The comparative genetics approach is often termed a “candidate gene” approach. Discovered in the 1990s, the first mutations identified in cats were for lipid and lysosomal storage diseases8,9 because these diseases have well-defined phenotypes and known genes with mutations are found in humans (see reviews by Banks and Chamberlain¹⁰ and Valayannopoulos et al.¹¹). Most of the common diseases, coat colors, and coat types have been deciphered in the cat following the same candidate gene approach, that is, by finding a replicate trait in another species, usually mice, and checking the same gene for causative mutations in the cat genome.

Once a mutation is known, a genetic test can be established. Genetic testing for domestic cat diseases and appearance traits is a rapidly growing asset for the veterinary community. Over 60 genes have been identified to have DNA mutations that cause feline health problems or alterations in appearance (Tables 52.1, 52.2, and e-Table 52.1). To date, other than the muscular dystrophy mutation, all mutations in the cat are autosomal (i.e., not found on the X or Y chromosomes (allosomes) but on the autosomal chromosomes). A variety of commercial laboratories can now perform feline genetic diagnostics, allowing both the clinician and the owner to obtain DNA test results. DNA is easily obtained from a cat by using a cotton bud, cotton tip applicator, or cytology brush as a buccal swab. The samples can be sent to any laboratory in the world because the DNA is stable at room temperature. The DNA test can identify carriers of the traits, predict the incidence of traits in breeding programs, and influence medical prognoses and treatments. Once a genetic test proves that an animal has a genetic trait, preventive therapies and dietary changes could be implemented to slow or prevent the onset and progression of the associated disease. Thus, genetic testing should not be viewed as an alternative to veterinary care but instead as a tool for veterinary care, part of a cat’s overall health management plan.

Domestic cats have been selected to produce breeds mainly based on aesthetic qualities, especially coloration, fur length and type, and some morphologic types such as folded or curled ears. Most of the genes controlling these traits are simple, and many of the causative mutations have been identified. Table 52.1 presents the common genes and loci that affect feline phenotypic traits. A trait is initially given a locus name, such as Brown, before the actual gene has been identified. The locus name usually is a descriptor of the trait, although the location in the genome for the locus will not be initially known; however, the mode of inheritance of the different alleles is usually determined. The alleles are given single- or two-letter designations, with lower case implying a recessive allele. Once the gene is identified, such as tyrosinase-related protein 1 (TRYP1) for Brown, the mutations are written to describe the genetic alteration within the gene, and the gene will be designated with the alleles, such as TRYP1^b for the brown allele.

Because the phenotypic mutations are of value to cat breeders for managing breeding programs, genetic tests for many traits are readily available from commercial laboratories. Since most of the mutations for the aesthetic traits are recessive, the mutant alleles must be present in both chromosome copies for the effect to be visible, and heterozygous cats can carry the mutation without detection. Recessive mutations tend to be found in the genes that produce the enzymes of biological pathways. Thus, most of the coat color mutations are recessive because they are usually part of disrupting the pigment production pathways.

Many genes that affect pathways also have more than one mutation causing different effects; this is termed an allelic series. The locus for brown color variants, Brown, has two mutations in the causative gene, TRYP1. The wild-type allele, B, which causes normal black pigment, is dominant to the brown allele, b, which causes a reduced amount of black pigment, producing a brownish hue to the fur. The brown allele is dominant to the light brown allele (b^l), which imparts a cinnamon color or reddish effect on the fur. The allelic series is written as B > b > b^l to indicate the dominance of one allele over another.

In the case of the Color locus, C, which is also an allelic series, sepia coloration (c^bc^b) which is a defining characteristic of the Burmese (Fig. 52.1) and Singapura (Fig. 52.2) breeds, is codominantly expressed with the Siamese points (c^sc^s) producing an additive affect. Thus, compound heterozygous cats (c^bc^s) have an intermediate coloration compared with that of the Burmese and the Siamese; this color is usually referred to as mink and is characteristic of the Tonkinese breed (Fig. 52.3). Complete albinos, which have an additional allele at the Color locus, have also been identified. The locus is controlled by the gene tyrosinase; TYR and the allelic series is written as C > c^b = c^s > c. An additional allele for complete albinism in TYR has been identified in the domestic cat, extending the allelic series to C > c^b = c^s > c = c².^12–14 In some cases, new variants within a gene, (i.e., new alleles) are rare and not all combinations of the allelic patterns have been identified; thus, the influence of one allele over another cannot always be deciphered, such as the newer mocha variant for the Color locus.¹⁵ Most coat color mutations are common to all cats and are effective for genetic typing in all breeds and populations. However, some color varieties are not found in all breeds, thus the variant(s) may not be present, and it maybe be wasteful to test for them. Even though long fur is common in pedigreed and random-bred cats, long fur is an exception in that it can be caused by five different mutations in the gene fibroblast growth factor 5 (FGF5).^16,17 One mutation is common to almost all breeds and populations, which suggests that this mutation is the most ancient and was present before breeds were developed. The other long fur mutations are more specific to particular breeds (Personal Communication, L.A. Lyons).¹⁸ Some cats have long fur because of two different mutations in the gene FGF5. These cats would be considered compound heterozygotes. Thus, all mutations must be genotyped to determine whether a cat carries a mutation for long fur. Ragdolls, Maine Coons, and Norwegian Forest cats each have a long hair variant that is most common in that breed.

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