Abstract
The white spotting locus (S) in dogs is colocalized with the MITF (microphtalmia-associated transcription factor) gene. The phenotypic effects of the four S alleles range from solid colour (S) to extreme white spotting (sw). We have investigated four candidate mutations associated with the sw allele, a SINE insertion, a SNP at a conserved site and a simple repeat polymorphism all associated with the MITF-M promoter as well as a 12 base pair deletion in exon 1B. The variants associated with white spotting at all four loci were also found among wolves and we conclude that none of these could be a sole causal mutation, at least not for extreme white spotting. We propose that the three canine white spotting alleles are not caused by three independent mutations but represent haplotype effects due to different combinations of causal polymorphisms. The simple repeat polymorphism showed extensive diversity both in dogs and wolves, and allele-sharing was common between wolves and white spotted dogs but was non-existent between solid and spotted dogs as well as between wolves and solid dogs. This finding was unexpected as Solid is assumed to be the wild-type allele. The data indicate that the simple repeat polymorphism has been a target for selection during dog domestication and breed formation. We also evaluated the significance of the three MITF-M associated polymorphisms with a Luciferase assay, and found conclusive evidence that the simple repeat polymorphism affects promoter activity. Three alleles associated with white spotting gave consistently lower promoter activity compared with the allele associated with solid colour. We propose that the simple repeat polymorphism affects cooperativity between transcription factors binding on either flanking sides of the repeat. Thus, both genetic and functional evidence show that the simple repeat polymorphism is a key regulator of white spotting in dogs.
Highlights
Coat colour variation has fascinated humans for centuries and it has become one of the most extensively studied traits, mainly in mice [1] and in domestic animals [2,3]
Our previous study demonstrated that the Extreme white allele in Boxers is not associated with coding changes in MITF [6]
A careful examination of the entire non-coding region showing the strongest association to white spotting, combined with a screen across a diverse panel of dogs, revealed four candidate mutations that showed the strongest association to white spotting
Summary
Coat colour variation has fascinated humans for centuries and it has become one of the most extensively studied traits, mainly in mice [1] and in domestic animals [2,3]. There is an extensive diversity of white spotting patterns within and between dog breeds caused by genetic factors and stochastic effects during melanocyte development. There is one major white spotting (S) locus that was defined by C. Little during the 1950s [4] He described four different alleles at this locus with phenotypic effects ranging from solid (S, Figure 1A), to a completely white coat, caused by homozygosity for the Extreme white allele (sw, Figure 1B). The two intermediate phenotypes were named Irish spotting (si, Figure 1D) and piebald (sp, Figure 1E). Piebald-coloured dogs display limited to extensive white spotting and the phenotype is observed in several breeds, including the Beagle and Fox Terrier.
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