Comprehensive genetic testing combined with citizen science reveals a recently characterized ancient MC1R mutation associated with partial recessive red phenotypes in dog

Abstract

Background The Melanocortin 1 Receptor (MC1R) plays a central role in regulation of coat color determination in various species and is commonly referred to as the “E (extension) Locus”. Allelic variation of the MC1R gene is associated with coat color phenotypes EM (melanistic mask), EG (grizzle/domino) and e1–3 (recessive red) in dogs. In addition, a previous study of archeological dog specimens over 10,000 years of age identified a variant p.R301C in the MC1R gene that may have influenced coat color of early dogs. Results Commercial genotyping of 11,750 dog samples showed the R301C variant of the MC1R gene was present in 35 breeds or breed varieties, at an allele frequency of 1.5% in the tested population. We detected no linkage disequilibrium between R301C and other tested alleles of the E locus. Based on current convention we propose that R301C should be considered a novel allele of the E locus, which we have termed eA for “e ancient red”. Phenotype analysis of owner-provided dog pictures reveals that the eA 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. Conclusions This study demonstrates a large genotype screening effort to identify the frequency and distribution of the MC1R R301C variant, one of the earliest mutations captured by canine domestication, and citizen science empowered characterization of its impact on coat color.

Canine coat pigmentation genetics: a review

“…MC1R is a G-protein coupled receptor expressed on the surface of melanocytes, with signalling pathways of MC1R and its receptor ligand, melanocyte-stimulating hormone, responsible for regulating eumelanin (dark pigment) synthesis (Kaelin et al 2012;Weich et al 2020). In many species, including the domestic dog, variants in the MC1R gene are known to alter the timing and distribution of eumelanin production, with MC1R loss-of-function mutations inhibiting eumelanin synthesis entirely (Newton et al 2000;Schmutz et al 2003;Dreger & Schmutz 2010;Drig et al 2018;Anderson et al 2020).…”

“…The 'e A ' variant is a non-synonymous SNP (C>T) that encodes an arginine to cysteine substitution at amino acid 301 (p. R301C) of the MC1R protein. Located within the cytosolic C-terminal extension, this amino acid substitution may disrupt expression of MC1R on the cell surface (Anderson et al 2020). Recessive to the wt allele 'E', the ancient red variant only alters coat colour in e A /e A or e A /e 1-3 dogs.…”

“…Canine coat colour phenotypes also play a role in animal welfare, with ongoing research indicating correlations between coat colour, disease effects and other traits such as behaviour (D€ urig et al 2016; van Rooy & Wade 2019;Anderson et al 2020). Consequently, genes influencing coat colour or patterns are of considerable importance from historical, religious, ethical and economic perspectives.…”

ASIP promoter variants predict sesame coat color in Shiba Inu dogs

“…This design cannot completely exclude involvement of other genes to sesame coat color. Indeed, for example recently characterized eA allele of MC1R gene showed somewhat similar pattern of pigmentation in different dog breeds (Anderson et al, 2020). As this allele is ancient in canine lineage, it was possible that it exists in Shiba Inu dogs.…”

Towards Forensic DNA Phenotyping for Predicting Visible Traits in Dogs

“…Hence, there was no requirement to search for new candidate markers possibly associated with morphological traits; rather, a panel of published markers was selected, as summarized in Table 1. Genotyping of various visible traits in dogs has already been established in the context of medical research [98] or to support breeding efforts within particular breeds [82,99]. Existing applications of genomic prediction, some of which are commercially available, are mainly intended to verify pedigrees or breeds, to select specific phenotypes according to market demands or studbook policies, and to avoid associated inherited diseases.…”