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

Possibly relevant human trait(s) and/or gene(s) (MIM number): 266300

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".

Species-specific name: Black/red coat colour; Haplotype HBR; Haplotype HHR

Species-specific symbol: MC1-R, MSH; HBR; HHR

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".

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.

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.

Associated gene: