STEPS ON THE PATH TO RESOLUTION
By: Dr. Patricia Wilkie, PhD
The problem of inherited disease in dogs is somewhat
different from other species. Every breeder has a commitment to decrease
the incidence of inherited disease as part of their efforts to produce
quality in the dogs they breed. Line-breeding, the tool largely responsible
for creating the tremendous variety of dog breeds and for setting type,
is also responsible for increasing the expression of recessive diseases
and aggregating the necessary deleterious genes to produce polygenic
disorders. Line-breeding can be thought of as "concentrating" the genes
encoding both desirable and undesirable traits, including disease. The
genes encoding these characteristics become more homogenous or similar
between dogs of a particular breed or line. It is a far more serious
situation if there is only one life-shortening inherited disease in
a breed, but nearly all of the dogs of that breed either carry the disease
gene or show symptoms of it, than if there are several less severe inherited
diseases in the breed and the disease producing genes are rare for all
of these diseases. A practical way of thinking about this issue is "How
likely is it that a particular breeding will produce affected offspring?"
If the particular disease gene is common in the breed and it is a close
line breeding, the answer is "very likely". Conversely, if the disease
gene is rare in a breed, it is improbable that affected offspring will
result, though it would be more likely when line-breeding than outcrossing.
Line-breeding is not the cause of inherited disease, it simply increases
the expression of disease genes by bringing them together. Recessive
and polygenic disorders are insidious because their significance remains
unnoticed until the disease becomes frequent enough to be recognized
as inherited. Generations may be unaffected when carriers are rare,
but in time, unaffected carriers become common. With line-breeding,
more affected individuals will appear unless unaffected carriers are
identified and selective breeding is practiced. Roughly the same situation
occurs with a dominant disease that has a post- reproductive age of
onset, since as many as half of the offspring of an affected dog will
become afflicted in their lifetime, but not until they have passed on
the disease gene to half of their offspring.
Even removal of affected individuals from the breeding population leaves
many carriers. For a recessive disease, all offspring of affected individuals,
two thirds of their normal full-siblings, half the offspring of either
parent and up to half the full-siblings of both parents carry a deleterious
gene and yet appear normal. There is little chance of eliminating all
carriers from a breeding program since they are not apparent 'until
affected offspring are produced. Recently, it has become possible to
identify presymptomatic dogs or carriers for a small number of inherited
diseases in a few breeds using molecular genetic tests. Conscientious
use of these tests by breeders can eliminate an inherited disease from
a breed in only a few generations. The most important reason molecular
genetic tests are so effective is that they allow breeders to identify,
at a very early age, dogs that are likely to pass on disease genes,
and to modify their breeding programs accordingly. This means no waiting
for a dog in question to mature past the age of disease onset to see
if it becomes affected, eliminating the need to do test breedings to
identify carriers, allows breeders to move toward their goals more rapidly
without the setbacks created by inherited diseases.
The resolution to the problem of inherited disease is also somewhat
different for dogs because they are partitioned into so many breeds
that are genetically related to varying degrees. The big question is
"How can we promote the development and use of molecular genetic tests
for more inherited diseases in more breeds"? Individually and through
the organization of breed clubs, breeders can play a key role in streamlining
many steps on the path to resolution of the problem of inherited diseases.
The most important things a breeder can do is to be informed enough
about the diseases in their breed to recognize possible symptoms, to
carefully observe their breeding animals and offspring and keep accurate
records of symptoms, age of onset and relationships of individuals in
affected families and of their living environments. These records are
essential to accomplishing several of the steps outlined below. Breeders
knowledgeable about the use of molecular genetic tests can participate
in their development, as well as, use the tests effectively as they
Steps in the development of an accurate molecular genetic diagnostic
Determine if the disease is of genetic or environmental origin or both.
Determine the inheritance pattern of the disease (dominant, recessive, sex-linked or polygenic). Once the mode of inheritance is known, more informed decisions can be made about which individuals are compatible for breeding.
Any experimental approach to identify markers for a disease gene requires samples for the isolation of the genetic material from both affected and unaffected dogs. Large families of three or more generations are ideal for many approaches, particularly if they include several affected members. The cooperation of many breeders/owners in sample collection is key to the success of this type of study.
The canine disease is compared to similar diseases in other species, most often humans, to determine if there are any possible candidate genes (i.e., genes that are known to be involved in these similar diseases or in the normal processes affected by the disease may offer important leads).
Various types of linkage tests have been most successful for identifying genetic markers located close enough to disease genes to be useful in diagnostic tests.
Searches for markers of disease genes can be done without genetic maps of the relative order and distance between markers, but will be more efficient as maps with small distances between markers (high resolution maps) become available in the future.
Maps of evenly spaced and highly informative (variable) markers for the breed under study make identifying a marker for a disease most efficient.
As markers flanking and successively closer to the disease gene are identified, the accuracy of a diagnostic linkage test is improved, but even relatively distant markers give some predictive information.
Identification of markers that flank the disease gene very closely make cloning the gene possible.
Once a disease gene is cloned, an extremely accurate diagnostic test known as a direct test (where the actual gene mutation is examined) becomes possible and the disease gene can be studied to determine how it causes the disease process. At this point, it becomes possible to rid the breed of this particular disease very rapidly.
Virtually all of you here have a strong commitment to your breed and knowledge of the people involved in it. In the next few years, your active participation will be crucial in making possible the research that can result in effective diagnostic tests for inherited diseases. As leaders of the Parent, Clubs, you are in the best possible position to make a significant difference to the future of your breed.
Dr. Patricia Wilkie, PhD, University of Minnesota
AKC Canine Health Foundation & American Kennel Club
1997 National Parent Club, Canine Health Conference