The Nature of Genetic Disease

by John Armstrong

MANY people label any problem that appears to be inherited a genetic disease. However, although 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 function and die around three 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.

Examples 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 bloat (gastric dilatation-volvulus, or GDV) and hip dysplasia clearly have a genetic component, but also an environmental component and, perhaps, a behavioral one, as well (which also may be determined partially by the genes).

Bloat is not a genetic disease in the same sense as the metabolic and other disorders described above, and it seems unlikely that a single gene is 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 also come into play. 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-to-width ratio 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 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. If the fancy as a whole decides that a taller, narrower dog looks more refined, more of that description will be kept for breeding purposes, and the population will be shifted toward a more bloat-prone conformation.

John Armstrong was working with the Canine Diversity Project and for the benefit of dogs until he died. His years of work to help breeders make the right choices to improve the health of their dogs continues now through the breeders who have taken his advice and information and put it to good use in their breeding kennels.