3.1.7 Predicting Genotype
Since alleles are inherited from both parents, it would be helpful to know how they combine in individuals and the impact that has on disease susceptibility. Two terms are important in this regard – genotype and phenotype.
Genotype refers to the actual genetic sequence determined in an animal, while phenotype describes what is clinically evident, compared to the normal or typical presentation. So, for any individual genetic trait (T), in which an animal could inherit a typical (T) or variant (t) gene from its parents, there are four combinations possible (TT, Tt, tT, tt) but really only three variants (TT, Tt, tt). If the condition is recessive (such as von Willebrand disease [vWD]) and the heterozygotes (Tt) cannot be clinically distinguished from one of the homozygotes (TT), then clinically there are three variants (TT, Tt, tt) but only two clinical phenotypes – normal (TT or Tt) and abnormal (tt). In the case of a recessive disorder like vWD, we have a genetic test that can tell us genotype (the actual gene pairing in the animal), but without the test we can only determine phenotype – normal versus abnormal, by evidence of bleeding factor tests. So, for a condition like hip dysplasia where currently we cannot identify genotype, we end up making the diagnosis with phenotypic tests such are radiographs or distraction index.
Progressive retinal atrophy in the Irish setter is inherited as an autosomal recessive trait, which means that an affected individual inherits a defective gene (rcd1) from each parent, whereas dogs that inherit a defective gene from only one parent may be difficult to identify, because they appear clinically normal. The good news for veterinary teams, even without a DNA test, is that an electroretinogram can identify affected individuals (with two copies of the abnormal gene) by 6 weeks of age. This identification means the dog can be removed from a breeding program so that it will not contribute its PRA genes to future generations. The bad news for veterinary teams and breeders is that carriers of the trait, those with only one abnormal variant and one normal variant, cannot be identified clinically, even with sophisticated procedures such as electroretinography. Therefore, without genetic testing, genetic counseling is a hit‐or‐miss enterprise until the animal produces affected offspring and we can determine its genotype. With direct DNA testing, though, animals that are affected, clear, or carriers can be identified (see 3.4 Predicting and Eliminating Disease Traits).
That's good news for Labrador retriever breeders; labs are also prone to PRA but a clinical diagnosis cannot be made until the dogs are 4 years old, and an electroretinogram will not identify affected pups until they are 18 months old. DNA testing can identify status early, in pups as young as one day of age. Unfortunately, the specificity of DNA testing is also one of its limitations. The gene that causes PRA in Labrador retrievers (prcd) is different from the one that causes it in Irish setters (rcd1), so the same DNA test cannot be used to diagnose these two forms of the disease (and there are dozens of different genetic forms of PRA). Fortunately, DNA testing for both prcd and rcd1 is now available, and for many other forms of PRA.
3.1.8 Genetics Versus Genomics
There is a lot of attention focused on the promises of genomic medicine, and it can sometimes be confusing when we use the terms genetics and genomics synonymously. Genetics is the study of genes and how traits or conditions are passed from one generation to the next. On the other hand, genomics is the study of the entire genome, and its combined influence on complex diseases and the impact of environmental factors such as diet, exercise, medications, and toxins on genes.
3.1.9 The Impact of Breeding
With mass or individual selection, the breeder selects the animals to be bred on the basis of their superior characteristics. Whereas many breeders select their breeding stock on the basis of conformation or other physical characteristics that exemplify the breed standard, genetic counseling is intended to temper enthusiasm for physical traits with a more holistic picture of genotypic and phenotypic health (see 3.8 Genetic Counseling). Veterinarians should also exert some self‐discipline by focusing not just on one health aspect (e.g., von Willebrand status) but rather on the whole animal. Otherwise, in the zeal to rid a line of one disease, another (or more) may inadvertently be fostered.
Selection works best at eliminating dominant traits from a population. After all, because all animals that carry the dominant allele develop the trait, it is theoretically possible to eliminate a dominant trait in one generation. Selection is complicated, however, by the fact that some dominant traits (e.g., dermatofibrosis) do not appear until later in life when animals may already have been bred, and by traits with incomplete dominance or variable expressivity, in which an affected animal may not be detected yet carry the trait. Fortunately, DNA testing is now available for some of these traits, including dermatofibrosis.
With recessive traits, selection can quickly remove homozygous affected animals from breeding, but if heterozygotes cannot be detected, carriers will persist in the population. The final elimination of the trait from a breed requires identifying carriers and ensuring that no carriers are bred to one another. Even though doing so does not eliminate the deleterious allele from the population, it does ensure that no affected animals are produced.
Genes don't cause diseases, but they may code for defective proteins that are associated with disease states.
For any particular genotype, each parent contributes one allelic variant for that trait.
Mutations can be responsible for changes along the length of a gene sequence that can have major or minor impact on the expression of that gene, depending on the mutation.
Diseases with the same name are not necessarily caused by the same genetic mutation in all breeds.
Genetic markers can prove useful in helping to identify disease risk, even when the specific disease gene has not yet been identified.
Abbreviations
DNADeoxyribonucleic acidORFOpen reading frameRNARibonucleic acid
Recommended Reading
1 Ackerman, L. (2011). The Genetic Connection. Lakewood, CO: AAHA Press.
2 Ackerman, L. (2020). Proactive Pet Parenting: Anticipating pet health problems before they happen. Problem Free Publishing.
3 Wang, W. and Kirkness, E.F. (2005). Short interspersed elements (SINEs) are a major source of canine genomic diversity. Genome Res. 15: 1798–1808.
3.2 Modes of Inheritance
Lowell Ackerman, DVM, DACVD, MBA, MPA, CVA, MRCVS
Global Consultant, Author, and Lecturer, MA, USA
3.2.1 Summary
To understand genetics, we try to make it as simple as possible. We like to believe that traits have to be dominant or recessive and appear either on the sex chromosomes or the autosomes. We enjoy nice, clean statistics such as “approximately 25% of offspring will be affected.” In reality, the deeper one delves into genetics and statistics, the more one realizes that, for most conditions, hard