In other species: lorises , coyote , dog , red fox , American black bear , domestic cat , jaguar , ass (donkey) , horse , Przewalski's horse , pig , Arabian camel , reindeer , taurine cattle , indicine cattle (zebu) , goat , 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 possible relevant human trait(s) and/or gene(s) in OMIM: 266300 (trait) , 155555 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: 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, black-headed

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) [omia.variant:229] together with a Asp --> Asn change at position 121 (D121N) [omia.variant:228] 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, omia.variant:228 & omia.variant:229) 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". Zhou et al. (2023) identified the same two variants (omia.variant:228 & omia.variant:229) identified by Våge et al. (1999) and Hepp et al. (2012) for dominant black in sheep to be associated with the black head in black-headed Dorper and black-headed Bayinbuluke.

Breeds: Bayinbuluke, China (Sheep) (VBO_0015737), Corriedale (Sheep) (VBO_0001382), Dala (Sheep) (VBO_0001389), Damara (Sheep) (VBO_0001390), Dorper (Sheep) (VBO_0001397), Gute (Sheep) (VBO_0001429), Massese, Italy (Sheep) (VBO_0016132), Merino (Sheep) (VBO_0001508), Tan, China (Sheep) (VBO_0015759), Valle del Belice, Italy (Sheep) (VBO_0016156), Värmlandsfår, Sweden (Sheep) (VBO_0016522).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: