OMIA 001199-9615 : Coat colour, extension in Canis lupus familiaris

In other species: cattle , horse , red fox , pig , sheep , jaguar , jaguarundi , American black bear , woolly mammoth , domestic cat , rabbit , domestic guinea pig , goat , Arctic fox , rock pocket mouse , oldfield mouse , gray squirrel , lesser earless lizard , little striped whiptail , water buffalo , domestic yak , alpaca , , coyote , reindeer , Geoffroy's cat , Colocolo , ass , Arabian camel , Mongolian gerbil , raccoon dog , fallow deer , zebu

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 266300 (trait) , 155555 (gene) , 203200 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2000

Cross-species summary: The extension locus encodes the melanocyte-stimulating hormone receptor (MSHR; now known as MC1R). This receptor controls the level of tyrosinase within melanocytes. Tyrosinase is the limiting enzyme involved in synthesis of melanins: high levels of tyrosinase result in the production of eumelanin (dark colour, e.g. brown or black), while low levels result in the production of phaeomelanin (light colour, e.g. red or yellow). When melanocyte-stimulating hormone (MSH) binds to its receptor, the level of tyrosinase is increased, leading to production of eumelanin. The wild-type allele at the extension locus corresponds to a functional MSHR, and hence to dark pigmentation in the presence of MSH. As explained by Schneider et al. (PLoS Genet 10(2): e1004892; 2015), "The most common causes of melanism (black coat) mutations are gain-of-function alterations in MC1R, or loss-of function alterations in ASIP, which encodes Agouti signaling protein, a paracrine signaling molecule that inhibits MC1R signaling". Mutations in MC1R have been associated with white colouring in several species.

Species-specific name: This is the classic E (Extension) locus described by Little (1957)

Species-specific symbol: E locus

History: Ollivier et al. (2013) reported that "Interestingly, a mutation at the same position ‘301’, namely an amino-acid change from Arginine->Serine was detected in the Mc1r sequence of a 43,000-year-old mammoth" (see OMIA OMIA 001199-37349)

Inheritance: As summarised by Dürig et al. (2018): "In dogs, three variant MC1R alleles in addition to the wildtype E^+ allele have been characterized on the molecular level: E^M > E^G > E^+ > e. The most dominant allele, E^M, caused by the amino acid exchange p.Val264Met, is found in dogs with a black mask such as Leonbergers or Malinois [OMIA 001590-9615] . . . . The E^G allele, caused by p.Gly78Val, is found in ‘grizzle’ Salukis or ‘domino’ Afghan Hounds [OMIA 001495-9615] . . . . Finally, the recessive loss‐of‐function allele e, caused by the p.Arg306Ter variant, is found in yellow‐ or red‐coloured dogs such as yellow Labrador Retrievers, red Irish Setters, and many others."

From the analysis of survey data, but not of inheritance, Anderson et al. (2020) concluded "Phenotype analysis of owner-provided dog pictures reveals that the eA allele has an impact on coat color and is recessive to wild type E and dominant to the e alleles. In dominant black (KB/*) dogs it can prevent the phenotypic expression of the K locus, and the expressed coat color is solely determined by the A locus. In the absence of dominant black, eA/eA and eA/e genotypes result in the coat color patterns referred to in their respective breed communities as domino in Alaskan Malamute and other Spitz breeds, grizzle in Chihuahua, and pied in Beagle".

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the gene corresponding to the extension locus in other species, including mice), Newton et al. (2000) were the first to sequence the canine MC1R gene. They discovered that a missense mutation "R306ter and a red/yellow coat were completely concordant except for the Red Chow". A few months later, Everts et al. (2000) reported what appears to be the same mutation: "a single C-->T mutation at nucleotide position 916 . . . This transition changed the codon for arginine at position 305 into a stop codon, resulting in the elimination of the evolutionary strongly conserved 10 carboxyterminal amino acid residues".

By amplifying "DNA fragments of two genes controlling coat color, Mc1r (Melanocortin 1 Receptor) and CBD103 (canine-β-defensin), in respectively 15 and 19 ancient canids (dogs and wolf morphotypes) from 14 different archeological sites, throughout Asia and Europe spanning from ca. 12 000 B.P. (end of Upper Palaeolithic) to ca. 4000 B.P. (Bronze Age)", Ollivier et al. (2013) discovered a hitherto unreported "variant (R301C) of the Melanocortin 1 receptor (Mc1r) . . . in each of the 9 dog samples coming from 5 archeological sites in South-Eastern Europe and Asia (Siberia)". For these 9 dogs, "five individuals were homozygous [for R301C] and four were heterozygous [for R301C] at this locus". Interestingly, these authors also "found R301C present in the Genbank database on sequences of present-day dogs belonging to two arctic breeds (Siberian Husky and Alaskan Malamute), whereas it was absent in the Boxer, Saluki and Afghan Hound". Ollivier et al. (2013) concluded that "The effect of the R301C mutation alone on coat color is not well established and we could not affirm that it is functional." Consequently, this variant has not been included in the OMIA variant table.

