Five genetic variants explain over 70% of hair coat pheomelanin intensity variation in purebred and mixed breed domestic dogs

Abstract

In mammals, the pigment molecule pheomelanin confers red and yellow color to hair, and the intensity of this coloration is caused by variation in the amount of pheomelanin. Domestic dogs exhibit a wide range of pheomelanin intensity, ranging from the white coat of the Samoyed to the deep red coat of the Irish Setter. While several genetic variants have been associated with specific coat intensity phenotypes in certain dog breeds, they do not explain the majority of phenotypic variation across breeds. In order to gain further insight into the extent of multigenicity and epistatic interactions underlying coat pheomelanin intensity in dogs, we leveraged a large dataset obtained via a direct-to-consumer canine genetic testing service. This consisted of genome-wide single nucleotide polymorphism (SNP) genotype data and owner-provided photos for 3,057 pheomelanic mixed breed and purebred dogs from 63 breeds and varieties spanning the full range of canine coat pheomelanin intensity. We first performed a genome-wide association study (GWAS) on 2,149 of these dogs to search for additional genetic variants that underlie intensity variation. GWAS identified five loci significantly associated with intensity, of which two (CFA15 29.8 Mb and CFA20 55.8 Mb) replicate previous findings and three (CFA2 74.7 Mb, CFA18 12.9 Mb, CFA21 10.9 Mb) have not previously been reported. In order to assess the combined predictive power of these loci across dog breeds, we used our GWAS data set to fit a linear model, which explained over 70% of variation in coat pheomelanin intensity in an independent validation dataset of 908 dogs. These results introduce three novel pheomelanin intensity loci, and further demonstrate the multigenic nature of coat pheomelanin intensity determination in domestic dogs.

Ancestry-inclusive dog genomics challenges popular breed stereotypes

“…We successfully replicated 17 published associations for physical traits other than size (table S10), including for genes MITF ( 14 ) with white spotting [ p = 2.89 × 10 −37 ; SNP effect size ( b ) = −0.78], FGF5 and RSPO2 ( 58 ) with coat length ( p = 5.46 × 10 −54 ; b = +0.37) and texture ( p = 6.35 × 10 −9 ; b = +0.11), USH2A ( 59 ) with roan and/or ticking ( p = 5.31 × 10 −16 ; b = +0.20), RUNX3 ( 60 ) with pheomelanin intensity ( p = 4.11 × 10 −8 ; b = −0.20), and the β-defensin region ( 61 – 63 ) with brindle coat patterns ( p = 2.50 × 10 −107 ; b = +0.35) (fig. S25, D to I, and data S16).…”

An SNN retrocopy insertion upstream ofGPR22is associated with dark red coat color in Poodles

“…Out of 47,095 total variants identified, 5,603 segregated by phenotype, including 4,834 SNV and 762 short indels. Variant effect prediction identified missense variants in 5 genes ( Table 2 ), including a previously reported variant in the SLC26A4 gene (chr18:12,910,382 T > C) that was associated with pheomelanin intensity across breeds ( Slavney et al 2021 ). While the 2 missense variants in ARMC10 and GSAP were predicted to be deleterious by both SIFT and Polyphen-2, none of the missense variants affected genes known to be involved in any pigment pathways.…”

“…While several genes involved in pheomelanin intensity have been identified across dog breeds, the single-breed GWAS presented in this study only identified the CFA18 locus as significant within the Poodle breed. One of the top SNVs was a missense variant in SLC26A4 which has previously been associated with pheomelanin intensity across dog breeds, where it was hypothesized to be the causative variant ( Slavney et al 2021 ). The researchers found that the CFA18 locus explained a relatively small % of the total variance in pheomelanin across dog breeds (adjusted R 2 = 0.047), whereas loci on CFA2 and CFA20 explained over 50% of the variance across breeds.…”

“…A missense variant in the MFSD12 gene and a copy number variant near KITLG have both been associated with pheomelanin intensity in a variety of breeds ( Hédan et al 2019 ; Weich et al 2020 ). An across breed analysis of pheomelanin intensity that was published while the current study was being performed identified that genetic variants at 5 loci explained 70% of pheomelanin intensity in dogs, which included the variants at MFSD12 and KITLG as well as 3 novel loci on canine chromosomes (CFA) 2, CFA18, and CFA21 ( Slavney et al 2021 ). However, it is unclear how much each of the loci contribute to pheomelanin intensity within individual breeds.…”

​Comparative genomics of Balto, a famous historic dog, captures lost diversity of 1920s sled dogs

“…2C ), within the acceptable range for today’s Siberian husky breed (53–60cm ( 8 )), and had a double layered coat ( 13 ) that was mostly black with only a little bit of white ( 14 ). He was homozygous for an allele conferring tan points ( 15 ) and one for blue eyes ( 16 ), but both were masked by his melanistic facial mask ( 17 ), and his predicted light-tan pigmentation ( 18 ) may have been indistinguishable from white. He carried neither the “wolf agouti” nor “Northern domino” patterns that are common in the Siberian husky and other sled dog breeds today ( 19 ).…”