OMIA:001199-9913 : Coat colour, extension in Bos taurus (taurine cattle)
In other species: lorises , coyote , dog , red fox , American black bear , domestic cat , jaguar , ass (donkey) , horse , Przewalski's horse , pig , Arabian camel , reindeer , 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: 1995
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: Black/red coat colour; Haplotype HBR; Haplotype HHR
Species-specific symbol: MC1-R, MSH; HBR; HHR
Species-specific description: For information relating to Bos indicus cattle see: OMIA 001199-9915 : Coat colour, extension in Bos indicus
Inheritance: As summarised by Lawlor et al. (2014), "Dominant inheritance of black over red hair color was suggested by Barrington and Pearson (1906), and later proven through a designed experiment by Lloyd-Jones and Evvard (1916) at Iowa State University".
As summarised by Hauser et al. (2002), "The order of dominance is ED > E + > e (Lawlor et al., 2014; Olson, 1999). Cattle that are e/e are red and ED /− are typically black, as ED is the dominant allele and eumelanin is permanently produced. Individuals with the genotypes E +/E + and E +/e can be of any colour as E + acts as a neutral allele and normal activity of the melanocortin‐1 receptor is assumed so that both types of pigment are produced simultaneously in different parts of the body ... (Klungland et al., 1995)".
Mapping: Klungland et al. (1995) reported close linkage (theta = 0.08) between the classic bovine E locus and RFLPs in the bovine MSHR gene.
Molecular basis: By cloning and sequencing the most likely comparative candidate gene (based on similar phenotypes in mice), Klungland et al. (1995) obtained molecular evidence for three alleles at the MSHR locus in Norwegian and Icelandic cattle. The wild-type allele (E+) encodes the normal functional receptor for MSH. The E^D allele contains a missense mutation, changing the 99th amino acid from leucine to proline (p.Leu99Pro). The resultant MSHR molecule is constitutively expressed, i.e. it is expressed without the need for MSH binding. This results in continuously high levels of tyrosinase, and hence production of eumelanin (black coat colour). The e allele contains a single base deletion (a frameshift mutation; c.772delG; p.Tyr155X) which gives rise to a non-functional receptor, and hence to low levels of tyrosinase, resulting in production of phaeomelanin (red coat colour). Because one copy of the E^D allele is sufficient to produce functional MSHR molecules and hence to produce black coat colour, this allele is dominant, while the e allele is recessive. Thus black is dominant to red. As expected, the coat colour associated with wild-type (E+) allele varies, depending, among other things, on the level of MSH produced.
Joerg et al. (1996) extended these results by showing that red coat colour in Friesians is due to the same deletion (c.772delG; p.Tyr155X) in the MSHR gene, which is now known as MC1R.
Olsen (1999) reports that the ancestral MC1R allele designated as E+ has been reported in various breeds of cattle.
Rouzaud et al. (2000): "A new allele, named E1, was found in either homozygous (E1/E1) or heterozygous (E1/E) individuals in Aubrac and Gasconne breeds. This allele displayed a 4 amino acid duplication (12 nucleotides) located within the third cytoplasmic loop of the receptor, a region known to interact with G proteins."
Hauser et al. (2022) summarise that "in addition to the three bovine E alleles mentioned above, two further protein‐changing MC1R variants, denoted Ed1 and Ed2 , have been identified in cattle, but neither for the p.Arg223Trp nor for the p.Gly220_Arg223dup variant can a clear influence on the base colour be demonstrated so far (Graphodatskaya et al., 2002; Kriegesmann et al., 2001; Rouzaud et al., 2000)."
Matsumoto et al. (2020) reported a (missense) variant (c.871G>A; p.(A291T)) that may account for the red coat colour of the Kumamoto sub‐breed of Japanese Brown cattle. More investigation is required before this variant can be added to the OMIA list.
Hauser et al. (2022) “performed a genome-wide allelic association study with black, red and wild-coloured cattle of three Alpine cattle breeds (Eringer, Evolèner and Valdostana), revealing a single significant association signal close to the MC1R gene. [The authors] … searched for candidate causative variants by sequencing the entire coding sequence and identified two novel protein-changing variants. [The authors] … propose designating the mutant alleles at MC1R:c.424C>T as ev1 and at MC1R:c.263G>A as ev2 . Both affect conserved amino acid residues in functionally important transmembrane domains (p.Arg142Cys and p.Ser88Asn). Both alleles segregate predominantly in the Swiss Evolèner breed. They occur in other European cattle breeds ... as well. [The authors] … observed almost perfect association between the MC1R genotypes and the coat colour phenotype in a cohort of 513 black, red and wild-coloured cattle. Animals carrying two copies of MC1R loss-of-function alleles or that were compound heterozygous for e, ev1 , or ev2 have a red to dark red (chestnut-like red) coat colour.”
Have human generated variants been created, e.g. through genetic engineering and gene editing
Prevalence: In a project involving the whole-genome sequencing (WGS) of 43 Fleckvieh cattle with average coverage 7.46X (range 4.17X to 24.98X), Jansen et al. (2013) showed that all but one of the animals was homozygous for the recessive red (deletion; c.772delG; p.Tyr155X) allele, consistent with the typical red and white colour of this breed. The other animal was heterozygous for the recessive red allele and the wild-type allele, but was also red and white.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|MC1R||melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor)||Bos taurus||18||NC_037345.1 (14705093..14706843)||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|
|1509||Abondance (Cattle) Brown Swiss (Cattle) Eastern Finncattle (Itäsuomenkarja) Evolèner, Switzerland (Cattle) Herens (Cattle) Holstein Friesian (Cattle) Original Schweizer Braunvieh, Switzerland (Cattle) Rotes Höhenvieh, Germany (Cattle) Simmental (Cattle)||Recessive red||MC1R||e^v2||missense||Naturally occurring variant||ARS-UCD1.2||18||g.14705638G>A||c.263G>A||p.(S88N)||NM_174108; NP_776533||2022||35451516|
|185||Angus (Cattle) Holstein Friesian (Cattle) Iceland Pony (Horse)||Dominant black||MC1R||E^D||missense||Naturally occurring variant||ARS-UCD1.2||18||g.14705671T>C||c.296T>C||p.(L99P)||NM_174108; NP_776533||rs109688013||rs109688013||1995||8535072||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
|485||Angus (Cattle) Fries Roodbont, Netherlands (Cattle) Simmental (Cattle)||Recessive red||MC1R||e||deletion, small (<=20)||Naturally occurring variant||ARS-UCD1.2||18||g.14705685del||c.310del||p.(G104Vfs*53)||NM_174108; NP_776533||rs110710422||rs110710422||1995||8535072||Variant information kindly provided or confirmed by Matt McClure and Jennifer McClure from "Understanding Genetics and Complete Genetic Disease and Trait Definition (Expanded 2016 Edition)" (https://www.icbf.com/wp/?page_id=2170)|
