Abstract
White coat color in mammals has been selected several times during the domestication process. Numerous dog breeds are fixed for one form of white coat color that involves darkly pigmented skin. The genetic basis of this color, due to the absence of pigment in the hairs, was suggested to correspond to extreme dilution of the phaeomelanin, by both the expression of only phaeomelanin (locus E) and its extreme dilution (locus I). To go further, we performed genome-wide association studies (GWAS) using a multiple breed approach. The first GWAS, using 34 white dogs and 128 non-white dogs, including White Shepherds, Poodles, Cotons de Tulear and Bichons allowed us to identify two significantly associated loci on the locus E and a novel locus on chromosome 20. A second GWAS using 15 other breeds presenting extreme phaeomelanin dilution confirmed the position of locus I on the chromosome 20 (position 55 Mb pcorrected = 6 × 10−13). Using whole-genome sequencing, we identified a missense variant in the first exon of MFSD12, a gene recently identified to be involved in human, mouse and horse pigmentation. We confirmed the role of this variant in phaeomelanin dilution of numerous canine breeds, and the conserved role of MFSD12 in mammalian pigmentation.
Highlights
White coat color is a common color in dogs caused by at least two underlying distinct genetic mechanisms: the absence of melanocytes in the skin/hair or the absence of pigment in the melanocytes or hairs
Thanks to a multiple step genome-wide association studies (GWAS) approach, we confirmed that solid white coat color in dogs may result from the absence of eumelanin (e/e at the MC1R locus) and an extreme dilution of phaeomelanin, confirming the hypothesis of Sponenberg and Rothschild on the existence of an I locus and later, the work of Schmutz and Berryere [10,11]
MFSD12 causes cream to white in many dog breeds, it is probable that other modifier alleles exist and explain the cream to white dilution in dogs
Summary
White coat color is a common color in dogs caused by at least two underlying distinct genetic mechanisms: the absence of melanocytes in the skin/hair or the absence of pigment in the melanocytes or hairs. The absence of melanocytes in the skin, called piebaldism or leucism, is a variable phenotype ranging from white spots to more extreme white patterns, resulting in almost-white coat color with few pigmented areas. These white spotting phenotypes involve different variants in the MITF or KIT gene [5,6,7,8]. Sponenberg and Rothschild suggested that the solid white phenotype would result from both the expression of only phaeomelanin and its extreme dilution at a locus I (Intensity) [10]. Based on several genome-wide association studies (GWAS), first using solid white dogs and non-white dogs from five breeds (White Shepherds, German Shepherds, Poodles, Cotons de Tulear and Bichons), and second, using 15 other breeds presenting phaeomelanin dilution, we identified the I locus on chromosome 20 and a missense variant linked to phaeomelanin dilution in dogs
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