Dürig et al. (2018) reported two new e alleles, namely a "variant within the MITF binding site of the canine MC1R promoter" (Chr5:63695679C>G) in Australian Cattle Dogs and "a 2-bp deletion in the coding sequence, MC1R:c.816_817delCT" in Alaskan and Siberian Huskies. Dürig et al. (2018) proposed that the first-reported e allele (c.916C>T; p.R306*) be named e^1, and that their two newly-reported variants be called e^2 and e^3, respectively.

Anderson et al. (2020) proposed "that R301C [reported initially by Ollivier et al., 2013] should be considered a novel allele of the E locus, which we have termed e^A for “e ancient red”".

Prevalence: Anderson et al. (2020): "Commercial genotyping of 11,750 dog samples showed the R301C variant of the MC1R gene was present in 35 breeds or breed varieties", ranging in frequency from 100% (i.e. fixed) in Alaskan Malamute to zero "in dog breeds with Eastern Asian origin (Akita, Chow Chow, Hokkaido, Kai, Kishu, Shar Pei, Shiba, Shikoku, Korean Jindo Dog) or Middle Eastern/Central Asian origin (Afghan Hound, Saluki, Tibetan Mastiff, Tibetan Spaniel, Tibetan Terrier, Lhasa Apso, Shih-Tzu, Central Asian Ovcharka)."

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
MC1R melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor) Canis lupus familiaris 5 NC_051809.1 (63923224..63922271) MC1R Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Alaskan Husky Siberian Husky White coat colour MC1R e^3 deletion, small (<=20) CanFam3.1 5 c.816_817delCT 2018 29932470
Irish Setter Labrador Retriever Red/yellow coat MC1R e^1 nonsense (stop-gain) CanFam3.1 5 g.63694334G>A c.916C>T p.(R306*) 2000 10602988 Genomic location provided by Professor Claire Wade
Australian Cattle Dog Crean coat colour MC1R e^2 regulatory CanFam3.1 5 g.63695679C>G 2018 29932470

