OMIA 001199-9940 : Coat colour, extension in Ovis aries
In other species: cattle , dog , horse , red fox , pig , 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 , lorises , antarctic fur seal
Category: Pigmentation phene
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal dominant
Considered a defect: no
Key variant known: yes
Year key variant first reported: 1999
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: Dominant black
Mapping: To "assess the feasibility of performing GWAS for a dominant trait for which the genetic basis was already known", Kijas et al. (2013) conducted a GWAS on "42 Manchega and Rasa Aragonesa sheep that segregate solid black or white coat pigmentation", each genotyped with the ovine SNP50 SNP chip (yielding 49,034 informative SNPs). The test was successful: the strongest association for this pigmentation trait was with the SNP nearest to MC1R, alleles at which (p.M73K and p.D121N; see Molecular section) had previously been shown, by Calco et al. (2006), to segregate perfectly with this trait in this breed.
Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the supposition that dominant black in sheep is an allele at the extension (E) locus, that in other species is encoded by the MC1R gene), Våge et al. (1999) "identified a Met-->Lys mutation in position 73 (M73K) together with a Asp --> Asn change at position 121 (D121N) showing complete cosegregation with dominant black coat color in a family lineage".
Deng et al. (2009) identified two novel alleles in Black-boned, Nanping indigenous and Romney Marsh sheep, namely p.A12G and p.G144C, with a "significant" effect on coat colour.
Fontanesi et al. (2010) identified a missense allele (c.199C>T; p.R67C) in Valle del Belice sheep. The authors proposed that this variant "represents the e allele at the ovine Extension series that was, so far, not completely recognized in sheep by classical genetic studies".
Hepp et al. (2012) reported the same two variants originally identified by Våge et al. (1999) (namely p.M73K and p.D121N) in Brazilian Creole sheep, and noted "The dominant allele (E(D): p.73K, and p.121N) was found only in colored animals, whereas the recessive allele (E⁺: p.73M, and p.121D) was homozygous only in white individuals."
Rochus et al. (2019) reported two new missense variants, namely c.452G>A and c.785C>T. The c.785C>T was present in sheep with white, black and grey wool and is therefore not likely to be causal.
Gebreselassie et al. (2020) reported "a missense variant (g.14231948 G>A) [rs409651063] that caused an amino acid change (Asp105Asn)" as being "probably responsible for white coat colour in Tan sheep". However, genotyping for this variant revealed the surprising result that "DNA genotyping revealed that all the individuals from the white phenotype were homozygous (GG), whereas all individuals from the black-head phenotype were heterozygous (GA)". While the numbers genotyped were small, these results suggest that there is more to this variant than has so far been reported.
Breed: Tan, China (Sheep) (VBO_0015759).
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|MC1R||melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor)||Ovis aries||14||NC_056067.1 (14251730..14252683)||MC1R||Homologene, Ensembl, NCBI gene|
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.
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|
|1110||Valle del Belice, Italy (Sheep)||Recessive pheomelanism||MC1R||e||missense||Naturally occurring variant||Oar_rambouillet_v1.0||14||g.15487353C>T||c.199C>T||p.(R67C)||2010||Reference not in PubMed; see OMIA 001199-9940 for reference details||The genomic location on Oar_rambouillet_v1.0 was determined by Katie Eager, EMAI, NSW Department of Primary Industries.|
|229||Corriedale (Sheep) Dala (Sheep) Damara (Sheep) Merino (Sheep)||Dominant black||MC1R||E^D||missense||Naturally occurring variant||Oar_rambouillet_v1.0||14||g.15487372T>A||c.218T>A||p.(M73K)||1999||9892731||c.218T>A obtained from Fontanesi et al. (2010); breeds obtained from Rochus et al. (2019); the genomic location on Oar_rambouillet_v1.0 was determined by Katie Eager, EMAI, NSW Department of Primary Industries.|
|228||Massese, Italy (Sheep)||Dominant black||MC1R||E^D||missense||Naturally occurring variant||Oar_rambouillet_v1.0||14||g.15487515G>A||c.361G>A||p.(D121N)||1999||9892731||c.361G>A obtained from Fontanesi et al. (2010); breed obtained from Ruchus et al. (2019); the genomic location on Oar_rambouillet_v1.0 was determined by Katie Eager, EMAI, NSW Department of Primary Industries.|
|1108||Gute (Sheep) Swedish Fur (Sheep) Värmlandsfår, Sweden (Sheep)||Dominant black||MC1R||missense||Naturally occurring variant||Oar_rambouillet_v1.0||14||g.15487606G>A||c.452G>A||p.(R151Q)||2019||31475378||The genomic location on Oar_rambouillet_v1.0 was determined by Katie Eager, EMAI, NSW Department of Primary Industries.|
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.
