Breeding Healthier Dogs
by Martine Huslig
With the
explosion in research, great strides are beginning to be made in understanding
canine genetics. The use of newly developed (and developing) genetic testing in
improving breeding programs is the subject of a great deal of discussion in the
canine community. Many of the presentations at the recent AKC Canine Health
Foundation National Parent Club Canine Health Conference held October 15, 16 and
17 were devoted to the discussion of genetics. While most breeders and pet
owners alike are very concerned about the possibility of genetic diseases in
their dogs, many find the topic of genetics confusing and overwhelming. They
also may believe that the potential of a genetic disease in their dogs is a
topic to be whispered about and swept under the carpet, rather than something to
be openly discussed. And yet, each individual dog (purebred or mixed breed) has
multiple "defective" genes. With the common breeding practices of line breeding
and inbreeding in dogs, negative recessive genes can easily be amplified and,
with late-onset diseases, a condition can be widespread in a line before even
one dog becomes affected with the problem. Even the most ethical of breeders can
produce dogs with genetic disease. The big question is how to deal with a
genetic disease in a breeding program or a breed when a problem is discovered.
With new research, breeders now have direct genetic testing for certain genetic
diseases; unfortunately, most potentially genetic diseases that concern Briards
do not have a gene test. The purpose of this article is to explain some basic
genetic principles and to discuss some of the recent publications on how genetic
principles can be applied to a breeding program. Three primary tools can be used
to address a potentially genetic disease in a breeding program. These are:
1)genetic tests, 2)phenotypic tests, and 3) pedigree analysis.
Some Genetic Basics First
As most of you
know, a puppy begins as a single cell created from an egg (from the mother) and
a sperm (from the father). In each cell are the chromosomes. The
chromosomes are the structures that carry the genes. Dogs have 39 chromosome
pairs (78 chromosomes total). The first 38 chromosome pairs are the numbered
pairs and the 39th pair are the sex chromosomes. When the sex chromosomes are
two "X" chromosomes, the dog is a female. When there is an "X" and a "Y", the
dog is a male.
Conditions (diseases, traits or characteristics) carried on chromosomes 1
through 38 (the numbered pairs) are referred to as autosomal. For
conditions carried on the autosomal chromosomes, an individual has two copies of
each gene. One gene on one chromosome inherited from the mother and a matching
gene on the matching chromosome inherited from the father. Autosomal conditions
typically affect males and females equally. Conditions found on the sex
chromosomes are referred to as X or sex linked. Sex-linked
conditions affect one sex (usually males) more frequently than the other sex.
Conditions are further referred to as recessive or dominant.
With a recessive disease, the gene inherited from both parents must be defective
for the offspring to have the disease. The offspring with the disease is often
referred to as affected. The parents of a puppy affected with an
autosomal recessive genetic disease are referred to as carriers. Carrier
is the term used to refer to an individual with one copy of the defective gene
for a recessive condition. They are unaffected but "carry the gene." With a
dominant genetic condition, one copy of the gene from one parent results in the
condition. Sometimes the parent who passed on a dominant gene will also be
affected with the disease, but not always. Dominant genes have decreased
penetrance. Decreased penetrance means that the dominant gene is present
and theoretically the disease should be present, but it isn't. Dominant
conditions also have variability in their expression. For example
the offspring may be severely affected with a condition but their parent who
passed on the gene is only mildly affected. Why exactly this occurs is unknown.
Genetic Tests
Two types of
tests are used to detect genetic diseases in dogs. These are direct
genetic tests and linkage based tests. Direct genetic
tests require that the exact gene has been identified and that the exact defect
in the gene that causes the disease is known. With a direct genetic test, your
dog can be tested, and you will be told with certainty that "yes, your dog has
the defective gene" or "no, your dog does not have the defective gene." A direct
genetic test was recently developed for the gene for Congenital Stationary Night
Blindness (CSNB) in Briards. CSNB is an autosomal recessive
genetic disease. (Autosomal because it is carried on one of the numbered
chromosomes and recessive because both copies of the gene must be defective in
order for a dog to be affected with the disease.) Andres Gal and associates,
Swedish researchers in human genetics, discovered the CSNB gene. They were
looking for the gene because it was similar to a disease found in humans.
(Looking for and finding a gene are like looking for a needle in a haystack.
Canine disease genes are often easier to find because there are usually larger
families, more affected individuals and the pedigrees are well documented.) Once
the defect in the CSNB gene was discovered, Optigen was able to develop a test
to determine if an individual dog carries the gene.
Unlike direct genetic tests, linkage based tests are not definitive. Linkage
tests rely on polymorphic markers. Linkage tests can be used when
the physical location (map site) of a gene on the chromosome is known but no
there is no way (no direct test) to identify the defective gene. (Markers are
like when someone has to pick up a stranger at the airport and they have the
stranger wear a red carnation. The stranger is the gene and the red carnation is
the marker.) A marker is a strand of DNA that is identifiable by scientists and
is known to occur consistently at certain locations on the chromosomes. The best
markers are in the middle of the gene but many markers are located close to
the gene. This can be a problem if the marker and the defective gene are
separated. When the egg and sperm are made, different combinations of
chromosomes are given to the offspring. In addition, the chromosome pairs will
swap some of their information through a process called crossing-over or
recombination. All of this is done to ensure genetic variability (and
probably part of why it is so difficult to consistently get what you want when
breeding.) If the crossover occurs between the gene and the marker then the
marker is no longer linked to the gene. (Imagine if the stranger dropped his red
carnation and someone else picked it up and put it on.) The results of these
types of linkage based tests are given in percentage likelihood that a specific
individual has the gene. This percentage is based on how likely it is that a
cross-over occurred. Linkage tests are valuable in some breeds, but currently
there are no linkage tests in Briards.
Phenotype
Tests
Unfortunately,
most of the genetic diseases of concern in Briards do not yet have gene tests.
For these diseases breeders must rely on phenotypic tests to try to improve
their breeding program. Genotype is the term used to refer to a
dog's genetic status such as 1) affected, 2) carrier or 3) non-carrier or clear. Phenotype is the term to refer to the how the dog appears. For
example black is dominant to tawny with respect to Briard color. If a dog is
black, that is his phenotype (he is black), but his genotype is unknown (he
could have two copies of the black color gene or one black and one tawny.) Since
tawny color is the recessive gene, when a dog is tawny, one knows his phenotype
(he is tawny) and his genotype (he has two tawny genes.) Tawny is the recessive
gene; therefore, one knows the dog must have two tawny genes. (There are many
other genes affecting Briard color and this is just a simple example.)
Phenotypic tests are detection methods that show if a dog has the condition. You
cannot see the gene that causes the condition. In some instances the exact
inheritance pattern of the condition may be unknown and is just known to "be
genetic." With a phenotypic test you can simply see if the dog is affected or
not. Some examples include hip and elbow X-rays and blood tests for thyroid and
Von Willebrand's disease.
Phenotypic tests unfortunately have lots of pitfalls. Unlike genetic tests that
can be done at almost any age (the genes are set from the very beginning),
phenotypic tests depend on the condition being expressed.
Therefore, some phenotypic exams cannot be performed until a certain age, some
have to be repeated each year and, with some conditions, individuals who carry
the gene never express the condition. In addition, phenotypic tests give no
information about whether or not a particular dog is a carrier of a disease
gene.
In cases of Progressive Retinal Atrophy (PRA), for example the diseases may not
show-up until after five years of age and the dog may have been bred multiple
times already. With phenotypic tests information on family members is important
and pedigree analysis can determine the likelihood that a particular dog is a
carrier if there are affected members in the family.
Pedigree Analysis
If there is no
genetic test for carriers, then relative risk assessments can be used for
genetic counseling. These are the risk figures that can be created for a
specific animal to be affected (or a carrier) after examining the pedigree and
knowing the genetic or phenotypic status of multiple family members. The
technique involves a careful examination of the pedigrees of the proposed mates,
called pedigree analysis. It involves the breeder (or genetic
counselor) drawing a dog's pedigree not just with ancestral names but also with
health information about each ancestor (if available.) Ideally this would
include family members not included in a typical pedigree (such as littermates
to individuals found in the pedigree.) If the breeder knows most of the health
history of the dogs in the pedigree, then a picture of how a particular health
characteristic is passed from generation to generation can begin to be formed.
The obvious pitfall in pedigree analysis is lack of information. Breeders do not
always keep
or
have access to extensive health information on their dogs. Unfortunately some
who have information, do not always openly share this information with others.
Another downside to this technique is that it applies selective pressure against
all relatives with involved pedigrees. Therefore genetically normal individuals
may be selected against. This can adversely impact the gene pool (the group of
genes collectively held by a breeding population such as Briards.) Genes can
become widely dispersed or can severely limit a breeding population due to
selective pressure against affected families.
Applying These Principles
So
how does this information help breeders to breed healthier dogs? This was the
topic of a presentation by Dr. Jarold Bell a veterinarian trained in genetics
and genetic counseling. He performs genetic counseling clinically and
administrates genetic disease control programs. Dr. Bell indicates that the
approach to breeding away from a disease is greatly affected by the type of test
that is available for the detection of that disease. The goal is to avoid
producing affected dogs and to decrease the number of carriers in the
population.
With the clear information provided by a direct genetic test, a
breeder can be less conservative. Take, for example, the condition CSNB. For
many years Briarders have known about CSNB and have either avoided breeding dogs
in families known to produce this condition or they have done so with great
anxiety and trepidation. Now that the gene has been found, people can go forward
with dogs from these families. Breeding a carrier is less devastating because
the offspring can be tested to determine if they are carriers. Dr. Bell cautions
in his recent address at the National Health conference that it is a mistake of
some breeders to think that the selection against carriers is unnecessary. He
emphasizes the need to replace carriers with non-carriers in a breeding program;
otherwise the frequency of carriers in the breed will increase. He suggests:"If
a quality normal-testing dog has not been produced after a number of matings, a
different method can be used. We can look to the common experience when a top
performer does not reproduce itself well, but a littermate produces far better
than itself. When left without quality genetically normal breeding stock,
breeding to an average, but genetically normal littermate may ultimately provide
the desirable offspring you want."
However, with a direct genetic test a line no longer has to be viewed
as a "hot potato." Instead, breeders can go forward intelligently with a
breeding program and breed carriers, and in some instances perhaps even affected
individuals, with the ultimate goal of reducing or eliminating the gene from
their breeding program in several generations.
Dr. Bell gives a model of how, without genetic tests, a breeder can
still reduce the carrier risk in their matings: "If a valuable breeding animal
is determined to be a carrier, he or she can be retired from breeding and
replaced by a quality offspring. The genes of the retired dog can be preserved
through the selected offspring, but the carrier risk can be cut in half. To
further limit the spread of the defective gene, the offspring should be only
used in a limited number of carefully planned matings, and should also be
replaced with one or two representative offspring. In this way, you are
maintaining the good genes of the line, reducing the carrier risk with each
generation, and replacing, not adding to the overall carrier risk in the
breeding population."
This method must be approached extremely carefully. Dogs from these
families MUST be bred to animals from low risk pedigrees or affected offspring
will be produced (that is unless the breeding is done as a test mating to
determine if the dog from the high-risk family is a carrier.)
When a specific gene test is not available, Dr. Bell points out that
it is important that frozen semen be stored on quality dogs with high-risk
pedigrees. It is important to store both semen and tissue such as blood and
cheek swabs so that testing can be done should a gene test be developed.
One big problem with trying to understand many genetic diseases is
when the inheritance pattern is unknown. This can be the case when a new disease
starts appearing in multiple individuals and people are starting to suspect that
it may have a genetic basis. This may also be the case when it may be clear that
a known disease "runs in the family" but a specific inheritance pattern is
unknown. For example, hip dysplasia is a condition that cannot be clearly
determined to be recessive dominant. Most people are aware that two dogs who
appear to be completely clear of hip dysplasia, perhaps both with excellent
hips, can still produce puppies affected with hip dysplasia. With the example of
hip dysplasia-this condition is felt to be polygenic. Polygenic
means that multiple different genes are felt to be involved in the occurrence of
a condition. Hip dysplasia can also be considered multifactorial
since multiple environmental factors play a role in addition to multiple genetic
factors1.
Given the complexity of hip dysplasia, detailed pedigree analysis is extremely
important. With pedigree analysis the breeder must evaluate the phenotypic
status of multiple family members. As Bell states, with polygenic diseases such
as hip dysplasia, the breadth of the pedigree (genetic status of multiple full
siblings) is as important if not more important than the depth of the pedigree
(parents and grandparents.) "Normal breeding dogs from mostly normal litters are
the best candidates for breeding."
The Challenges
When new conditions that appear to be genetic occur or when the inheritance
pattern is unknown, the only way to determine the potential inheritance is by
the open sharing of information. Dr. George A. Padgett, DVM. is a veterinary
pathologist at Michigan State University with special interest in canine
genetics and what role breed clubs play in the control of the genetic diseases
in their particular breed. He cites the need for open record keeping which will
report all evaluations (abnormal as well as normal) as being essential to health
improvement in a colony of dogs or a breed as a whole. Dr. Padgett was one of
the founders of the GDC (Genetic Disease Center) which is this kind of registry.
Dr. Padgett states: "We need to quit whispering about defects, and gossiping
about defects, and instead set up a sound program that allows the standard
selection procedures to go on so that we breed good dogs and avoid major
defects." Dr. Padgett also states in his book Control of Canine Genetic
Diseases: "If we want to make any impact in controlling genetic disease in dogs,
we must agree that an ethical approach is based on fairness, openness and
honesty. While traditions are important to us and should remain important, they
should be changed if they conflict with the exercise of our ethics as dog
breeders."
Although Dr. Padgett's hope for complete and open sharing of
information is a tall order and perhaps somewhat idealistic, the primary point
must not be lost-you must identify the problems before you can attempt to fix
the problems. A first step for a breed to attempt to learn where problems lie is
through health surveys. If it will help reporting, measures can be taken to be
certain that these are completely anonymous. The Briard Club of America will
send out a health survey in April 2000 to try to identify all of the potentially
genetic diseases affecting Briards. This survey will be received and compiled by
a third party group. No one owning a Briard will know the result of any
individual survey (except their own, of course.) Hopefully, with this survey, if
certain problems are found to be widespread, then perhaps a climate of openness
and understanding can allow for sharing of information. In this way pedigrees
can be analyzed and strides can be made to determine inheritance patterns,
develop new tests (genetic of phenotypic) and hopefully decrease the occurrence
of the diseases in the Briard. To meet these lofty goals those who own, breed,
and love Briards can rise to the challenge.