Pet-Specific Care for the Veterinary Team. Группа авторов
considered a completely recessive trait without influence? If the bitch that is the carrier of one hemophilia gene has no spontaneous bleeding episodes but has complications with bleeding during surgery or whelping, is she truly phenotypically “normal”? Young Labrador retrievers with late‐onset rod–cone degeneration may have measurably reduced retinal function.
In cutaneous asthenia, a disease of skin fragility, gene mutations that produce abnormal collagen are considered dominant because heterozygotes produce enough abnormal collagen to be evident, whereas procollagen‐processing mutations are considered recessive because heterozygotes (those with only one abnormal gene variant) usually have enough enzyme activity to convert procollagen to collagen. Thus, as more is learned about genetic conditions and testing improves, suppositions about dominant and recessive traits will have less impact on our genetic counseling skills.
3.3.3 Dominance and Disease
Now let's take a look at dominance. A trait that is completely dominant is easy to spot because the parent is affected and so are all or most offspring. In the case of a dog that is homozygous for a dominant trait, all pups should be affected. In the case of a dog that is heterozygous for a dominant trait, that dog and 50% of its offspring should be affected. What happens in many instances is that there is incomplete dominance or expression of a dominant trait with variable expressivity. This basically means the trait has dominant features with a spectrum of possibilities in the offspring. If penetrance of a dominant gene is complete, all progeny receiving the allele will express the trait. If penetrance is 50%, only half will express the trait. With variable expressivity, some genes may produce different degrees of expression of a phenotype, ranging from severe expression to absence of the trait.
For example, dermatomyositis in collies was originally believed to be an autosomal dominant trait, but it is now believed that, although the trait has dominant features, environmental components (likely viral infection) are required for full manifestation of the disorder. Other traits may be co‐dominant, each contributing to the phenotype. For dermatomyositis, the current DNA testing situation is that there appear to be at least three loci associated with an increased risk for developing the disease (PAN2 gene on chromosome 10, MAP3K7CL gene on chromosome 31, DLA‐DRB1 on chromosome 12) and the three can be considered in aggregate when trying to determine relative risk. This can help identify pets that might be a low, moderate, or high risk for developing the condition. Other loci could eventually also prove to be associated with the condition.
An example of a dominant trait is merling of coat color. The normal, recessive genotype is the homozygote, mm. The heterozygous (Mm) animal has the characteristic merle coat coloring. The homozygous dominant (MM) animal is nearly all white, has blue eyes, and has a higher incidence of deafness. Although merle is a desirable feature in some dog breeds, the deafness and white coat color are completely undesirable. Breeders wishing to perpetuate merle in their lines will breed normal (mm) to merle (Mm) to achieve half typically colored offspring and half merle offspring. Fortunately, genetic testing for the merle trait is now available to facilitate that process, and avoid inadvertently creating homozygous dominant animals (MM) with health issues.
In most cases, recessive disorders are often attributable to enzyme deficiencies because heterozygotes with only 50% as much enzyme likely still have enough to perform needed functions. In contrast, dominant traits may be caused by defects in structural or substrate proteins, such that heterozygotes will be expected to be affected because these polypeptides are required in relatively large quantities. As more and more research accumulates, however, these suppositions seem to consist of more generalization than fact, and each trait is best considered individually.
A lot has been learned since Mendel began playing with peas, and new genetic tests that actually identify genotype deserve much of the credit (see 3.6 Genetic Testing). Some of the old rules just do not apply, though. For example, mitochondrial myopathy in Clumber and Sussex spaniels is believed to be a sex‐linked but not an X‐linked trait. The trait is passed from the mitochondrial DNA of the maternal line to both sexes. Therefore, hemophilia A is X linked and is transmitted principally from mother to son, whereas mitochondrial myopathy is believed to be passed from mother to both sons and daughters.
3.3.4 More on Penetrance and Expressivity
Genetic testing allows us to detect discrete genetic variants for diseases and traits, and yet in real life, the manifestations sometimes appear more like shades of gray than black and white (see 3.4 Predicting and Eliminating Disease Traits). If a pet has a genetic variant detected, shouldn't that mean that the clinical result is a foregone conclusion? Like much of medicine, the answer is both yes and no. Here's why.
To understand the situation, we need to go back to a basic tenet of genetics – genetic mutations/variants don't cause disease; they code for proteins that may not be fully functional and it is this dysfunction that is interpreted as disease (see 3.1 Genetic Basics). The body tends to have a lot of redundant systems, so there may be other genes, epigenetic markers, modifiers, suppressors, and environmental factors that all impact the clinical manifestations in the living patient.
Clinical diagnosis also requires that we be able to clinically differentiate between the “normal” gene and the “variant” gene in all cases within a population of animals, and this is referred to as penetrance. Penetrance can be defined as the percentage of individuals in a population with a given genetic variant (genotype) that fully display the clinical manifestations (phenotype), and this is rarely 100%. Because of this, many conditions are described as having incomplete penetrance and this explains why we can't fully predict the clinical situation, even with sophisticated genetic screening. Some disorders may have full (100%) penetrance, but many more do not.
In contradistinction to penetrance, which looks at genetic manifestations on a population level, expressivity measures the extent to which a genetic variant (genotype) actually expresses the so‐called clinical abnormality (phenotype) on an individual level. There can be different degrees of expression of identical variants in different individuals based on other genes present or environmental factors. Because of this, we might describe that there could be variable expressivity for this variant in different individuals.
These features of penetrance and expressivity make genetic counseling as much an art as a science, even given the certainty of genetic screening. It is also a great reason why genetic testing favors the nuanced interpretation by well‐trained veterinary teams to properly counsel pet owners on the benefits of pet‐specific care and the goal of helping pets live long, healthy, and happy lives.
3.3.5 Epistasis
As if penetrance and expressivity didn't add enough variability to the equation, it's important to realize that there may be diseases, phenes, and traits caused by the effects of more than one gene. Some loci have a variety of different alleles that could participate in a gene pair. Nowhere is this more apparent than in coat coloration (Table 3.3.1). Epistasis is when the action of one gene depends on the action of another gene. Epistasis is wonderfully illustrated by the coat colors possible with different combinations of alleles from different loci. All breeds have all the loci mentioned, but they do not necessarily have all the possible alleles mentioned. Even within a given locus, some alleles are dominant over others.
Table 3.3.1 The genetics of coat color
| Locus and allele | Effect |
|---|---|
| Agouti | |
| A | Solid color |