|1508||Angus (Cattle) Brown Swiss (Cattle) Eastern Flanders White‐Red Evolèner, Switzerland (Cattle) Herens (Cattle) Holstein Friesian (Cattle) Limousin (Cattle) Normande (Cattle) Original Schweizer Braunvieh, Switzerland (Cattle)||recessive red||MC1R||e^v1||missense||Naturally occurring variant||ARS-UCD1.2||18||g.14705799C>T||c.424C>T||p.(R142C)||NM_174108; NP_776533||rs3423445958||2022||35451516|
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||Hong, R., Yan, Y., Zhu, C., Zuo, F., Zhang, G.W. :|
|Rapid genotyping of bovine MC1R gene c.296T>C and c.310delG haplotypes using high-resolution melting analysis. Anim Genet , 2023. Pubmed reference: 37873887. DOI: 10.1111/age.13373.|
|2022||Bertolini, F., Moscatelli, G., Schiavo, G., Bovo, S., Ribani, A., Ballan, M., Bonacini, M., Prandi, M., Dall'Olio, S., Fontanesi, L. :|
|Signatures of selection are present in the genome of two close autochthonous cattle breeds raised in the North of Italy and mainly distinguished for their coat colours. J Anim Breed Genet 139:307-319, 2022. Pubmed reference: 34841617. DOI: 10.1111/jbg.12659.|
|Hauser, M., Signer-Hasler, H., Küttel, L., Capitan, A., Guldbrandtsen, B., Hinrichs, D., Flury, C., Seefried, F.R., Drögemüller, C. :|
|Identification of two new recessive MC1R alleles in red-coloured Evolèner cattle and other breeds. Anim Genet 53:427-435, 2022. Pubmed reference: 35451516. DOI: 10.1111/age.13206.|
|He, Y., Huang, Y., Wang, S., Zhang, L., Gao, H., Zhao, Y., E, G. :|
|Hereditary basis of coat color and excellent feed conversion rate of red Angus cattle by next-generation sequencing data. Animals (Basel) 12:1509, 2022. Pubmed reference: 35739846. DOI: 10.3390/ani12121509.|
|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.|
|Kunene, L.M., Muchadeyi, F.C., Hadebe, K., Mészáros, G., Sölkner, J., Dugmore, T., Dzomba, E.F. :|
|Genetics of base coat colour variations and coat colour-patterns of the South African Nguni cattle investigated using high-density SNP genotypes. Front Genet 13:832702, 2022. Pubmed reference: 35747604. DOI: 10.3389/fgene.2022.832702.|
|2021||Goud, T.S., Upadhyay, R.C., Pichili, V.B.R., Onteru, S.K., Chadipiralla, K. :|
|Molecular characterization of coat color gene in Sahiwal versus Karan Fries bovine. J Genet Eng Biotechnol 19:22, 2021. Pubmed reference: 33512595. DOI: 10.1186/s43141-021-00117-2.|
|Jiang, L., Kon, T., Chen, C., Ichikawa, R., Zheng, Q., Pei, L., Takemura, I., Nsobi, L.H., Tabata, H., Pan, H., Omori, Y., Ogura, A. :|
|Whole-genome sequencing of endangered Zhoushan cattle suggests its origin and the association of MC1R with black coat colour. Sci Rep 11:17359, 2021. Pubmed reference: 34462508. DOI: 10.1038/s41598-021-96896-2.|
|2020||Goud, T.S., Upadhyay, R.C., Onteru, S.K., Pichili, V.B.R., Chadipiralla, K. :|
|Identification and sequence characterization of melanocortin 1 receptor gene (MC1R) in Bos indicus versus (Bos taurus X Bos indicus). Anim Biotechnol 31:283-294, 2020. Pubmed reference: 30890019. DOI: 10.1080/10495398.2019.1585866.|
|Kasprzak-Filipek, K., Sawicka-Zugaj, W., Litwińczuk, Z., Chabuz, W., Šveistienė, R., Bulla, J. :|
|Polymorphism of the Melanocortin 1 Receptor (<i>MC1R</i>) Gene and its Role in Determining the Coat Colour of Central European Cattle Breeds. Animals (Basel) 10, 2020. Pubmed reference: 33066670. DOI: 10.3390/ani10101878.|
|Matsumoto, H., Kojya, M., Takamuku, H., Kimura, S., Kashimura, A., Imai, S., Yamauchi, K., Ito, S. :|
|MC1R c.310G>- and c.871G > A determine the coat color of Kumamoto sub-breed of Japanese Brown cattle. Anim Sci J 91:e13367, 2020. Pubmed reference: 32285552. DOI: 10.1111/asj.13367.|
|2016||Niemi, M., Sajantila, A., Vilkki, J. :|
|Temporal variation in coat colour (genotypes) supports major changes in the Nordic cattle population after Iron Age. Anim Genet 47:495-8, 2016. Pubmed reference: 27297978. DOI: 10.1111/age.12445.|
|2014||Hanna, L.L., Sanders, J.O., Riley, D.G., Abbey, C.A., Gill, C.A. :|
|Identification of a major locus interacting with MC1R and modifying black coat color in an F₂ Nellore-Angus population. Genet Sel Evol 46:4, 2014. Pubmed reference: 24460986. DOI: 10.1186/1297-9686-46-4.|
|Lawlor, T.J., VanRaden, P.M., Null, D., Levisee, J., Dorhorst, B. :|
|Using haplotypes to unravel the inheritance of Holstein coat color. Proceedings, 10th World Congress of Genetics Applied to Livestock Production, Vancouver :Comm. 289, 2014.|
|Zhang, Y., Li, Q., Ye, S., Faruque, M.O., Yu, Y., Sun, D., Zhang, S., Wang, Y. :|
|New variants in the melanocortin 1 receptor gene (MC1R) in Asian cattle. Anim Genet 45:609-10, 2014. Pubmed reference: 24702190. DOI: 10.1111/age.12160.|
|2013||Druet, T., Pérez-Pardal, L., Charlier, C., Gautier, M. :|
|Identification of large selective sweeps associated with major genes in cattle. Anim Genet 44:758-62, 2013. Pubmed reference: 23859468. DOI: 10.1111/age.12073.|
|Jansen, S., Aigner, B., Pausch, H., Wysocki, M., Eck, S., Benet-Pagès, A., Graf, E., Wieland, T., Strom, T.M., Meitinger, T., Fries, R. :|
|Assessment of the genomic variation in a cattle population by re-sequencing of key animals at low to medium coverage. BMC Genomics 14:446, 2013. Pubmed reference: 23826801. DOI: 10.1186/1471-2164-14-446.|
|Schmutz, S.M., Dreger, D.L. :|
|Interaction of MC1R and PMEL alleles on solid coat colors in Highland cattle. Anim Genet 44:9-13, 2013. Pubmed reference: 22524257. DOI: 10.1111/j.1365-2052.2012.02361.x.|
|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.|
|2008||Mohanty, T.R., Seo, K.S., Park, K.M., Choi, T.J., Choe, H.S., Baik, D.H., Hwang, I.H. :|
|Molecular variation in pigmentation genes contributing to coat colour in native Korean Hanwoo cattle. Anim Genet 39:550-3, 2008. Pubmed reference: 18557975. DOI: 10.1111/j.1365-2052.2008.01746.x.|
|2007||Gan, H.Y., Li, J.B., Wang, H.M., Gao, Y.D., Liu, W.H., Li, J.P., Zhong, J.F. :|
|[Relationship between the melanocortin receptor 1 (MC1R) gene and the coat color phenotype in cattle]. Yi Chuan 29:195-200, 2007. Pubmed reference: 17369176. DOI: 10.1360/yc-007-0195.|
|2003||Klungland, H., Vage, D.I. :|
|Pigmentary switches in domestic animal species Annals of the New York Academy of Sciences 994:331-8, 2003. Pubmed reference: 12851333.|
|2002||Graphodatskaya, D., Joerg, H., Stranzinger, G. :|
|Molecular and pharmacological characterisation of the MSH-R alleles in Swiss cattle breeds. J Recept Signal Transduct Res 22:421-30, 2002. Pubmed reference: 12503631. DOI: 10.1081/rrs-120014611.|
|Maudet, C., Taberlet, P. :|
|Holstein's milk detection in cheeses inferred from melanocortin receptor 1 (MC1R) gene polymorphism Journal of Dairy Science 85:707-715, 2002. Pubmed reference: 12018414. DOI: 10.3168/jds.S0022-0302(02)74127-1.|
|2001||Kriegesmann, B., Dierkes, B., Leeb, T., Jansen, S., Brenig, B. :|
|Two breed-specific bovine MC1-R alleles in Brown Swiss and Saler breeds Journal of Dairy Science 84:1768-1771, 2001. Pubmed reference: 11467827. DOI: 10.3168/jds.S0022-0302(01)74612-7.|
|2000||Graphodatskaya, D., Joerg, H., Stranzinger, G. :|
|Polymorphism in the MSHR gene of different cattle breeds Veterinarni Medicina 45:290-295, 2000.|
|Kantanen, J., Olsaker, I., Brusgaard, K., Eythorsdottir, E., Holm, LE., Lien, S., Danell, B., Adalsteinsson, S. :|
|Frequencies of genes for coat colour and horns in Nordic cattle breeds. Genet Sel Evol 32:561-76, 2000. Pubmed reference: 14736370. DOI: 10.1051/gse:2000137.|
|Rouzaud, F., Martin, J., Gallet, P.F., Delourme, D., Goulemot-Leger, V., Amigues, Y., Ménissier, F., Levéziel, H., Julien, R., Oulmouden, A. :|
|A first genotyping assay of French cattle breeds based on a new allele of the extension gene encoding the melanocortin-1 receptor (Mc1r). Genet Sel Evol 32:511-20, 2000. Pubmed reference: 14736379. DOI: 10.1186/1297-9686-32-5-511.|
|1999||Klungland, H., Vage, D.I. :|
|Presence of the dominant extension allele E-D in red and mosaic cattle Pigment Cell Research 12:391-393, 1999. Pubmed reference: 10614579.|
|Klungland, H., Roed, K.H., Nesbo, C.L., Jakobsen, K.S., Vage, D.I. :|
|The melanocyte-stimulating hormone receptor (MC1-R) gene as a tool in evolutionary studies of Artiodactyles Hereditas 131:39-46, 1999. Pubmed reference: 10628296.|
|Olson, T.A. :|
|Genetics of colour variation. The genetics of cattle. Wallingford: CABI Fries, R. & Ruvinsky, A. (Eds.):33-53, 1999.|
|1996||Joerg, H., Fries, H.R., Meijerink, E., Stranzinger, G.F. :|
|Red coat color in Holstein cattle is associated with a deletion in the MSHR gene Mammalian Genome 7:317-318, 1996. Pubmed reference: 8661706.|
|Werth, L.A., Hawkins, G.A., Eggen, A., Petit, E., Elduque, C., Kreigesmann, B., Bishop, M.D. :|
|Rapid communication - melanocyte stimulating hormone receptor (MC1R) maps to bovine chromosome 18 Journal of Animal Science 74:262, 1996. Pubmed reference: 8778108.|
|1995||Adalsteinsson, S., Bjarnadottir, S., Vage, D.I., Jonmundsson, J.V. :|
|Brown coat color in icelandic cattle produced by the loci extension and agouti Journal of Heredity 86:395-398, 1995. Pubmed reference: 7560875.|
|Klungland, H., Vage, D.I., Gomezraya, L., Adalsteinsson, S., Lien, S. :|
|The role of melanocyte-stimulating hormone (msh) receptor in bovine coat color determination Mammalian Genome 6:636-639, 1995. Pubmed reference: 8535072.|
|1921||Watson, J.A.S. :|
|A Mendelian experiment with Aberdeen-Angus and West Highland cattle Journal of Genetics 11:59-67, 1921.|
|1916||Lloyd-Jones, O., Evvard, J. :|
|Inheritance of color and horns in blue gray cattle. Iowa State College Research Bulletin No. 30 , 1916.|
|1906||Barrington, A., Pearson, K. :|
|On the inheritance of coat color in cattle. Biometrika 4:427-464, 1906.|
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