|2022||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.|
|Lv, F.H., Cao, Y.H., Liu, G.J., Luo, L.Y., Lu, R., Liu, M.J., Li, W.R., Zhou, P., Wang, X.H., Shen, M., Gao, L., Yang, J.Q., Yang, H., Yang, Y.L., Liu, C.B., Wan, P.C., Zhang, Y.S., Pi, W.H., Ren, Y.L., Shen, Z.Q., Wang, F., Wang, Y.T., Li, J.Q., Salehian-Dehkordi, H., Hehua, E., Liu, Y.G., Chen, J.F., Wang, J.K., Deng, X.M., Esmailizadeh, A., Dehghani-Qanatqestani, M., Charati, H., Nosrati, M., Štěpánek, O., Rushdi, H.E., Olsaker, I., Curik, I., Gorkhali, N.A., Paiva, S.R., Caetano, A.R., Ciani, E., Amills, M., Weimann, C., Erhardt, G., Amane, A., Mwacharo, J.M., Han, J.L., Hanotte, O., Periasamy, K., Johansson, A.M., Hallsson, J.H., Kantanen, J., Coltman, D.W., Bruford, M.W., Lenstra, J.A., Li, M.H. :|
|Whole-genome resequencing of worldwide wild and domestic sheep elucidates genetic diversity, introgression, and agronomically important loci. Mol Biol Evol 39:msab353, 2022. Pubmed reference: 34893856. DOI: 10.1093/molbev/msab353.|
|2021||Gebreselassie, G., Liang, B., Berihulay, H., Islam, R., Abied, A., Jiang, L., Zhao, Z., Ma, Y. :|
|Correction: Genomic mapping identifies two genetic variants in the MC1R gene for coat colour variation in Chinese Tan sheep. PLoS One 16:e0245674, 2021. Pubmed reference: 33439914. DOI: 10.1371/journal.pone.0245674.|
|2020||Gebreselassie, G., Liang, B., Berihulay, H., Islam, R., Abied, A., Jiang, L., Zhao, Z., Ma, Y. :|
|Genomic mapping identifies two genetic variants in the MC1R gene for coat colour variation in Chinese Tan sheep. PLoS One 15:e0235426, 2020. Pubmed reference: 32817695. DOI: 10.1371/journal.pone.0235426.|
|2019||Rochus, C.M., Westberg Sunesson, K., Jonas, E., Mikko, S., Johansson, A.M., Rochus, C.M., Westberg Sunesson, K., Jonas, E., Mikko, S., Johansson, A.M. :|
|Mutations in ASIP and MC1R: dominant black and recessive black alleles segregate in native Swedish sheep populations. Anim Genet 50:712-717, 2019. Pubmed reference: 31475378. DOI: 10.1111/age.12837.|
|2016||Hepp, D., Gonçalves, G.L., Moreira, G.R., de Freitas, T.R. :|
|Epistatic interaction of the melanocortin 1 receptor and agouti signaling protein genes modulates wool color in the Brazilian Creole sheep. J Hered 107:544-52, 2016. Pubmed reference: 27288530. DOI: 10.1093/jhered/esw037.|
|Mahmoud, A.H., Mashaly, A.M., Al-Anazi, K.M., Rady, A.M., Saleh, A.A. :|
|Allelic variation of Melanocortin-1 Receptor (MC1R) locus in Saudi indigenous sheep exhibiting different color coats. Asian-Australas J Anim Sci :, 2016. Pubmed reference: 27492350. DOI: 10.5713/ajas.16.0138.|
|Muniz, M.M.M., Caetano, A.R., McManus, C., Cavalcant, L.C.G., Façanha, D.A.E., Leite, J.H.G.M., Paiva, S.R. :|
|Application of genomic data to assist a community-based breeding program: A preliminary study of coat color genetics in Morada Nova sheep Animal 190:89-93, 2016. DOI: 10.1016/j.livsci.2016.06.006.|
|2013||Kijas, J.W., Serrano, M., McCulloch, R., Li, Y., Salces Ortiz, J., Calvo, J.H., Pérez-Guzmán, M.D. :|
