Categories: Pigmentation phene

Possibly relevant human trait(s) and/or gene(s) (MIM number): 600201 (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: 2021

Species-specific description: Dreger et al. (2013) identified a duplication in an intron of the RALY gene encoding hnRNP associated with lethal yellow that discriminated black-and-tan and saddle tan Basset Hounds and Pembroke Welsh Corgis. The RALY gene is located upstream of ASIP and the intronic duplication is in linkage disequilibrium with the likely causal variant in the ventral promoter of ASIP identified by Bannasch et al. (2021). For more detail on the likely causal variant in the ASIP promoter see OMIA 000201-9615 : Coat colour, agouti in Canis lupus familiaris

Inheritance: Dreger et al. (2013) provided data that enabled them to conclude that "it appeared that the black-and-tan pattern is recessive to saddle tan".

Mapping: Using genotype data from the Affymetrix Canine Array v2.0 100K SNP chip, Dreger et al. (2013) conducted a GWAS on "130 black-and-tan and saddle tan cases and 596 non-pattern controls" and another GWAS on "33 saddle tan cases and 97 black-and-tan controls". The first GWAS confirmed the ASIP locus on chromosome CFA24 as being responsible for the black-and-tan and saddle tan phenotypes (see OMIA 000201-9615). The second GWAS revealed that "the saddle tan phenotype maps specifically to a region separate from and upstream of ASIP".

Markers: By sequencing the most likely candidate gene in the candidate region upstream from ASIP, Dreger et al. (2013) proposed that the black-and-tan/saddle tan polymorphism is due to "a 16-bp duplication (g.1875_1890dupCCCCAGGTCAGAGTTT) in an intron of hnRNP associated with lethal yellow (RALY), which segregates with the black-and-tan phenotype in a group of 99 saddle tan and black-and-tan Basset Hounds and Pembroke Welsh Corgis. In these breeds, all dogs with the saddle tan phenotype had RALY genotypes of +/+ or +/dup, whereas dogs with the black-and-tan phenotype were homozygous for the duplication. The presence of an a y/_ fawn or e/e red genotype is epistatic to the +/_ saddle tan genotype. Genotypes from 10 wolves and 1 coyote indicated that the saddle tan (+) allele is the ancestral allele, suggesting that black-and-tan is a modification of saddle tan."

However, the authors also reported that "An additional 95 dogs from breeds that never have the saddle tan phenotype have all three of the possible RALY genotypes", indicating that this variant is unlikely to be the causal variant.

Subsequently, Bannasch et al. (2021) proposed that the intronic duplication is in linkage disequilibrium with a likely causal variant in the ventral promoter of ASIP. Bannasch et al. (2021) identified a series of structural variants within 1.5 kb of the transcription start sites that are likely to affect promoter function and propose that the black saddle (BS) allele is caused by the delin g.23378062_23379640delins[MT319116.1:424_663] (CanFam3.1) in combination with an inactivated ASIP hair cycle promoter. See OMIA 000201-9615 : Coat colour, agouti in Canis lupus familiaris) for more detail.

The g.1875_1890dupCCCCAGGTCAGAGTTT (CanFam3.1; chr24: 23252754_23252770dup) variant reported by Dreger et al. (2013) is therefore more likely an indirect marker and has therefore been removed as a likely causal variant from the variant table for this phene. [8/11/2021]

Breeds: Basset Hound, Pembroke Welsh Corgi.

Associated gene: