The Nature of Genetic Disease
by John Armstrong
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 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.
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 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.
When it comes to the question of correcting this problem, the
solution, in theory, is simple. We stop breeding for a bloat-prone conformation
and select for a slightly smaller dog 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 of GDV somewhat while retaining some of the desired
"refinement."
While it may be argued that there is nothing wrong with a tall,
narrow dog 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 a
conformational extreme, because the breeder or the public thinks it looks more
attractive or just different. Two such extreme 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.
In such a case, one may not be dealing with genes that are
"bad" and make a nonfunctional or defective
product, just with a bad combination of genes. But if, during this
"unnatural selection," the genes necessary to make a good combination
have been discarded, where does this leave the breed?
Copyright 1997, 1998 John
B. Armstrong. Reprinted with permission.
It may be reprinted providing it is not altered and appropriate credit
is given.
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