Identification of a Missense Variant in MFSD12 Involved in Dilution of Phaeomelanin Leading to White or Cream Coat Color in Dogs - PubMed (original) (raw)
doi: 10.3390/genes10050386.
Edouard Cadieu 2, Nadine Botherel 3, Caroline Dufaure de Citres 4, Anna Letko 5, Maud Rimbault 6, Cord Drögemüller 7, Vidhya Jagannathan 8, Thomas Derrien 9, Sheila Schmutz 10, Tosso Leeb 11, Catherine André 12
Affiliations
- PMID: 31117290
- PMCID: PMC6562630
- DOI: 10.3390/genes10050386
Identification of a Missense Variant in MFSD12 Involved in Dilution of Phaeomelanin Leading to White or Cream Coat Color in Dogs
Benoit Hédan et al. Genes (Basel). 2019.
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 _p_corrected = 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.
Keywords: Dog; Locus I; MFSD12; phaeomelanin dilution.
Conflict of interest statement
The authors declare that they have no conflict of interest. Caroline Dufaure de Citres is a employee of Antagene (Lyon, France), a private company selling diagnostic tests in dogs.
Figures
Figure 1
Genome-wide association study results based on 34 white dogs (White Shepherds, Poodles, Cottons de Tulear and Bichons) versus 128 non-white dogs (German Shepherds and Poodles). (A) Quantile-Quantile plot displaying a genomic inflation λ of 1.000015, indicating no residual inflation. (B) Manhattan plot displaying the results from the GWAS. This analysis pointed out two loci on chromosome 5 (Chr5:63,666,161 _p_corrected = 6.7 × 10−8) and on chromosome 20 (Chr20:55,213,866, _p_corrected = 4.7 × 10−8).
Figure 2
Results of the genome-wide association study for the phaeomelanin dilution phenotype, using 138 cases (dogs with diluted phaeomelanin) and 2325 controls (dogs with undiluted phaeomelanin). (A) Quantile-Quantile plot of GWAS displaying a genomic inflation λ of 1.000039. (B) Manhattan plot displaying the results from the GWAS: two significant SNVs on chromosome 20 (chr20:55,850,145, _p_raw = 5.5 × 10−289, _p_corrected = 6.01 × 10−13 and chr20:55,213,866, _p_raw = 1.26 × 10−175, _p_corrected = 2.16 × 10−8). (C) Quantile-Quantile plot of GWAS with imputed SNVs from the candidate region of chromosome 20 displaying a genomic inflation λ of 1.000045. (D) Manhattan plot displaying the results from the GWAS with imputed SNVs from the candidate region of chromosome 20: a unique highly significant locus on chromosome 20 (two best SNVs Chr20:55,850,145, _p_raw = 5.5 × 10−289, _p_corrected = 6.82 × 10−12 and chr20: 55847284, _p_raw = 15.08 × 10−286, _p_corrected = 8.74 × 10−12), separated by 2 kb.
Figure 3
Screenshot of the locus on the canine chromosome 20 locus associated with the phaeomelanin dilution. The GWAS p-values of the 444 imputed variants on the 138 cases and 2325 controls are represented on the top. The best GWAS SNV (indicated by a *) located ~5 kb upstream of the MFSD12 gene is represented on the middle and the MFSD12 exon position, relatively to the gap position is illustrated on the bottom.
Figure 4
Photos and MFSD12 genotypes of relevant tested breeds.
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