OMIA:001199-9615 : Coat colour, extension in Canis lupus familiaris (dog)
In other species: lorises , coyote , red fox , American black bear , domestic cat , jaguar , ass (donkey) , horse , Przewalski's horse , pig , Arabian camel , reindeer , taurine cattle , indicine cattle (zebu) , goat , sheep , rabbit , Mongolian gerbil , domestic guinea pig , domestic yak , fallow deer , alpaca , gray squirrel , raccoon dog , antarctic fur seal , woolly mammoth , rock pocket mouse , oldfield mouse , lesser earless lizard , Geoffroy's cat , jaguarundi , Colocolo , little striped whiptail , water buffalo , Arctic fox
Categories: Pigmentation phene
Links to MONDO diseases: No links.
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). For additional phenes due to MCR1 variants in dogs see: OMIA 001495-9615 : Coat colour, grizzle in Canis lupus familiaris OMIA 001590-9615 : Coat colour, melanistic mask in Canis lupus familiaris
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”."
Have human generated variants been created, e.g. through genetic engineering and gene editing
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)."
|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|
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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.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|343||Irish Setter (Dog) Labrador Retriever (Dog)||Red/yellow coat||MC1R||e^1||nonsense (stop-gain)||Naturally occurring variant||CanFam3.1||5||g.63694334G>A||c.916C>T||p.(R306*)||NM_001014282.2; NP_001014304.2; ROS_Cfam_1.0:g.63922309A>G||rs851563576||rs851563576||2000||10602988||Genomic location provided by Professor Claire Wade|
|1645||Alaskan Klee Kai (Dog) Alaskan Malamute (Dog) Basenji (Dog) Basset Fauve de Bretagne (Dog) Beagle (Dog) Chesapeake Bay Retriever (Dog) Chihuahua (Dog) Chinese Crested (Dog) Chinook (Dog) English Foxhound (Dog) Finnish Hound (Dog) Finnish Lapphund (Dog) Finnish Spitz (Dog) Karelian Bear Dog (Dog) Lapponian Herder (Dog) Peruvian Hairless Dog (Dog) Phalène (Dog) Plott Hound (Dog) Saarloos Wolfhond (Dog) Siberian Husky (Dog) Tamaskan Dog (Dog)||Coat colour, reduced expression of eumelanin||MC1R||e^A||missense||Naturally occurring variant||CanFam3.1||5||g.63694349G>A||c.901C>T||p.(R301C)||NM_001014282.2; NP_001014304.2; variant was initially identified in ancient canids and later reported in additional breeds PMID:33292722||2013||24098367|
|997||Alaskan Husky (Dog) Siberian Husky (Dog)||White coat colour||MC1R||e^3||deletion, small (<=20)||Naturally occurring variant||CanFam3.1||5||g.63694433_63694434del||c.816_817del||p.(I272Mfs*22)||NM_001014282.2; NP_001014304.2; published as c.816_817delCT||2018||29932470||Genomic coordinates in CanFam3.1 provided by Zoe Shmidt and Robert Kuhn.|
|998||Australian Cattle Dog (Dog)||Cream coat colour||MC1R||e^2||regulatory||Naturally occurring variant||CanFam3.1||5||g.63695679C>G||c.-432G>C||NM_001014282.1||2018||29932470|
Cite this entry
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.
|2023||Arizmendi, A., Rudd Garces, G., Crespi, J.A., Olivera, L.H., Barrientos, L.S., Peral García, P., Giovambattista, G. :|
|Analysis of Doberman Pinscher and Toy Poodle samples with targeted next-generation sequencing. Gene 853:147069, 2023. Pubmed reference: 36427679. DOI: 10.1016/j.gene.2022.147069.|
|2022||[No authors listed] :|
|Canine coat pigmentation genetics: a review. Anim Genet 53:474-475, 2022. Pubmed reference: 35510419. DOI: 10.1111/age.13185.|
|Brancalion, L., Haase, B., Wade, C.M. :|
|Canine coat pigmentation genetics: a review. Anim Genet 53:33-34, 2022. Pubmed reference: 34751460. DOI: 10.1111/age.13154.|
|Ji, R.L., Tao, Y.X. :|
|Melanocortin-1 receptor mutations and pigmentation: Insights from large animals. Prog Mol Biol Transl Sci 189:179-213, 2022. Pubmed reference: 35595349. DOI: 10.1016/bs.pmbts.2022.03.001.|
|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||Dreger, D.L., Hooser, B.N., Hughes, A.M., Ganesan, B., Donner, J., Anderson, H., Holtvoigt, L., Ekenstedt, K.J. :|
|True Colors: Commercially-acquired morphological genotypes reveal hidden allele variation among dog breeds, informing both trait ancestry and breed potential. PLoS One 14:e0223995, 2019. Pubmed reference: 31658272. DOI: 10.1371/journal.pone.0223995.|
|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.|
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