In other species: lorises , coyote , red fox , American black bear , domestic cat , jaguar , ass (donkey) , horse , Przewalski's horse , pig , Arabian camel , reindeer , taurine cattle , indicine cattle (zebu) , goat , sheep , 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

Disease-related: no

Key variant known: yes

Year key variant first reported: 2000

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: This is the classic E (Extension) locus described by Little (1957).

Species-specific symbol: E locus

Species-specific description: For additional phenes due to MCR1 variants in dogs see:
OMIA 001495-9615 : Coat colour, grizzle in Canis lupus familiaris 
OMIA 001590-9615 : Coat colour, melanistic mask in Canis lupus familiaris

History: Ollivier et al. (2013) reported that "Interestingly, a mutation at the same position ‘301’, namely an amino-acid change from Arginine->Serine was detected in the Mc1r sequence of a 43,000-year-old mammoth" (see OMIA OMIA 001199-37349)

Inheritance: As summarised by Dürig et al. (2018): "In dogs, three variant MC1R alleles in addition to the wildtype E⁺ allele have been characterized on the molecular level: E^M > E^G > E⁺ > e. The most dominant allele, E^M, caused by the amino acid exchange p.Val264Met, is found in dogs with a black mask such as Leonbergers or Malinois [OMIA 001590-9615] . . . . The E^G allele, caused by p.Gly78Val, is found in ‘grizzle’ Salukis or ‘domino’ Afghan Hounds [OMIA 001495-9615] . . . . Finally, the recessive loss‐of‐function allele e, caused by the p.Arg306Ter variant, is found in yellow‐ or red‐coloured dogs such as yellow Labrador Retrievers, red Irish Setters, and many others." From the analysis of survey data, but not of inheritance, Anderson et al. (2020) concluded "Phenotype analysis of owner-provided dog pictures reveals that the e^A allele has an impact on coat color and is recessive to wild type E and dominant to the e alleles. In dominant black (KB/*) dogs it can prevent the phenotypic expression of the K locus, and the expressed coat color is solely determined by the A locus. In the absence of dominant black, eA/eA and eA/e genotypes result in the coat color patterns referred to in their respective breed communities as domino in Alaskan Malamute and other Spitz breeds, grizzle in Chihuahua, and pied in Beagle".
Honkaned et al. (2024) identified a new MC1R variant in sable English Cocker Spaniel dogs and propse naming it "allele e^H and further show that the e^A , e^H and e^G (previously known as E^G ) alleles associate with similar phenotypes in dogs impacting genotypes regulated by beta-defensin 103 gene (CBD103; K locus) and agouti signaling protein gene (ASIP; A locus) in the absence of the E^M and E alleles. This suggests that all three alleles are putative reduced-function variants of the MC1R gene. We propose the revised and updated E locus dominance hierarchy to be E^M > E > e^A /e^H /e^G > e^1-3 ."

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the gene corresponding to the extension locus in other species, including mice), Newton et al. (2000) were the first to sequence the canine MC1R gene. They discovered that a missense mutation "R306ter and a red/yellow coat were completely concordant except for the Red Chow". A few months later, Everts et al. (2000) reported what appears to be the same mutation: "a single C-->T mutation at nucleotide position 916 . . . This transition changed the codon for arginine at position 305 into a stop codon, resulting in the elimination of the evolutionary strongly conserved 10 carboxyterminal amino acid residues". By amplifying "DNA fragments of two genes controlling coat color, Mc1r (Melanocortin 1 Receptor) and CBD103 (canine-β-defensin), in respectively 15 and 19 ancient canids (dogs and wolf morphotypes) from 14 different archeological sites, throughout Asia and Europe spanning from ca. 12 000 B.P. (end of Upper Palaeolithic) to ca. 4000 B.P. (Bronze Age)", Ollivier et al. (2013) discovered a hitherto unreported "variant (R301C) of the Melanocortin 1 receptor (Mc1r) . . . in each of the 9 dog samples coming from 5 archeological sites in South-Eastern Europe and Asia (Siberia)". For these 9 dogs, "five individuals were homozygous [for R301C] and four were heterozygous [for R301C] at this locus". Interestingly, these authors also "found R301C present in the Genbank database on sequences of present-day dogs belonging to two arctic breeds (Siberian Husky and Alaskan Malamute), whereas it was absent in the Boxer, Saluki and Afghan Hound". Ollivier et al. (2013) concluded that "The effect of the R301C mutation alone on coat color is not well established and we could not affirm that it is functional." Consequently, this variant has not been included in the OMIA variant table. Dürig et al. (2018) reported two new e alleles, namely a "variant within the MITF binding site of the canine MC1R promoter" (Chr5:63695679C>G) in Australian Cattle Dogs and "a 2-bp deletion in the coding sequence, MC1R:c.816_817delCT" in Alaskan and Siberian Huskies. Dürig et al. (2018) proposed that the first-reported e allele (c.916C>T; p.R306*) be named e¹, and that their two newly-reported variants be called e² and e³, respectively. Anderson et al. (2020) proposed "that R301C [reported initially by Ollivier et al., 2013] should be considered a novel allele of the E locus, which we have termed e^A for “e ancient red”."
Honkanen et al. (2024) "examined genetic variation in MC1R, and found one new non-synonymous variant, c.250G>A (p.(Asp84Asn)), consistently associated with the English Cocker Spaniel 'sable' phenotype." The authors propose to call the allele e^H.

Prevalence: Anderson et al. (2020): "Commercial genotyping of 11,750 dog samples showed the R301C variant of the MC1R gene was present in 35 breeds or breed varieties", ranging in frequency from 100% (i.e. fixed) in Alaskan Malamute to zero "in dog breeds with Eastern Asian origin (Akita, Chow Chow, Hokkaido, Kai, Kishu, Shar Pei, Shiba, Shikoku, Korean Jindo Dog) or Middle Eastern/Central Asian origin (Afghan Hound, Saluki, Tibetan Mastiff, Tibetan Spaniel, Tibetan Terrier, Lhasa Apso, Shih-Tzu, Central Asian Ovcharka)."

Associated gene: