In other species: cattle , dog , horse , red fox , sheep , 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

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

Mode of inheritance: Autosomal

Considered a defect: no

Key variant known: yes

Year key variant first reported: 1998

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.

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on recent discoveries of the molecular basis of the Extension coat-colour locus in cattle, horses, foxes and chickens), Kijas et al. (1998) identified five different missense mutations in the porcine MC1R gene, and showed their correspondence with documented alleles at the porcine Extension (E) locus:

G274A + T296C; p.Val92Met + p.Leu99Pro: dominant black in Asian pigs (E^D1)

G361A; p.Asp121Asn: dominant black in European pigs (E^D2)

C491T + G727A; p.Ala164Val + Ala243Thr: red (e)

Kijas et al. (2001) added another allele: nt67insCC (Codon 23): black spotting on red or white background (E^P)

Since then, many other alleles have been documented.

(from Table 4 of Switonski et al., 2013)

Linderholm et al. (2016) reported a new haplotype (0601) for black.

Wu et al. (2017) "found 2 haplotypes, E^QY and E^qy, from 13 closely linked mutations of MC1R" and "E^qy presented a recessive inheritance mode in black spotted Qingyu pigs"

Jia et al. (2017) reported a likely causal variant for recessive white in Bama miniature pigs: "A 2-bp CC insertion mutation (c.67_68insCC) was identified and co-segregated with the mutant phenotype completely . . . . This CC insertion at codon 23 results in a frameshift mutation (p.Arg23ProfsTer33) that produces a prematurely terminated, nonfunctional receptor."

Associated gene: