Golden cats: A never-ending story!

In the British feline breed a golden coat modification, called light-gold, akita or copper, was reported by breeders during the 2010s. This modification restricted eumelanin to the tip of the tail and hairs showed a wideband modification. Pedigree analyses revealed an autosomal recessive inheritance pattern. A single candidate region was identified using a genome-wide association study. Within that region, we identified CORIN (Corin, serine peptidase) as the strongest candidate gene, since two CORIN variants have previously been identified in Siberian cats with a golden phenotype. A homozygous CORIN:c.2425C>T nonsense variant was identified in copper British cats. Segregation of the variant was consistent with recessive inheritance. This nonsense CORIN:c.2425C>T variant, located in CORIN exon 19, was predicted to produce a truncated CORIN protein - CORIN:p.(Arg809Ter) - that would lack part of the scavenger receptor domain and the trypsine-like serine protease catalytic domain. All 30 copper cats were T/T homozygous for the variant, which was also found in 20 C/T heterozygous British control cats but was absent in 340 cats from the 99 Lives dataset. Finally, genotyping of 218 cats from 12 breeds failed to identify carriers in cats from other breeds. We propose that this third CORIN:c.2425C>T variant represents the wbBSH (British recessive wideband) allele in the domestic cat.

In the Siberian cat breed, two variants were identified in the CORIN (Corin, serine peptidase) gene, a suppressor of the ASIP (agouti signaling protein) pathway (Enshell‐Seijffers et al., 2008) that causes golden coat modifications characterized by enlarged subapical pheomelanin bands in hairs and reduced dark tips (Abitbol et al., 2022; Beauvois et al., 2021). These modifications, called sunshine and extreme‐sunshine, are similar to the golden modification of tigers (Xu et al., 2017). In British cats, breeders from Germany and Russia have reported since the 2010s a coat modification that is distinct from the known golden shaded (Vella et al., 1999) and golden ticked phenotypes (Lyons et al., 2021). This modification was supposed to be polygenic as several phenotypes differing in their warm tone and countershading were observed, ranging from a classical golden ticked phenotype to a ‘copper’ phenotype characterized by a red mantle with marked ivory belly and ivory spots on the uppersides of the paws (Figure 1a–d). However, careful examination of pedigree data indicated a probable autosomal recessive inheritance pattern. DNA and phenotypic data from these copper British cats and from control cats were collected. Twenty‐five British cats (including 10 copper cats) were genotyped using the Illumina Feline 63 k SNP array, among which 60 599 SNPs yielded usable results (minor allele frequency >5%, genotyping rate >95%). All 25 cats had genotyping rates >95% and all were conserved for the analysis. Following basic case–control analysis, the genomic inflation factor was 1.59 and the 25 highest significant associations were identified for 25 SNPs, among which 18 markers were located on chromosome B1 (Appendix S1, Figure 1e, Table S1). After Bonferroni correction of the P raw values for multiple tests, no SNP had a significant P Bonferroni value (Figure 1e, Table S1). Seventeen of the 18 SNPs from chromosome B1 were located between position 164 738 782 bp and position 175 627 824 bp (Table S1) according to Felis_catus 9.0 reference genome and defined the genome‐wide association study candidate region. This region contains a strong candidate gene, CORIN (chromosome B1: 167 578 182 bp to 167 835 768 bp, Felis_catus 9.0). Exons and exon–intron boundaries from CORIN were sequenced in two copper cats and compared with the reference feline sequence (Appendix S1, Table S2). Three variants were identified. We found the previously described CORIN:c.1449C>G SNP (rs43981625, ensembl.org; Beauvois et al., 2021) predicted by PROVEAN to be a neutral variant (Appendix S1) and a synonymous CORIN:c.2684C>T variant. In exon 19, we found that the two copper cats were T/T homozygous for a CORIN:c.2425C>T nonsense variant predicted to change an arginine at position 809 in the protein into a stop codon: CORIN:p.(Arg809Ter).

Figure 1

The copper phenotype in British cats is governed by a CORIN nonsense allele. (a) Golden ticked phenotype in a black tabby British cat. Note the blond tone and the agouti phenotype owing to agouti banded hairs. (b–d) Copper phenotype variations in black tabby British cats. (b) Note the red tone with a discrete lightening of the belly, ivory marks on the uppersides of the paws and the black tail tip. (c) Note the blond to apricot tone with marked ivory belly and ivory marks on the uppersides of the paws. (d) Note the red mantle with marked light ivory to white belly and large ivory marks on the uppersides of the paws. The three copper cats (b–d) were T/T homozygous for the CORIN:C.2425C>T variant and showed tipped hairs. The golden ticked cat (a) showed agouti ticked hairs and was heterozygous for the CORIN:C.2425C>T variant (Table S3, Figure S2). (e) Manhattan plot of the genome‐wide association study. The plots represent the P raw and P Bonferroni values of each SNP included in the case–control association study. The association study compared the 10 copper British cats with 15 control British cats. A suggestive association with chromosome B1 was detected. The three SNPs with the highest association were chrB1.188265817, chrB1.188367525 and chrB1.188505613, with a P raw value of 2.21 × 10−6 and a P Bonferroni value of 0.11 (Table S1). UN, Unknown. (f) Schematic of the 13 domains of CORIN (Appendix S1). The CORIN:C.839G>A missense variant of extreme‐sunshine Siberian cats, the CORIN:C.1759C>T missense variant of golden tigers and the CORIN:C.2383C>T missense variant of sunshine Siberian cats are depicted in black. The CORIN:C.2425C>T nonsense variant of copper British cats is depicted in red

We genotyped a total of 84 British cats for the CORIN:c.2425C>T variant. All 30 copper cats were T/T homozygous. The copper cat group included cats with or without a marked ivory belly but showing a gold to red tone and ivory marks on the uppersides of the paws (Figure 1b–d). Among 54 British control cats, 20 were C/T heterozygous for the CORIN:c.2425C>T variant and included five copper obligate carriers. Additionally, in the group of 17 golden ticked and golden shaded British control cats, 13 individuals were C/T heterozygous and four cats were wild‐type homozygous (Table S3).

We searched for the CORIN:c.2425C>T variant in the 340 cats of the 99 Lives cat whole genome sequencing project (Buckley et al., 2020) and we genotyped a total of 218 control cats from 12 breeds for CORIN:c.2425C>T, including golden shaded Persian and Exotic cats and sunshine Siberian cats. We failed to identify the mutant allele (Table S3).

Alignment of the feline CORIN protein sequence with the human sequence and the sequences from 12 mammals with agouti hairs (Figure S1, Table S4) shows that the CORIN:c.2425C>T nonsense variant was predicted to produce a truncated CORIN protein – CORIN:p.(Arg809Ter) – lacking part of the scavenger receptor domain and the trypsin‐like serine protease catalytic domain. CORIN was described as a transmembrane serine protease functioning as a suppressor of the agouti pathway. It regulates the length of the functioning period of ASIP during the hair growth cycle, producing tipped hairs characterized by enlarged subapical pheomelanin bands and reduced dark tips (Enshell‐Seijffers et al., 2008; Xu et al., 2017). In copper cats we observed only tipped hairs whereas golden ticked cats showed non‐modified agouti hairs (Figure S2). Thus, the copper modification of British cats was fully consistent with a wideband phenotype.

In conclusion, we identified a third CORIN variant associated with the copper modification of British cats. We propose that this CORIN:c.2425C>T variant represents the wb (British recessive wideband) allele in the domestic cat, which further enlarges the panel of recessive CORIN wideband alleles described in animals.

CONFLICT OF INTEREST

The authors declare that they have no competing interests.

Appendix S1

Click here for additional data file.

Figure S1

Click here for additional data file.

Figure S2

Click here for additional data file.

Table S1

Click here for additional data file.

Table S2

Click here for additional data file.

Table S3

Click here for additional data file.

Table S4

Click here for additional data file.