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Canine Hip Dysplasia is a physically debilitating disorder
that is both emotionally and financial draining for dog owners. With no cure other than pain management or hip
replacement surgery, diagnosis of hip dysplasia is the breeder’s as well as the
pet owner’s heartbreak. Stocky breeds
such as the Bulldog and those weighing over 60 pounds such as the St. Bernard
experience hip dysplasia rates of up to 72% and 46% respectively. It is estimated by Cornell University that
22% of canine hospitalizations in the USA are hip dysplasia related. Interestingly,
the disease’s occurrence is minimal in sight hounds such as the whippet,
saluki, borzoi and greyhound with an average occurrence of just 1-2%. Border collies fall in the middle range of dysplasia
occurrence at around 11%.
For over 40 years, breeders have attempted to minimize the occurrence
of canine hip dysplasia (CHD) through the use of phenotypical screening
methods. As a predictive method for removing poor
breeding candidates from their breeding programs, responsible breeders have
submitted x-rays of mature dogs for hip scoring to institutions such as the OFA,
BVA, FCI and University of Pennsylvannia seeking to determine the laxity of the
hip joint, and therefore the likelihood of the animal developing CHD as a trait
that might be passed on to its progeny.
Various studies of the efficacy of these screening programs
have met with mixed results. Some
studies show little to no improvement in the occurrence of CHD. Even in
countries, such as Finland, where an enforced threshold of hip scores was
applied to registrations, results were varied across breeds, with some breeds
demonstrating a lower incidence of CHD and others showing an actual increase in
CHD.
Canine hip dysplasia is understood to be influenced by both
genetic and environmental factors. As a
polygenetic mode of inheritance has long been suspected, attempts to isolate
the genetics of the disease have long been frustrated. Breeders seeking to improve their lines and
their breed have been marginally successful as a whole, despite their best
efforts. Forty years of breeders’ best
efforts may call into question the scoring methodologies of the various
institutions.
OFA vs. PennHIP
OFA uses a single radiographic view, the hip-extended view,
to determine laxity of the hip joint (a predictive measure of the likelihood of
developing CHD). By contrast, the PennHIP
method uses 3 radiographic views (the distraction view, the compression view
and the hip-extended view) to determine the laxity of the joint. A study released in 2010 by the University of
Pennsylvania (http://webcanine.com/2010/canine-hip-dysplasia-may-be-underreported/),
compared results from dogs scored by both OFA and PennHIP to determine the
likelihood of CHD onset. Their findings were disturbing. According to Penn
researchers, “Even if breeders were to selectively breed only those dogs having
OFA-rated “excellent” hips — the highest ranking but in some breeds, a very
small gene pool, the study suggests that 52-100 percent of the progeny, depending
on breed, would be susceptible to hip dysplasia based on the Penn Vet scoring
method.” In fact 52% of the dogs with
OFA “excellent” scores, 82% of the OFA “good” scores and 95% of the OFA “fair”
scores fell below the PennHIP threshold of.3, making them by PennHIP standards
susceptible to CHD. (It should be noted that the University of Pennsylvania
holds the patent for the PennHIP test, and a financial incentive could exist in
their findings). Could the PennHIP
method provide the key to a significant reduction in incidence of CHD?
PennHIP allows for early testing of puppies; they may be
tested as early as sixteen weeks, which is still well beyond the typical puppy
placement age of around 8 weeks. By contrast, OFA scores may not be obtained
until the dog has reached 2 years of age.
As 3 x-ray views are required for the PennHIP testing method, depending
on your area of the country, the cost can be substantially greater than OFA
testing. Additionally, the PennHIP
method does not currently have the same recognition international as the OFA
methodology. What if a genetic test existed
that could predict the likelihood of developing CHD?
Genetic Testing
The Beijing researchers’ model was based on 359 dogs in the
first sample and 38 dogs in the second sample.
The dogs whose results were used in the study came from the Baker
Institute, The Guiding Eyes for the Blind and Cornell University Hospital for
Animals (as the 38 dog control group).
They began by developing an Estimated Breeding Value (EBV)
of each of the dogs based on 4 criteria: the dog’s Norberg Angle (NA), OFA
score, the distraction index (DI) and the dorsolateral subluxation score (DLS).
The former two are evaluated from the extended hip projection and are phenotypically
as well as genetically correlated while the latter two are evaluated on
different x-ray views and are also phenotypically and genetically correlated.
It is interesting to note that the researchers believed that no measure alone
completely represents hip morphology. In fact, their methodology was the similar
to that of the PennHIP with the OFA score thrown in for good measure. In the final analysis, the Norberg angle (NA)
correlated to the OFA score and as most dogs had NAs measured, NA was chosen
for this study to determine the EBV. The researchers then used 22,000 SNP’s
across the genome and the EBV of the sample dogs to produce the predictive
formula, an algorithm, termed the Genomic Breeding Value (GBV).
Validation of the Formula Methodology:
The researchers performed two types of validations consisting
of a cross validation and an independent validation. For the cross validation
they used a Jackknife Cross Validation.
This consisted of hiding the dog’s EBV and removing its GBV from the
dataset used to create the original predictive formula. The formula was then recalculated
by using the EBV and genotype from the other 358 dogs in the study. This
process was repeated for each of the 359 dogs. The cross validation performed showed
a strong correlation (R>0.7) above 70% between the EBV (phenotype) and the
GBV (genetic).
To develop the independent validation, the GBV formula was
applied to 38 Labrador retriever dogs with no pedigree relationship to the original
359 dogs from which the GBV formula was derived. Correlations between the
predicted GBV and the actual EBV (the physical conformation of the dog) were
compared.
The Results:
When 5,000 SNPs out of the original 22,000 SNPs remained in
the formula, the correlation was remarkable, above 0.98 or 98%. The researchers
then identified the 100-500 most influential SNPs that had provided the most
information to the GBV formula. The reduced number of SNPs showed that genomic
prediction could remain effective with the most influential 100-500 SNPs chosen
from the original 22,000SNPs. However,
as the number of SNPs in the reference panel dropped below 50, the formula became
significantly less reliable.
The Beijing researchers expect that a reliable GBV predictive
formula for hip conformation will be available for most breeds of interest, “Prediction
of CHD from genomic data is feasible, and can be applied for risk management of
CHD and early selection for genetic improvement to reduce the prevalence of CHD
in breeding programs. The prediction can be implemented before maturity, at
which age current radiographic screening programs are traditionally applied,
and as soon as DNA is available.” However, phenotypical testing (hip x-ray
grading) will continue to be necessary in order to retrain the GBV predictive
formula, and thereby refine the accuracy of the genomic predictive model.
While the majority of the 359 dogs used in the study were
Labrador retrievers and Lab crosses with Greyhounds, other minor breeds’ hip morphologies
were also well predicted by the GBV formula. Therefore, we can expect that multiple
breeds will be able to be integrated together into a single genetic test, even
though they are from diversified phenotypic and genotypic populations.
The possibility of a genetic test for predicting CHD in
young puppies raises some interesting ethical questions. Puppies genetically predisposed to CHD should be removed
from breeding programs, but where do they go?
What are the ethics of breeders presenting puppies to pet puppy buyers
knowing that they have a strong likelihood (70% or greater) of developing CHD? Additionally, if the genetic statistics
correspond with those of the University of Pennsylvania survey, we are left
with a very small gene pool in many breeds.
Add to that other genetic disorders being researched, such as cancer and
breed specific issues, and the gene pool of good breeding candidates is likely
to grow even smaller. Relying on a
substantially reduced gene pool could have unintended consequences. Recessive, genetic “trash” could manifest into
new, more terrifying health issues.
These are all questions that are sure to be discussed
heatedly as understanding of the canine genome progresses. Once these tests are
available to the public, they will have to be financially feasible in order to effectively
make an impact on breeding programs. As
we approach this new era in breeding prospect selectivity, perhaps a stepped
approach to improving breeding prospects is in order. Under this approach, initially breeders would
breed one dog with a relatively high EBV and GBV to one with a moderate EBV and
GBV, and seek to improve the GBV threshold for the sire or dam on each
successive generation. This would be a
measured approach, however canine generations evolve very quickly – every 2
years compared with 20 years in humans.
Your thoughts and comments are welcomed!
photo credit: Dimas_ via photopin cc
photo credit: Dimas_ via photopin cc