|Genomewide association for a dominant pigmentation gene in sheep. J Anim Breed Genet 130:468-75, 2013. Pubmed reference: 24236609. DOI: 10.1111/jbg.12048.|
|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.|
|Yang, G.L., Fu, D.L., Lang, X., Wang, Y.T., Cheng, S.R., Fang, S.L., Luo, Y.Z. :|
|Mutations in MC1R gene determine black coat color phenotype in Chinese sheep. ScientificWorldJournal 2013:675382, 2013. Pubmed reference: 24082855. DOI: 10.1155/2013/675382.|
|2012||Hepp, D., Gonçalves, G.L., Moreira, G.R., Freitas, T.R., Martins, C.T., Weimer, T.A., Passos, D.T. :|
|Identification of the e allele at the Extension locus (MC1R) in Brazilian Creole sheep and its role in wool color variation. Genet Mol Res 11:2997-3006, 2012. Pubmed reference: 22653672. DOI: 10.4238/2012.May.22.5.|
|2011||Fontanesi, L., Dall'Olio, S., Beretti, F., Portolano, B., Russo, V. :|
|Coat colours in the Massese sheep breed are associated with mutations in the agouti signalling protein (ASIP) and melanocortin 1 receptor (MC1R) genes. Animal 5:8-17, 2011. Pubmed reference: 22440696. DOI: 10.1017/S1751731110001382.|
|Fontanesi, L., Beretti, F., Dall'Olio, S., Portolano, B., Matassino, D., Russo, V. :|
|A melanocortin 1 receptor (MC1R) gene polymorphism is useful for authentication of Massese sheep dairy products. J Dairy Res 78:122-8, 2011. Pubmed reference: 21214968. DOI: 10.1017/S0022029910000890.|
|2010||Fontanesi, L., Beretti, F., Riggio, V., Dall'Olio, S., Calascibetta, D., Russo, V., Portolano, B. :|
|Sequence characterization of the melanocortin 1 receptor (MC1R) gene in sheep with different coat colours and identification of the putative e allele at the ovine Extension locus. Small Ruminant Research 91:200-207, 2010.|
|2009||Deng, WD., Shu, W., Yang, SL., Shi, XW., Mao, HM. :|
|Pigmentation in Black-boned sheep (Ovis aries): association with polymorphism of the MC1R gene. Mol Biol Rep 36:431-436, 2009. Pubmed reference: 18075782. DOI: 10.1007/s11033-007-9197-9.|
|2008||Loehr, J., Worley, K., Moe, J., Carey, J., Coltman, D.W. :|
|MC1R variants correlate with thinhorn sheep colour cline but not individual colour. Canadian Journal of Zoology 86:147-150, 2008.|
|2006||Calvo, J.H., Bouzada, J.A., Jurado, J.J., Serrano, M. :|
|Genetic substructure of the Spanish Manchega sheep breed. Small Rumin. Res. 64:116–125, 2006.|
|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.|
|Våge, D.I., Fleet, M.R., Ponz, R., Olsen, R.T., Monteagudo, L.V., Tejedor, M.T., Arruga, M.V., Gagliardi, R., Postiglioni, A., Nattrass, G.S., Klungland, H. :|
|Mapping and characterization of the dominant black colour locus in sheep. Pigment Cell Res 16:693-7, 2003. Pubmed reference: 14629728.|
|1999||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.|
|Vage, D.I., Klungland, H., Lu, D., Cone, R.D. :|
|Molecular and pharmacological characterization of dominant black coat color in sheep Mammalian Genome 10:39-43, 1999. Pubmed reference: 9892731.|
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