Jana Carraway reports on the MCKC 2000 Education Seminar, featuring renowned canine geneticist George Padgett DVM.
Part 2 of 2

".there is no hope for control without knowledge."

In Part One of Control of Canine Genetic Disease, I tried to convey Dr. Padgett's philosophy (as seen in the above quote) and key points in controlling canine genetic disease. I expressed Dr. Padgett's statement, made many times, that it is the breed clubs and breeders who are responsible for controlling genetic diseases in purebred dogs. I believe Dr. Padgett emphasizes this point, not to place blame, but to focus this breed club and breeders (of Soft Coated Wheaten Terriers) on their responsibility.

As previously stated, the actions a breed club can take to support club members and other breeders to control genetic disease in a breed include:

  • Assess the problems in the breed via a health survey - Done.
  • Establish an Open Registry - Done.
  • Provide literature outlining the diseases in the breed, including clinical signs, method of diagnosis, and treatment - Done.
  • Support breeders and owners. "They should strongly support those breeders and owners with the honesty, courage and foresight to openly register dogs affected with genetic disease, because there is not hope for control without knowledge." - On going.
  • And finally, provide literature which offers various systems that can be used to control genetic disease and how to evaluate or estimate potential risks.

Dr. Padgett's presentation addresses the final action item by presenting a system that can be used to control canine genetic disease and evaluate or estimate potential risks. Dr. Padgett's presentation was given as "bullets" on slides. I have added verbiage to make it more applicable as a printed presentation while striving to remain true to Dr. Padgett's actual presentation.

PLE/PLN IN SOFT COATED WHEATEN TERRIERS
This is a difficult disease to control because:

  • Age of onset is late
    • Perhaps as late as 9 yrs of age.
    • The vast majority of cases show clinical signs by 6 to 8 years of age.
  • Early diagnosis is difficult and sometimes inaccurate because only a Screening test is available.
  • Accurate diagnosis is important and difficult, requiring blood tests or blood and urine or biopsy or all three.
  • THE MODE OF INHERITANCE HAS NOT BEEN DETERMINED.

PLE/PLN PEDIGREE ANALYSIS:

  • YOU ARE IN THE YEAR 2000 (01)
  • YOU ARE LOOKING RETROSPECTIVELY AT PLE/PLN
  • A LATE ONSET DISEASE
  • ESTIMATES OF THE FREQUENCY OF PLE/PLN VARY FROM
      —  5+% Survey
      —  10% Estimate
      —  15% Estimate

We do not know the mode of inheritance of this disease. So, we cannot accurately use the Hardy-Weinberg Law. The Hardy-Weinberg Law calculates the carrier frequency for simple recessive or dominant traits only. There is no model that calculates the frequency of polygenic traits, as PLE/PLN are believed to be. But we need to have an idea of the carrier frequency to see what we are facing.

This is a GUESSTIMATE of Gene Frequency using the Hardy-Weinberg Law:
IF THE TRAIT TURNS OUT TO BE POLYGENIC, THE GUESSTIMATE WILL BE LOWER (NOT HIGHER) THAN ACTUALITY.

Disease Frequency Guesstimate of
Minimum Gene Frequency
5+% Survey 34%
10% Estimate 44%
15% Estimate 48%

You can see if the frequency of the trait is as high as we think it is, there is a problem in selecting breeding stock. Due to the fact that this is a late onset disease, we need to look at historical data to predict what is present in our dogs.

We have the major tools necessary for this process: AN OPEN REGISTRY. IF BREEDERS PARTICIPATE IN THE REGISTRY, THIS DISEASE CAN BE CONTROLLED.

REMEMBER: If this disease is genetic, there must be genetically normal dogs in the population. If there were no genetically normal (or clear) dogs, ALL OF OUR DOGS WOULD BE AFFECTED1. There is a necessary percentage of carriers to produce the frequency of affected dogs approximated by the survey or by estimates. Based on the Carrier Frequency and Frequency of Disease, there is also a Frequency of Genetically Normal Dogs.

Frequency of
Disease
Frequency of
Carriers
Frequency of
Genetically Normal Dogs
5%34%61%
10%44%46%
15%48%37%

How to calculate gene frequency using the Hardy-Weinberg Law

  • Using:
    • bb as homozygous recessive,
    • Bb as heterozygous, and
    • BB as homozygous dominant.
  • Hardy-Weinberg Law: (p+q)2 = p2 + 2pq + q2, where
    • BB = p2,
    • Bb = 2pq, and
    • bb = q2.
  • If the estimated disease frequency is 5% and it is calculated as a recessive (bb) trait:
    • 5% = bb = q2
      ...then q = the square root of .05 = 0.22
    • Since p+q = 1.0 (100%),
      ...then p = 1.0 - 0.22 = 0.78.
  • Using p = 0.78 and q = 0.22, we can calculate the carrier rate, Bb, and clear dogs BB.
    • BB = p2 = 0.78 x 0.78 = 0.60, or 60%, and
    • Bb = 2pq = 2 x 0.78 x 0.22 = 0.34 or 34%.

This says that if a disease is caused by a simple recessive gene, bb at 5%, then the carrier population is Bb at 34% and the clear population is BB at 61%. Conversely, if the trait is dominant as opposed to recessive, then BB would be the disease frequency at 61%, Bb again the carrier frequency at 34%, and bb the clear frequency at 5%. REMEMBER: Carriers identify themselves because in the correct circumstances they produce disease. Normals or clear dogs are not so kind; they make you wait and worry. You can never be absolutely sure they are genetically normal, like you can be with carriers.

Our goal is to find DOGS THAT SIGNIFICANTLY LOWER THE RISK OF PRODUCING DISEASE and that allow us to dilute the gene and thus reduce the frequency of this trait. And we want this to occur in dogs that can win in the show ring (or in obedience, or hunting, etc.)

Since this is a late onset disease, we must use retrospective test mating. That is, we look at matings that have already occurred to predict the genotype of current breeding stock. REMEMBER, we cannot identify one normal dog and everybody use it, because that one dog could not represent all of the desirable phenotypes in the breed. And we would spread other genes he/she carries across the breed, giving us the same problem we have now with a different disease.

Therefore, we need to look at pedigrees so we can assign genotypes and identify the mating situations that help us. In order to accomplish this task, we need breeder participation. AND IF WE DO IT RIGHT, NOBODY GETS HURT. Let's look at PEDIGREE 1.

PEDIGREE ANALYSIS:
PEDIGREE 1

  • We have an affected dog in the litter, designated "1".
    What is the genotype of the parents and littermates?
    • Parents:
        —  PROVEN CARRIERS
        —  THEY PRODUCED DISEASE
  • What is the genotype of the littermates?
    • Littermates:
        —  66.6% risk of being carriers 1

1 Control of Canine Genetic Diseases, Dr. Padgett, page 63, Table 5.6.

Risk of being a carrier if related to an affected dog (autosomal recessive trait).

Degree of relationshipMinimum Carrier risk
Parent, Progeny 1100.0%
Full brother, sister 166.6%
Grandparents, aunts, uncles, half-brothers or sisters, grandchildren 250.0%
Niece, nephew 233.3%
Great-grandparents, first cousins, half-aunts and uncles, great grandchildren 325.0%
G-g-grandparents, first cousin once removed, second cousins12.5%
G-g-g-grandparents, first cousin twice removed, third cousins6.25%

PEDIGREE 2

  • What is the genotype of the grandparents, dogs 5, 6, 7 and 8?
    What is the genotype of Litter B, born in 1991?
    • Grandparents:
        —  50% chance of being carriers.
    • Litter B:
        —  Each puppy has a 50/50 chance of being a carrier.
        —  NOTE: These are Half-siblings to an affected dog)
  • What is the risk of Litters C and D carrying PLE/PLN?
    What is the genotype of Bitch 4?
    • Each puppy in Litters C and D has a 50/50 chance of being a carrier.
    • Bitch 4 has been test mated to a PROVEN carrier, dog 3. No affected puppies in her litter. She has an 82.2% chance of being genetically normal.2

2 Control of Canine Genetic Diseases, Dr. Padgett, page 55, Table 5.1.

Probability that an unknown animal is homozygous dominant (AA) for a given autosomal recessive trait when bred to an animal that is a carrier (Aa, heterozygous) for that trait. Table not included here. Based on 6 normal offspring, the dam has a 82.2% chance of being genetically normal.

PEDIGREE 3

  • We have added 3 litters to the pedigree (E, F and G).
    What is the risk for Litter E?
    What is the carrier risk for the littermate of the affected bitch in Litter F?
    • Litter E 50% since the sire is a known carrier.
    • Litter F each littermate has a 66.6% risk of being a carrier.
  • What is the carrier risk for Litter G?
    What is the status of Bitch 4?
    • We cannot ascertain the genetic status of Litter G because we have no data on the sire, Dog 11.
      BUT!! This is the situation we are looking for:
    • Bitch 4 has been test mated twice to known carriers, dogs 3 and 9.
    • She has produced 10 normal pups.
    • She is 94.4% sure to be genetically normal for PLE/PLN2.

2From Table 5.1, not reproduced here. Based on 10 normal offspring, the dam has 94.4% chance of being genetically normal.

PEDIGREE 4

  • In Pedigree 4 we have added 14 litters - HOW DOES THAT HELP US?
  • We need to evaluate the status of the dogs in the pedigree.
  • Mark in all of the dogs that must, at a minimum, be carriers.

PEDIGREE 4a

  • Did we miss any dogs that must, at a minimum, be a carrier?
    • YES, BITCH 12.
      She was bred 3 times to a known affected male and produced an affected male in Litter H in 1995 - Mark it in.

PEDIGREE 4b

  • With Bitch 12 as a proven carrier,
    we are going to get more affected dogs in litters H, I and J.
  • The dogs in these 3 litters are 5, 4 and 3 years old, so we are waiting.

PEDIGREE 4c

  • What's the probable genotype of Bitch 13?
    • She has been test mated against an affected dog (#1) with no affected puppies at this time (the litter is 5 years old).
  • If her 8 offspring stay normal, she has about a 97.6% chance of being genetically normal2.
     
    2 From Table 5.1, not reproduced here. Based on 13 normal offspring, the dam has 97.6% chance of being genetically normal (if dog 14 is a known carrier as well).
  • To determine the genotype of Bitch 13, we are looking for the first dog in litter K to come down with PLE/PLN. We don't have to wait for all of them. The first affected dog tells us the genotype of Bitch 13.
    • No affected dogs in a 5-year old litter of 8 produced by an affected male. We could start thinking this bitch is normal.
  • So, what is the genotype of litter N out of Bitch 13?
    • We can't tell because we have no information on Dog 14. We must trace him, look at any other offspring he produced. We need to look at his littermates, the littermates of his parents and both of their offspring as well as his grandparents and their littermates.
  • We also need to check the lineage of Bitch 13. If she is normal genetically, there may be others. REMEMBER: She has been test mated normal so no matter what is in her background, she is still normal (unless her sire or dam was affected). We need to check the age of Bitch 13. Is she still breedable? Depending on the background of Dog 14, litter N may be a good risk.
  • What is the minimum risk of all puppies in litters O, P, Q, R, S, T, U and V?
    • Minimum risk for all puppies in litters O, P, Q, R, S, T, U and V is 50/50;
      Sire 18 is a defined carrier since his father was affected.
  • Bitches 19-26 have been test mated. What is their chance of being genetically normal for PLE/PLN?
    • Can't tell yet. All of these litters were born in 1999 or 2000, so, the puppies have not had a chance to develop PLE/PLN. REMEMBER: You are looking for the first puppy in any litter to develop PLE/PLN. The first puppy tells you if the dam is a carrier. We need to wait to see if she is genetically normal.

