Ticked Tabby Cats and Their Genetic Bases Elucidated – JD Supra

The domestic cat has been the subject of much study, recently involving its genetic structure, genomic DNA sequence, and comparisons with other felines. The first such study was published in 2014, when an international effort led by Stephen J. O'Brien at the Oceanographic Center, Nova Southeastern University, Ft. Lauderdale, Florida reported the complete genomic sequencing of the domestic cat, Felix catus. The report, entitled "Annotated features of domestic cat Felis catusgenome," was published inGigaScience2014,3:13 (August 5, 2014) (see"Domestic Cat Genome Sequenced"). The study reported sequencing of a female Abyssinian cat named Cinnamon, a mixed-breed cat from Russian named Boris, and Sylvester, a wildcat ancestor of domestic cats. The report showed that domestic cats have retained "a highly conserved ancestral mammal genome organization" in comparison with ancestral cats (seeDriscollet al., 2007, "The near eastern origin of cat domestication,"Science317: 51923). Both species, F. catusandFelix silvestris, have 38 chromosomes, 18 pairs of autosomes, and two pairs of dimorphic gender-determining chromosomes. Details of the domestic cat genome structure included the presence of 217 loci of endogenous retrovirus-like elements (amounting to 55.7% of the entire genome, comprised of long interspersed elements (LINEs), short interspersed elements (SINEs), satellite DNA, retroviral long terminal repeats (LTRs) and "others"); 21,865 protein coding genes (open reading frames or ORFs), detected by comparison with eight mammalian genomes (from human, chimpanzee, macaque, dog, cow, horse, rat, and mouse); and a wealth of genetic variability in single nucleotide polymorphisms (SNPs), insertion/deletion events (indels); novel families of complex tandem repeat elements; and short terminal repeat (STR) loci.

Since that time more individual cat genomic sequences have been determined and assembled in the 99 Lives Cat Genome Consortium. These efforts resulted in a more comprehensive elucidation of the feline genome and insights into genetic bases for disease. A paper published in the Public Library of Science, entitled "A new domestic cat genome assembly based on long sequence reads empowers feline genomic medicine and identifies a novel gene for dwarfism,"PLoS Genetics 16(10): e1008926 on October 20, 2020, reported a revisit of the genomic sequence of Cinnamon, an Abyssinian breed domestic cat previously sequenced. Rather than focusing on one cat, this group* performed whole genome sequencing (WGS) of 54 domestic cats and aligned the sequences to detect single nucleotide variants (SNVs) and structural variants (SVs). As a consequence of these studies, sequences comprising the ~300,000 gaps in the annotated sequence reported to the Cinnamon Abyssinian were obtained, to produce a new reference cat genome denoted in relevant databases as Felis_catus_9.0. This genome comprised 2.84 gigabasepairs (Gb), of which only 1.8% (1.38 megabasepairs, Mb) was not assigned to a specific chromosomal location.

While such assessments of global genetic structure are informative, analysis of genes resulting in well-known phenotypes have been slower to arrive. One such study was published in March 2021 in Animal Genetics 52: 321-32, entitled "Mining the 99 Lives Cat Genome Sequencing Consortium database implicates genes and variants for the Ticked locus in domestic cats (Felis catus)." In this paper, scientists from the U.S. and Australia* reported the genetic basis of the Ticked tabby coat pattern, a phenotype whose genetics long have been used empirically by cat breeders. (Amathematically, the Consortium database contains genetic information from 195 individual cats.)

Three autosomal alleles at a single genetic locus in wild and domestic cats are understood to control the tabby coat pattern: Abyssinian (Ta, also known as "ticked"); mackerel (Tm, aka striped); and blotched (tb, aka classic, blotched) (where these allelic abbreviations follow the convention that capital letters indicate Mendelian dominant traits and lower-case letters are inherited as recessive genes); the blotched phenotype was designated as the "classic" tabby by Linnaeus in 1758. Various combinations of these alleles result in complicated coat patterns involving the legs, head/face, tail, and torso.

Failure of this understanding to explain cats that have spotted coats, like Egyptian mau and ocicat, induced further genetic analyses that uncovered at least three other loci involved in coat pattern; these include Tabby and Ticked, where the Tabby locus affects the mackerel and blotched patterns. Located on the cat A chromosome, the candidate gene encoded by this locus, laeverin (LVRN) or transmembrane aminopeptidase Q, Taqpep, encodes 'a membrane-bound metalloprotease and plays a regulatory role in extravillous trophoblast migration." The genetic bases for coat patterns involving the Tabby locus were found to be even more complex, involving genes in a pigment switching signaling pathway, and can have a phenotype having individual hairs in the coat pattern that alternates between melanin types that are seen illusorily to be brown.

The other locus, the Ticked locus, had been localized on the cat B1 chromosome but the gene residing at the locus had not been determined until this report. The famous Cinnamon had the ticked pattern and accordingly her DNA was used by these researchers in one strategy as having the "reference" allele and in another as having the "variant" allele in performing their search for the gene or genes at the Ticked locus. Of the 195 cats in the 99 Cat Consortium database, 80 had either solid or white coats and their ticked-tabby phenotype could not be determined (regardless of their underlying genotype). Among the cats whose genomic DNA was assessed were two obligate heterozygous ticked cats identical by descent for their ticked allele as they are parentoffspring bred from a ticked Somali"; three known Abyssinians, including Cinnamon; and three other cats showing the ticked phenotype.

The researchers used eight short tandem repeats that segregated with the Ticked phenotype as identified by genome scanning methods to find a 17 centoMorgan (cM) linked region on cat chromosome B1 for their analysis of candidate variants. Seven phenotype filters were applied (e.g., "eliminate intergenic, intronic and synonymous variants; (ii) consider the variant zygosity for the [whole genome sequencing entry for Cinnamon;" etc.) to identify increasingly rare variants in this region of the B1 chromosome; after filtering only one variant remained, located in the gene for Dickkopf Wnt Signaling Pathway Inhibitor 4 (DKK4). The protein encoded by this gene is known to be "a member of the dickkopf (Dkk) family of cysteine-rich secretory proteins that are antagonists of Wnt signaling pathways, involved in antero-posterior axial patterning, limb development, somitogenesis and eye formation." These researchers report finding a G>A transition mutation at position 188 of this gene, resulting in a Cys63Tyr amino acid sequence change in the encoded protein. The researchers also reported finding at lower frequency another transition mutation (C>T) in this gene, resulting in a change at amino acid 18 from Ala to Val. The position of these mutations is shown in the following Figure:

These researchers further report that protein structure modeling suggests that these mutations disrupt "a key disulfide bond" in a "cysteine-rich domain" in the first mutation or a signal peptide cleavage site in the Dkk protein in the second mutation. The resulting change in protein conformation for the first mutation is illustrated in the following Figure:

In either case the researchers conclude that disrupting the function of this protein (as the consequences of these mutations suggest) results in the observed ticked phenotype.

The authors recognize that the ticked phenotype is rare in outbred cats (and the observed allele frequency, wherein no other cats from the 195 cats in the database have this allele, is consistent with its rarity) and dominant, suppressing patterning and resulting in cats having no discernable coat pattern. But they also recognize the search for genes that influence coat pattern in cats is not concluded, stating:

Additional genotyping of the proposed variants, in a large cohort of phenotyped cats, as well as supportive functional data, would clarify the role of these variants in cat coat pattern development. The identified variants do not clarify the pathways leading to the production of the spotted coat phenotype in cats, suggesting that additional genes influence other tabby patterns in domestic cats. The allelic series for the Ticked locus is suggested as TiA = TiCK > Ti+, where the TiA allele represents the p.Cys63Tyr variant and the TiCK allele represents the p.Ala18Val variant.

* From the Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri Columbia, Columbia, MO and the School of Health and Behavioural Sciences, University of the Sunshine Coast, Sippy Downs, Australia; the paper in an appendix credits the hundreds of researcher who have contributed to the 99 Live Cat Genome Consortium.

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Ticked Tabby Cats and Their Genetic Bases Elucidated - JD Supra