ArticleTitleGenetic association and cellular function of MC1R variant alleles in human pigmentation Ann NY Acad Sci 994 348–358 Occurrence Handle1:CAS:528:DC%2BD3sXmtVCktbs%3D Occurrence Handle12851335

    CAS  PubMed  Google Scholar 

  • S Takeuchi H Suzuki M Yabuuchi S Takahashi (1996) ArticleTitleA possible involvement of melanocortin-1 receptor in regulating feather color pigmentation in the chicken Biochim Biophys Acta 1308 164–168 Occurrence Handle1:CAS:528:DyaK28XksVGnsrw%3D Occurrence Handle8764834

    CAS  PubMed  Google Scholar 

  • E Theron K Hawkins E Bermingham RE Ricklefs NI Mundy (2001) ArticleTitleThe molecular basis of an avian plumage polymorphism in the wild: a melanocortin-1-receptor point mutation is perfectly associated with the melanic plumage morph of the bananaquit, Coereba flaveola Curr Biol 11 550–557 Occurrence Handle10.1016/S0960-9822(01)00158-0 Occurrence Handle1:CAS:528:DC%2BD3MXjtlenurY%3D Occurrence Handle11369199

    Article  CAS  PubMed  Google Scholar 

  • DI Vage DS Lu H Klungland S Lien S Adalsteinsson et al. (1997) ArticleTitleA non-epistatic interaction of agouti and extension in the fox, Vulpes vulpes Na Genet 15 311–315 Occurrence Handle10.1038/ng0397-311 Occurrence Handle1:CAS:528:DyaK2sXhsVGqsbs%3D

    Article  CAS  Google Scholar 

  • DI Vage H Klungland D Lu RD Cone (1999) ArticleTitleMolecular and pharmacological characterization of dominant black coat color in sheep Mamm Genome 10 39–43 Occurrence Handle10.1007/s003359900939 Occurrence Handle1:CAS:528:DyaK1MXnvVaitQ%3D%3D Occurrence Handle9892731

    Article  CAS  PubMed  Google Scholar 

  • C Vila JE Maldonado RK Wayne (1999) ArticleTitlePhylogenetic relationships, evolution, and genetic diversity of the domestic dog J Hered 90 71–77 Occurrence Handle10.1093/jhered/90.1.71 Occurrence Handle1:STN:280:DyaK1M7kt1eqtA%3D%3D Occurrence Handle9987908

    Article  CAS  PubMed  Google Scholar 

  • H Vrieling DM Duhl SE Millar KA Miller GS Barsh (1994) ArticleTitleDifferences in dorsal and ventral pigmentation result from regional expression of the mouse agouti gene Proc Natl Acad Sci USA 91 5667–5671 Occurrence Handle1:CAS:528:DyaK2cXksFCms7w%3D Occurrence Handle8202545

    CAS  PubMed  Google Scholar 

  • RK Wayne EA Ostrander (1999) ArticleTitleOrigin, genetic diversity, and genome structure of the domestic dog Bioessays 21 247–257 Occurrence Handle10.1002/(SICI)1521-1878(199903)21:3<247::AID-BIES9>3.0.CO;2-Z Occurrence Handle1:STN:280:DyaK1M3ms1aktA%3D%3D Occurrence Handle10333734

    Article  CAS  PubMed  Google Scholar 

  • DH Willard W Bodnar C Harris L Kiefer JS Nichols et al. (1995) ArticleTitleAgouti structure and function: characterization of a potent alpha-melanocyte stimulating hormone receptor antagonist Biochemistry 34 12341–12346 Occurrence Handle1:CAS:528:DyaK2MXnvVGmsr8%3D Occurrence Handle7547977

    CAS  PubMed  Google Scholar 

  • MB Willis (1989) Genetics of the dog Howell New York

    Google Scholar 

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Acknowledgments

We thank J. Faraco and E. Mignot for providing the canine BAC library, and J. Longmire for his support of JAK. We are grateful to the dog breeders who generously submitted DNA samples from their litters and to the DogMap and the FHCRC dog genome project for providing public access to the canine map and marker data at http://www.dogmap.ch/ index.html and http://www.fhcrc.org/science/ dog_genome/ .

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Correspondence to Gregory S. Barsh.

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Genbank accession numbers are AC092250 (bacterial artificial chromosome clone RP81-20712) and AY714374 (Doberman Pinscher Agouti cDNA).

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Kerns, J.A., Newton, J., Berryere, T.G. et al. Characterization of the dog Agouti gene and a nonagoutimutation in German Shepherd Dogs. Mamm Genome 15, 798–808 (2004). https://doi.org/10.1007/s00335-004-2377-1

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