DISCUSSION

How can we assign a specific risk on these dogs? We cannot assign a specific numerical risk to a dog or bitch in this situation because. we do not know the mode of inheritance of this trait.

In spite of the fact that we do not know the mode of inheritance of PLE/PLN, we can assign a relative risk. Because, what we are really doing is PROGENY TESTING our dogs and we are doing it RETROSPECTIVELY. We are looking at what happened in past breedings and then assigning risks relative to what we see in the offspring. We are looking at historical litters.

RIGHT NOW WE ARE CREATING HISTORY!

We need to follow these puppies so we can determine the genotypes. Accurate diagnosis is a very important part of this process. We must know where the gene(s) is(are) so we need to follow our puppies.

To better see the results from the Pedigrees, construct a Test Mating Table:
If all of the puppies in litters O-V stay normal, the Retrospectively Test Mated chance the bitch is normal is:

Bitch # # of Puppies Probability she is Normal
23357.8
24468.4
20, 21, 25576.3
19682.2
22786.6
26890.0

Obviously the chance they are normal varies with the number of puppies produced. BUT! If we follow these bitches, additional test matings may occur. If we follow our dogs and assign probable genotypes and if we use this information to breed low risk litters, then we will reduce the frequency of PLE/PLN and it will not take long to do it.

EDITORIAL COMMENT
Dr. Padgett's presentation was far more extensive than the information I am able to present here. I urge all readers to purchase his book, Control of Canine Genetic Diseases, available through Amazon.com by following the link at right, for a more complete understanding of Dr. Padgett's approach and topics relating to genetic diseases in purebred dogs.

One of his messages, repeated through out the day, is that breeders and the breed club are responsible for the health of the breed and for taking actions to minimize the frequency of disease in the breed. That it is up to the breeders to know the dogs, present and past, in their pedigrees, to keep complete records of breedings and progeny, and to provide and share information. That it is up to the breeders and breed club to support breeders who are honest about health issues, who are forth coming with health history, and who participate in the Open Registry.

Another message is that we have an opportunity, as tragic as it is, to learn something about many of the dogs in our breed by the breedings done with Dockers. We have an opportunity to assign risk factors to many dogs in our breed by documenting all test matings of bitches to Dockers, documenting all other breedings of those bitches, and documenting all progeny of those bitches and on to the present. Somewhere in those breedings, we will find bitches who have produced no problems and their offspring who have produced no problems. We cannot guarantee that these are clear lines, but we can begin to believe they are lower risk. As has been said in many ways recently, documented history will be the current data from which we determine potential risk for today's breedings.

And we can use this process in the present as well. For breeders who own stud dogs, document the breedings of your dog and the other breedings of the bitches to whom he has been or is being bred. You are test mating your male, just like test mating the females. The chances are a stud dog in use today has been bred to an affected female or known carrier. What has been produced in those breedings? Does he begin to look like a genetically normal dog? For many, it is too soon to tell, but starting the documentation at this time is easier than trying to reconstruct it 10 years from now.

I used RFFlow to produce the genetic pedigrees. A trial download is available from the company on their website; www.rff.com. The cost is quite reasonable. This is a user-friendly package with good instructions. However, it is not necessary to use a software program to create genetic pedigrees. Use a spiral bound notebook and start with your oldest dog. Document everything you know about his/her littermates and sire and dam. Add all health information you can dig up. Then add the first breedings, each sire a bitch was bred to, her offspring per litter and all health information you have on those puppies. If your first Wheaten was a male, create a chart for each of his breedings, the offspring and any information you have on his offspring. Then proceed to the next generation. Although this feels like only a small thing we can do, it is perhaps, the most important thing we can do for the next few years.

Return to Part 1 » 

Rev 8/22/10


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