Identification of a Missense Variant in MFSD12 Involved in Dilution of Phaeomelanin Leading to White or Cream Coat Color in Dogs

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.

Pigment Intensity in Dogs is Associated with a Copy Number Variant Upstream of KITLG

“…Brown coat color in dogs is an example of eumelanin lightening and is due to recessive alleles at TYRP1, which disrupt pigment production along the eumelanin pathway [14][15][16]. Pheomelanin appearance in dogs can vary from cream to deep red, with identical homozygous loss-of-function alleles at MC1R and MFSD12 ( [12] and results presented here), indicating that there are additional loci that can affect pigment intensity in dogs.…”

“…Two other phenomenalistic breeds with non-functional MC1R that show coat color variation are the Golden Retriever (GR) and the yellow Labrador Retriever (LR). Their variation is not explained by the variant identified at MFSD12 [12]. Neither of these breeds showed a significant association with the copy number and light or dark coat color (GR, p = 0.9977, light n = 8, medium n = 19, dark n = 8; LR, p = 0.7377, light n = 8, dark n = 8).…”

“…A GWAS was performed to identify a region in the genome that is associated with this variation in coat color using 23 light red NSDTR and 13 dark red NSDTR. All dogs were wild type for the previously identified variant at MFSD12 (orthologous to the human variant rs751,585,493 (ENST00000355415: Chr19:3,557,253 G > A (C > T in dogs); p.(Arg51Cys))) associated with lighter pheomelanin coat color [12]. One SNV was genome-wide significant with a pBonferroni of <0.05 on CanFam2 chr15: 32,383,555 (CanFam3.…”

“…Genetic variants have been identified that modify the basic coat colors. Breeds with exclusive pheomelanin production with a white or light cream-colored coat are enriched for a missense variant in the MFSD12 gene encoding major facilitator superfamily domain-containing 12 [12]. The dilution of pigment in some dogs can be the result of loss-of-function variants in the MLPH gene encoding melanophilin, resulting in abnormal clumping of pigment in the hair shaft and keratinocytes [13].…”

A quantitative trait locus on chromosome 2 was identified that accounts for a substantial proportion of phenotypic variance of the yellow plumage color in chicken

“…In recent years, genome-wide association studies ( GWAS ) were widely applied in coat coloration of animals, including Iranian Markhoz goats ( Nazari-Ghadikolaei et al., 2018 ), mice ( Miao et al., 2017 ), horses ( Kim et al., 2017 ), and dogs ( Hedan et al., 2019 ), to screen novel candidate regions. For the black and brown colors of chicken plumage, previous studies adopted GWAS to discover significant SNP on chromosomes 1, 2, 3, and 5 ( Yang et al., 2017 ) and on chromosomes 1, 2, 3, 4, 6, 8, 19, 24, and 33 ( Park et al., 2013 ).…”