In other species: Rhesus monkey , dog , American black bear , domestic cat , leopard , horse , pig , taurine cattle , goat , rabbit , golden hamster , North American deer mouse , Mongolian gerbil , American mink

Categories: Pigmentation phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 612271 (trait) , 203290 (trait) , 115501 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: no

Key variant known: yes

Year key variant first reported: 2007

Inheritance: The dark vs light coat colour segregation in Soay sheep is consistent with single-locus inheritance in which dark is dominant to light (Doney et al., 1974; Ryder et al., 1974; Coltman and Pemberton, 2004)

Mapping: In Soay sheep, Beraldi et al. (2006) mapped this locus to a small region of OAR2 very near microsatellite BMS678. Comparative mapping implicated the well-known TRYP1 (brown) coat-colour locus, in which a causative mutation was subsequently found (see below). In a QTL resource flock derived from an Awassi x Merino x Merino backcross, Raadsma et al. (2013) conducted a genome scan for 13 skin and fibre pigmentation traits, using 189 microsatellites on 177 backcross wethers, the F1 sire and both grandparents. Of the 19 highly-significant QTL detected, 13 mapped to a region of chromosome OAR2 that includes the TYRP1 gene, and 5 mapped to a single region of chromosome OAR19 that includes another coat-colour gene, namely MITF. By conducting a GWAS on 51 brown and 38 black sheep of the Valais Red breed that is characterised by its brown coat, Paris et al. (2019) mapped the brown/black polymorphism in this breed to the TYRP1 gene on chromosome OVA2.

Markers: Having identified the TYRP1 gene as a strong positional candidiate, subsequent sequencing and association analysis enabled Raadsma et al. (2013) to show that 10%-46% of variation in 13 pigmentation traits is due to a non-synonymous SNP (c.2240C>G) in exon 2 of TYRP1. Up to 83% of variation was accounted for when the model also included the MITF-containing QTL on chromosome OAR19.

Molecular basis: Details of the Soay mutation were reported by Gratten et al. (2007): "a G→T transversion at nucleotide position 869 in exon IV (hereafter TYRP1 869G→T) was perfectly associated with coat colour; light sheep (n=6) were homozygous for T at this position, whereas dark sheep (n=6) were either homozygous for G or heterozygous (Fisher's exact test, p=0.002). . . . The TYRP1 869G→T mutation is predicted to cause the replacement of a cysteine (Cys) residue with phenylalanine at codon 290 (C290F). An amino acid alignment revealed that the Cys residue is conserved across all available vertebrates, suggesting that nucleotide position 869 may be under strong functional constraint and that dark coat colour is ancestral to light". Interestingly, the above mutation was not present in the Awassi x Merino x Merino resource flock reported by Raadsma et al. (2013), and in which a new likely causal variant (c.2240C>G; p.A???V) was reported. By analysing sequence data in and around the TYRP1 locus, obtained from whole-genome-sequencing of two brown and one black Valais Red sheep, Paris et al. (2019) identified two new brown alleles, namely a "frame‐shift variant TYRP1:c.86_87delGA [designated] as b^VS1 and the nonsense variant TYRP1:c.1066C>T [desiganted] as b^VS2".

Prevalence: Paris et al. (2019) reported that "the b^VS 1 allele occurs only in local breeds of Switzerland whereas the b^VS 2 allele seems to be more widespread across Europe."

Breeds: Soay (Sheep) (VBO_0001605), Valais Red (Sheep) (VBO_0001666).
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: