In other species: domestic yak

Categories: Pigmentation phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 172800 (trait) , 164920 (gene)

Single-gene trait/disorder: yes

Mode of inheritance: Autosomal incomplete dominant

Disease-related: no

Key variant known: yes

Year key variant first reported: 2011

Species-specific name: Color-sided

Species-specific symbol: SP

Species-specific description: Fontanesi  et al. (2010): "[V]ariation in the white spotting in several cattle breeds is largely influenced by the multiple allelic series at the S locus, which includes at least four alleles (Olson 1999): SH (Hereford pattern), SP (Pinzgauer pattern or lineback), S+ (non-spotted) and s (spotting pattern). The SH allele gives white face, belly, feet and tail, often with a white stripe over the shoulder when homozygous. The SP allele gives pigmented body sides with variable amounts of white appearing along the dorsal and ventral areas extending forward from the tail and rump. The S+ allele gives the non-spotted (solid) phenotype, and is considered to be the wild-type allele, having as example the Angus breed. The spotting pattern allele (s) gives irregular areas of pigmented and white with feet, belly and tail usually white. This spotting pattern is characteristic of the Holstein, among other spotted breeds. Alleles SH and SP appear to be codominant to each other and incompletely dominant over S+. All these three alleles appeared to be completely dominant over the s allele (Olson 1981, 1999).
For spotting and white-headed phenotype see: OMIA:001737-9913 : Coat colour, white spotting, KIT-related in Bos taurus (taurine cattle)

Inheritance:  Küttel et al. (2019): "The so‐called Pinzgauer spotting is inherited as an autosomal incompletely dominant trait."

Mapping: Küttel et al. (2019): "A genome‐wide association study using 27 white spotted and 16 solid‐coloured Tux‐Zillertaler cattle, based on 777k SNP data, revealed a strong signal on chromosome 6 at the KIT locus. Haplotype analyses defined a critical interval of 122 kb downstream of the KIT coding region."

Molecular basis: As reported by Pennisi (2011), at the Biology of Genomes meeting at Cold Spring Harbor in May 2011, Durkin (2011) presented a poster reporting that the dorsal white stripe in cattle (called "colour-sided"), which maps to chromosome BTA29, appears to be due to the insertion of a duplicated 480kb fragment of DNA from BTA6 that includes the KIT gene but not all its regulators. The stripe appears to result from the at-least-partially unregulated expression of the translocated KIT. Interestingly, the gene order in the translocated segment on BTA29 is different from the gene order on BTA6, consistent with the duplicated region forming a loop which broke at a different location before being inserted in BTA29. Durkin (2011) also reported evidence that copies of the translocated fragment had escaped from BTA29, formed loops, and then were inserted alongside the original fragment on BTA6. This is the first report of such a phenomenon. Georges (2012) reported further on this phenomenon. A full account is provided by Durkin et al. (2012) who summarised the results as "colour sidedness is determined by a first allele on chromosome 29 (Cs(29)), which results from the translocation of a 492-kilobase chromosome 6 segment encompassing KIT to chromosome 29, and a second allele on chromosome 6 (Cs(6)), derived from the first by repatriation of fused 575-kilobase chromosome 6 and 29 sequences to the KIT locus. We provide evidence that both translocation events involved circular intermediates. This is the first example, to our knowledge, of a phenotype determined by homologous yet non-syntenic alleles that result from a novel copy-number-variant-generating mechanism." The same unusual mutation [called Cs(29)] was observed by Brenig et al. (2013) in two other breeds: "Homozygous (Cs(29) /Cs(29) ) White Galloway cattle and White Park cattle exhibit the [white] mismarked phenotype, whereas heterozygous (Cs(29) /[wild-type]wt(29) ) [white] individuals are either well or strongly marked. In contrast, fully black individuals are characterised by [homozygosity for] the wild-type chromosome 29." Medugorac et al. (2017) provided evidence that the colour-sided variant has been introgressed from Mongolian Turano cattle into Mongolian yaks, with which they have been herded form more than 1,500 years, enabling the backcrossing of female yak-cattle hybrids to male yaks.
Küttel et al. (2019): "Whole‐genome sequencing of a Pinzgauer cattle and comparison to 338 control genomes revealed a complex structural variant consisting of a 9.4‐kb deletion and an inversely inserted duplication of 1.5 kb fused to a 310‐kb duplicated segment from chromosome 4." From "the largest GWAS of white spotting to date", conducted on New Zealand cattle (Jersey, Holstein-Friesian and their cross), Jivinji et a. (2019) "extend[ed] those [results] of previous studies that reported KIT as a likely causal gene for white spotting, and report novel associations between candidate causal mutations in both the MITF and PAX3 genes." 
Häfliger et al. (2020): " A Brown Swiss cow showing a piebald pattern resembling colour-sidedness was referred for genetic evaluation. Both parents were normal solid-brown-coloured cattle. The cow was tested negative for the three known DNA variants in KIT, MITF and TWIST2 associated with different depigmentation phenotypes in Brown Swiss cattle. Whole-genome sequencing of the cow was performed and a heterozygous variant affecting the coding sequence of the bovine KIT gene was identified on chromosome 6. The variant is a 40 bp deletion in exon 9, NM_001166484.1:c.1390_1429del, and leads to a frameshift that is predicted to produce a novel 50 amino acid-long C-terminus replacing almost 50% of the wt KIT protein, including the functionally important intracellular tyrosine kinase domain (NP_001159956.1:p.(Asn464AlafsTer50))."
Artesi et al. (2020) discovered that the KIT^PINZ variant reported by Kuttel et al. (2019) as being causative for a form of colour-sidedness in Pinzgauer cattle (see OMIA 001737-9913) is also responsible for the same phenotype in Gloucester cattle.

Prevalence: Küttel et al. (2019): the KIT^PINZ "variant allele was present in all Pinzgauer and most of the white spotted Tux‐Zillertaler cattle. In addition, we detected the variant in all Slovenian Cika, British Gloucester and Spanish Berrenda en negro cattle with similar spotting patterns. Interestingly, the KIT^PINZ variant occurs in some white spotted animals of the Swiss breeds Evolèner and Eringer. The introgression of the KIT^PINZ variant confirms admixture and the reported historical relationship of these short‐headed breeds with Austrian Tux‐Zillertaler and suggests a mutation event, occurring before breed formation." 

Breeds: Belgian Blue (Cattle) (VBO_0000139), Berrenda en Negro, Spain (Cattle) (VBO_0004704), Brown Swiss (Cattle) (VBO_0000166), Cikasto govedo, Slovenia (Cattle) (VBO_0005270), Evolèner, Switzerland (Cattle) (VBO_0004498), Galloway (Cattle) (VBO_0000207), Gloucester, United Kingdom of Great Britain and Northern Ireland (Cattle) (VBO_0002964), Herens (Cattle) (VBO_0000233), Pinzgau (Cattle) (VBO_0000334), Tux-Zillertaler, Austria (Cattle) (VBO_0004409), White Park, United Kingdom of Great Britain and Northern Ireland (Cattle) (VBO_0004345).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: