In other species: cattle , horse , domestic cat , sheep , pig , golden hamster , North American deer mouse , goat , American mink , rabbit , Mongolian gerbil , American black bear

Categories: Pigmentation phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 612271 (trait) , 203290 (trait) , 115501 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2002

Species-specific name: This is the classic B (Brown) locus described by Little (1957)

Species-specific symbol: B locus

Species-specific description: Brancalion et al. (2021): "The Brown (B) locus is controlled by Tyrosinase-related protein 1 (TYRP1. I), located on CFA11 (Schmutz et al. 2002). TYRP1. I encodes an intramelasomal peptide with a key role in the pathway of eumelanin biosynthesis (Kaelin et al. 2012). Consequently, variants in TYRP1 disrupt the production of eumelanin but have no effect on pheomelanin synthesis. Three recessive TYRP1 alleles, termed ‘bs’, ‘bd’ and ‘bc’, are commonly responsible for the dilution of black pigment to brown (Schmutz et al. 2002; ...). The dominant wt allele, ‘B’, favours the production of normal black eumelanin. ... As TYRP1 variants affect the synthesis of eumelanin and not pheomelanin, they have no effect on coat colour in dogs that are homozygous recessive at MC1R (e/e). Further, the variation in coat colour from yellow to red in e/e dogs was not found to be attributed to variants at the Brown locus (Schmutz et al. 2002). A two-gene interaction between the genotype at TYRP1 and MC1R, however, has been found to determine colouration of the nose and paw pads. Normally black, the nose and paw pads of E/e or E/E dogs with two or more recessive Brown alleles were found to be lightened to brown, whereas in e/e dogs, the normally black nose and paw pads were lightened to either brown or ‘self’ coloured. This phenomenon occurs because different genetic pathways control the migration of pigment into the hair shaft and keratinised skin (Schmutz et al. 2002; Schmutz & Berryere 2007)."

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the gene corresponding to the brown locus in mice), Schmutz et al. (2002) were the first to sequence the TYRP1 gene in dogs. They identified three likely causal variants, namely "a premature stop codon in exon 5 (Q331ter) [named allele b^s], . . .a [deletion of a] proline residue in exon 5 (345delP) [named allele b^d] . . . [and] A third variant in exon 2 (S41C) [named allele b^c). . . . All 43 of the brown group carried two or more of these sequence variants likely to interfere with TYRP1 function, whereas 0 of 34 in the black group carried two or more of these variants (10 carried one variant)". The authors concluded that "all three [mutations] affect eumelanin production and alter black pigmentation to brown".

Gerding et al. (2011) showed that the typical "grey" coat colour in Weimaraners is due to homozygosity for a non-functional allele (or heterozygosity for different non-functional alleles) at the TYRP1 locus; and that the "blue" coat colour in the same breed is due to the presence of one or two functional alleles at this locus. Thus, "blue" is dominant to "grey". By studying haplotypes, they were also able to show that the funcational allele is not a "reversion" from within the breed.

Letko and Drögemüller (2017) identified alleles b^c and b^d in Leonberger dogs.

Hrckova Turnova et al. (2017) reported a new allele (c.555T>G; p.Tyr185*) in a single pedigree of Australian Shepherd dogs.

Jancuskova et al. (2018) reported the same c.555T>G allele as being more widespread in the Australian Shepherd breed and "also its close relative Miniature American Shepherd".

Wright et al. (2019) reported a likely causal variant (CFA11:33326719; c.1025T>G; p.Phe342Cys) strongly associated with liver colour in Lancashire Heelers.

Van Buren et al. (2021) reported a 6th variant: "(NM_001194966.1, c.125G>A, p.Cys42Tyr) in exon 1 of the husky and husky‐mixes whose brown phenotype could not be explained by the previously known b‐variants." They named this variant b^h.

Prevalence: Van Buren et al. (2021): "All genotyped brown husky and husky‐mixes carrying the b^h allele were compound heterozygotes with either the bs or bc alleles, consistent with two mutant alleles required for a brown coat. No unrelated huskies had the b^h allele."

Breeds: Australian Shepherd, German Shepherd Dog, Lancashire heeler, Leonberger, Miniature American Shepherd, Siberian Husky.

Associated gene: