In other species: domestic cat , horse , llama , taurine cattle , domestic guinea pig , water buffalo

Categories: Pigmentation phene , Hearing / vestibular / ear phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 193510 (trait) , 103500 (trait) , 156845 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Disease-related: no

Key variant known: yes

Year key variant first reported: 2007

Cross-species summary: Variable degree of white spotting ranging from tiny white spots up to completely white animals. The absence of pigment is caused by the absence of skin melanocytes ("leucism, leucistic"), not by failure in the biochemical reactions required for pigment synthesis.

Species-specific symbol: S

Inheritance: This locus was described by Little (1957). As summarised by Körberg et al. (2014), Little "described four different alleles at this locus with phenotypic effects ranging from solid (S, . . .), to a completely white coat, caused by homozygosity for the Extreme white allele (sw, . . .). The two intermediate phenotypes were named Irish spotting (si, . . .) and piebald (sp, . . .). Irish spotting is characterized by modest white spotting, often present as a white collar and a white belly, as demonstrated by breeds such as the Bernese Mountain dog and Basenji. Piebald-coloured dogs display limited to extensive white spotting and the phenotype is observed in several breeds, including the Beagle and Fox Terrier."

Mapping: van Hagen et al. (2004) were able to exclude KIT and EDNRB from the list of candidate genes for white spotting. Using a linkage analysis of "5 families with heterozygous parents and offspring that included 11 white, 6 brown, and 19 spotted dogs", each genotyped for 1500 SNPs having a genome-wide coverage (with an average spacing of 1.6Mb), Leegwater et al. (2007) mapped this locus to a region of chromosome CFA20 which contains a very likely comparative candidate gene, namely MITF. In a landmark study, Karlsson et al. (2007) mapped the white-spotting locus to less than 1 Mb on CFA20 via one of the first Genome-Wide Association Studies (GWAS) using 27,000 SNPs on just a few (approx 20) dogs. Subsequent fine mapping implicated the positional candidate gene MITF. By conducting a proof-of-principle across-breed GWAS on "31 cases for white spotting from 11 breeds and 31 controls from 14 breeds", each genotyped with the Affymetrix Version 2 Custom Canine SNP (comprising 49,663 SNPs), Bannasch et al. (2010) confirmed the white-spotting locus to be MITF on CFA20. Brancalion et al. (2021) describe “a common retrotransposed pseudogene of the canine MITF gene. Using a novel mapping strategy, the pseudogene was located on CFA19 and/or CFA32. We also describe an inverted assembly contig in Canfam3.1 … . These factors should be carefully considered when mapping genotype–phenotype correlations at this locus.” In an erratum to their paper, Brancalion et al. (2022) commented that they were "unaware that the retrocopies had been located on the Y-chromosome by another research group by applying a genome-wide association study using sex as the mapped phenotype (Tsai et al., 2019). Tsai et al. (2019) also detected signal on CFA19."

Molecular basis: In the words of Karlsson et al. (2007), "Complete sequencing of the white and solid haplotypes identifies candidate regulatory mutations in the melanocyte-specific promoter of MITF". As summarised by Körberg et al. (2014), Karlsson et al. (2007) identified "a short list of three candidate mutations within or in the vicinity of the MITF-M promoter, and one in the MITF-1B exon located upstream of MITF-M. The first of these is a canine-specific short interspersed nucleotide element (SINEC-Cf element), located about 3 kb upstream of the MITF-M transcription start site (TSS). The SINE insertion was only found in dogs presenting the extreme white (sw/sw) or piebald (sp/sp) phenotypes, and was absent in Irish-spotted (si/si) and solid (S/S) dogs. . . . The second candidate (SNP#21), a SNP located approximately 1.2 kb upstream of MITF-M TSS, occurs in a highly conserved region and the A allele at this locus is associated with white spotting alleles . . . . The third polymorphism is a variable length polymorphism (Lp) approximately 100 bp upstream of the MITF-M TSS. Long variants of the Lp (LpWhite) are associated with all three white-spotting alleles (sw, sp and si), whereas all solid dogs examined carried short Lp variants .. . , [from here on named LpSolid]. The fourth candidate mutation, a 12 bp deletion in exon 1B (Exon1B_del) also showed a very strong association with white spotting. It was found on all Extreme white and Piebald chromosomes tested, but it was also found in the heterozygous state in 4 out of 76 solid dogs." Extensive sequence comparisons of MITF in wolves and dogs enabled Körberg et al. (2014) to conclude that "the simple repeat polymorphism [Lp above] has been a target for selection during dog domestication and breed formation", that it "affects promoter activity" by affecting "cooperativity between transcription factors binding on either flanking sides of the repeat"; and hence "the simple repeat polymorphism is a key regulator of white spotting in dogs".

Associated gene: