The Nature of Genetic Disease
by John Armstrong PhD

Many people label any problem that appears to be inherited a "genetic disease". However, though there are legitimate genetic diseases, there are also a variety of problems that have an inherited component, but are of a fundamentally different nature. Dealing effectively with any genetic problem requires an understanding of the relationship between the genes (genotype) and the phenotype. In many cases this is lacking. In this article, I would like to describe some of the differences in order to give breeders and owners a better understanding of what they are dealing with.


Inborn errors of metabolism: the true genetic "diseases" 

The first clearly-described relationship between genotype and metabolic deficiencies is credited to Sir Archibald Garrod, an English physician. In 1901, he showed that the inherited disease alkaptonuria results from an inability to metabolize certain amino acids, leading to the accumulation of homogentisic acid. Some of this compound accumulates in skin and cartilage (the latter leading to arthritis). The rest is excreted in the urine, turning it black. Garrod suggested that the metabolic block was caused by an enzyme deficiency, though this was not confirmed until the enzyme (homogentisic acid oxidase) was characterized in 1958.

Since Garrod's time, many other inherited metabolic diseases have been discovered. Some can be managed by careful attention to diet; others cannot. A particularly nasty example is Tay- Sachs disease, which involves an enzyme important in lipid metabolism. Individuals homozygous for a deficiency in this enzyme accumulate a compound called a ganglioside in the nervous system. They appear normal at birth but progressively lose motor functions and die around 3 years of age. There is no treatment.

Most of these conditions involve mutations that lead to the production of a nonfunctional enzyme, or one that is totally absent. In heterozygotes, the single good copy of the gene is generally able to produce sufficient enzyme to handle the normal workload. However, in a few cases, carriers as well as affected individuals have to be careful about their diet, or may exhibit less severe phenotypic effects.

Example of inherited metabolic diseases in dogs include phosphofructokinase deficiency in Cocker and Springer Spaniels, and pyruvate kinase deficiency in Basenjis.

Not all mutations involve metabolic pathways. Some involve proteins that have structural roles in cells and tissues. Others involve regulatory genes that control the correct sequence of events during development. These may lead to such problems as septal defects in the heart or the failure of the embryonic kidney to develop into the adult form. Nevertheless, all can legitimately be considered genetic diseases as there is a direct one-to-one relationship between a single mutated gene and a particular problem.


Conformational "diseases" - the result of unnatural selection

Problems such as hip dysplasia and bloat clearly have a genetic component, but also an environmental component, and perhaps a behavioral one as well (which may also be partially determined by the genes). Gastric torsion is not a genetic disease, and it would be foolish to think that one can identify a single gene responsible for bloat. One might better compare a bloat attack to a bad case of indigestion in a human. Some people are more prone to such attacks than others, and there may well be an inherited component, but other factors play a substantial role. Research into bloat suggests that diet, behavior and conformation may all play a role.

Leaving aside the question of the role of genetics in behavior, the results suggest that the incidence of bloat increases with the size of the dog and the depth and width of the chest cavity. This is a conformational problem, not a genetic disease. Certainly the overall conformation is, ultimately, determined by the genes, but not by a single gene. There is no bloat gene we can identify and eliminate. There are probably dozens or hundreds of genes that go into determining the shape and size of the head, trunk and limbs. Wherever there is genetic variability, one can select for larger, smaller, narrower, wider, etc. Because the fancy as a whole decided that a taller, narrower Standard Poodle looked more "refined", more of that description were kept for breeding purposes and the population has been shifted toward a more bloat-prone conformation. [This is not exclusively a poodle problem. There are other large breeds in which it is even more frequent.]

When it comes to the question of correcting it, the solution, in theory, is simple. We stop breeding for a bloat-prone conformation and go back to a slightly smaller Standard with a chest cavity that is not so deep or narrow. Some may regard this as a retrogressive step, but we have to decide which we want to sacrifice.

I do not rule out the possibility that two dogs of identical conformation may have one or more genes that lead to one being more bloat-prone than the other. If we could identify these genes, we might be able to reduce the incidence somewhat while retaining some of the desired "refinement". However, my prediction is that if we succeed in correlating the presence of some particular alleles for some genes with bloat, not breeding the individuals that carry these alleles will likely give us a shorter, wider poodle.

While it may be argued that there is nothing wrong with a tall, narrow poodle aside from the greater risk for bloat, selecting for a conformation that is not functionally sound is a recipe for disaster. Wild canids do not move awkwardly. Any that did would be eliminated by natural selection. After thousands of years of evolution, the musculoskeletal system of the average wolf has found a combination that works efficiently. Because there is diversity in the gene pool, there is always the possibility of a chance combination of genes that produces an individual that can move more quickly and efficiently. There is also the possibility that a less efficient combination may arise, but it is not likely to be favored.

In the artificial world of the show dog, one can insulate an individual from natural selection and favor an extreme - because the breeder or the public thinks it looks attractive... or just different. Two such dogs, bred together, may lead to something even more extreme, and more popular. However, the changes in one component must be accompanied by changes in others, or the result, from a structural standpoint, may impose stresses that the components are not designed for. The result will be components easily damaged or deformed while the puppy is still growing. One may not be dealing with genes that are "bad" and make a nonfunctional or defective product, just with a bad combination of genes. If, during this "unnatural selection", the genes necessary to make a good combination have been discarded, where does this leave the breed?