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2020 Anderson, H., Honkanen, L., Ruotanen, P., Mathlin, J., Donner, J. :
Comprehensive genetic testing combined with citizen science reveals a recently characterized ancient MC1R mutation associated with partial recessive red phenotypes in dog. Canine Med Genet 7:16, 2020. Pubmed reference: 33292722. DOI: 10.1186/s40575-020-00095-7.
2019 van Rooy, D., Wade, C.M. :
Association between coat colour and the behaviour of Australian Labrador retrievers. Canine Genet Epidemiol 6:10, 2019. Pubmed reference: 31798910. DOI: 10.1186/s40575-019-0078-z.
2018 Dürig, N., Letko, A., Lepori, V., Hadji Rasouliha, S., Loechel, R., Kehl, A., Hytönen, M.K., Lohi, H., Mauri, N., Dietrich, J., Wiedmer, M., Drögemüller, M., Jagannathan, V., Schmutz, S.M., Leeb, T. :
Two MC1R loss-of-function alleles in cream-coloured Australian Cattle Dogs and white Huskies. Anim Genet 49:284-290, 2018. Pubmed reference: 29932470. DOI: 10.1111/age.12660.
2013 Nowacka-Woszuk, J., Salamon, S., Gorna, A., Switonski, M. :
Missense polymorphisms in the MC1R gene of the dog, red fox, arctic fox and Chinese raccoon dog. J Anim Breed Genet 130:136-41, 2013. Pubmed reference: 23496014. DOI: 10.1111/jbg.12005.
Ollivier, M., Tresset, A., Hitte, C., Petit, C., Hughes, S., Gillet, B., Duffraisse, M., Pionnier-Capitan, M., Lagoutte, L., Arbogast, R.M., Balasescu, A., Boroneant, A., Mashkour, M., Vigne, J.D., Hänni, C. :
Evidence of coat color variation sheds new light on ancient canids. PLoS One 8:e75110, 2013. Pubmed reference: 24098367. DOI: 10.1371/journal.pone.0075110.
Switonski, M., Mankowska, M., Salamon, S. :
Family of melanocortin receptor (MCR) genes in mammals-mutations, polymorphisms and phenotypic effects. J Appl Genet 54:461-72, 2013. Pubmed reference: 23996627. DOI: 10.1007/s13353-013-0163-z.
Wang, G.D., Cheng, L.G., Fan, R.X., Irwin, D.M., Tang, S.S., Peng, J.G., Zhang, Y.P. :
Signature of balancing selection at the MC1R gene in Kunming dog populations. PLoS One 8:e55469, 2013. Pubmed reference: 23424634. DOI: 10.1371/journal.pone.0055469.
2012 Dreger, D.L., Schmutz, S.M. :
A case of canine chimerism diagnosed using coat color tests. Mol Cell Probes 26:253-5, 2012. Pubmed reference: 22433982. DOI: 10.1016/j.mcp.2012.03.004.
Schmutz, S.M., Melekhovets, Y. :
Coat color DNA testing in dogs: theory meets practice. Mol Cell Probes 26:238-42, 2012. Pubmed reference: 22507852. DOI: 10.1016/j.mcp.2012.03.009.
2011 Oguro-Okano, M., Honda, M., Yamazaki, K., Okano, K. :
Mutations in the melanocortin 1 receptor, β-defensin103 and agouti signaling protein genes, and their association with coat color phenotypes in Akita-inu dogs. J Vet Med Sci 73:853-8, 2011. Pubmed reference: 21321476.
2008 Nie, QH., Liu, QS., Fang, MX., Xie, L., Zhang, XQ. :
[Analysis on molecular evolution of MC1R gene in dog] Yi Chuan 30:469-74, 2008. Pubmed reference: 18424418.
2007 Evans, JJ., Wictum, EJ., Penedo, MC., Kanthaswamy, S. :
Real-time polymerase chain reaction quantification of canine DNA. J Forensic Sci 52:93-6, 2007. Pubmed reference: 17209917. DOI: 10.1111/j.1556-4029.2006.00305.x.
2006 Yang, QY., Ye, JH., Ren, J., Xie, AF., Xu, B. :
[Melanocortin 1 receptor (MC1R) gene phylogenetic tree and canine coat colors] Yi Chuan 28:357-61, 2006. Pubmed reference: 16551606.
2004 Guo, D., Su, YH., Ba, CF., Zhu, BQ., Zhang, YB., Li, N., Chen, QH., Gu, XJ. :
[The research on the relationship between the polymorphism of T105A locus in MC1R gene and coat color in dogs.] Yi Chuan 26:455-9, 2004. Pubmed reference: 15640039.
2003 Kerns, JA., Olivier, M., Lust, G., Barsh, GS. :
Exclusion of melanocortin-1 receptor (mc1r) and agouti as candidates for dominant black in dogs. J Hered 94:75-9, 2003. Pubmed reference: 12692166.
2002 Schmutz, S.M., Berryere, T.G., Goldfinch, A.D. :
TYRP1 and MC1R genotypes and their effects on coat color in dogs Mammalian Genome 13:380-387, 2002. Pubmed reference: 12140685. DOI: 10.1007/s00335-001-2147-2.
2001 Schmutz, S.M., Moker, J.S., Berryere, T.G., Christison, K.M., Dolf, G. :
An SNP is used to map MC1R to dog chromosome 5 Animal Genetics 32:43-44, 2001. Pubmed reference: 11419347.
2000 Everts, R.E., Rothuizen, J., van, Oost, B.A. :
Identification of a premature stop codon in the melanocyte-stimulating hormone receptor gene (MC1R) in Labrador and Golden retrievers with yellow coat colour Animal Genetics 31:194-199, 2000. Pubmed reference: 10895310.
Newton, J.M., Wilkie, A.L., He, L., Jordan, S.A., Metallinos, D.L., Holmes, N.G., Jackson, I.J., Barsh, G.S. :
Melanocortin 1 receptor variation in the domestic dog Mammalian Genome 11:24-30, 2000. Pubmed reference: 10602988.
1987 Sponenberg, D.P., Bigelow, B. :
An extension locus mosaic Labrador retriever dog Journal of Heredity 78:406 only, 1987. Pubmed reference: 3429845.
1957 Little, C.C. :
The Inheritance of Coat Color in Dogs Comstock Publishing Associates, Cornell University Press, Ithaca, NY :, 1957.

Edit History


  • Created by Frank Nicholas on 24 Jan 2008
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 20 Sep 2012
  • Changed by Frank Nicholas on 22 Sep 2012
  • Changed by Frank Nicholas on 01 Aug 2018
  • Changed by Frank Nicholas on 17 Sep 2019
  • Changed by Frank Nicholas on 18 Dec 2020