In other species: cattle , dog , horse , red fox , pig , sheep , jaguar , jaguarundi , American black bear , 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

Categories: Pigmentation phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 266300 (trait) , 155555 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2006

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.

History: Interestingly, an MC1R polymorpophism at position 301 has also been discovered in ancient and present-day dogs (see OMIA 001199-9615)

Molecular basis: By sequencing the MC1R gene from bone of a 43,000-year-old woolly mammoth (Mammuthus primigenius) from Siberia, Rompler et al. (2006) discovered that the individual was heterozygous at three sites within the MC!R gene, namely Thr21Ala, Arg67Cys, and Arg301Ser. The authors reported that "Functional testing of each position variable in the mammoth individually and all possible combinations of the three mammoth-specific amino acids revealed the Arg67Cys substitution as the main cause for MC1R dysfunction . . . the reduction in activity of the Arg67Cys variant would be sufficient to result in substantially lighter hair color". The authors concluded that "it is possible that mammoth populations were polymorphic with regard to hair color, harboring both dark- and light-haired individuals."

Associated gene: