Badger Lair is the underground home of Glen of Imaal Terrier enthusiasts.

Friday, February 24, 2006

AUTOSOMAL RECESSIVE

The following piece is about the genetic disease PRA found in Glen of Imaal Terriers.


Autosomal Recessive


This chart shows the expected results of particular matings, based on the genotype and phenotype of the parents. Before you study it, however, be aware that, to date, we have managed to find no Normal dogs. We will continue to test offspring. We will not be able to identify Normal dogs until we have a genetic marker linked to the DNA sequence of PRA.















































































NOTES:
The results of the above matings are on average. This is the chance for each pup individually. For example each pup produced in a mating between two Carriers has a 25% chance of being a Normal, a 50% chance at being a Carrier, and finally a 25% chance at being an Affected.
Orange dogs and yellow dogs are genetically identical. Both appear Normal, but carry a copy of the defective gene, which they will pass to half of their offspring. The difference is in origin.

Orange dogs have an Affected parent which means that we know their status after the parent is diagnosed as Affected. They have to be at least a Carrier because their Affected parent passed the gene to all its pups.
Yellow dogs are those who have produced offspring with PRA. Same genetic phenotype and genotype, but we don't find out until they produce an Affected.
Blue dogs are not really identifiable. We do not know which dogs are truly Normal.
Red dogs are identifiable, after the fact. We know a dog is Affected once it is diagnosed with PRA.

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Every dog has 39 pairs of chromosomes. Each chromosome contains thousands of genes. A dog receives one of each chromosome pair from each parent. Thus it has TWO copies of each gene, one inherited from each parent.

Over the course of time, the DNA sequence of a gene may undergo mutation, forming a new sequence or allele, . A new allele may cause a change in the biochemical action of the gene. A dog may inherit the original allele, or it may inherit one of the new alleles, but it will receive one allele from each parent.

In dogs, most of the mutations that cause disease are recessive. For a recessive mutation to cause disease, a dog must receive two copies of it, one from each parent. If the dog receives one Normal allele, and one recessive mutation, it will appear Normal, but will pass the recessive allele to half his offspring on average. This dog is referred to as a heterozygous Normal, or a Carrier. He displays the dominant gene, but carries the recessive. Alternatively, if a dog inherits a Normal gene from each parent, he will be a homozygous Normal.

Without a DNA test, it is impossible to tell if a dog is carrying the recessive mutation unless:
1. One of the parents is Affected, or
2. It is bred to another dog also carrying a copy of the gene, and one or more of the resulting pups is Affected.
A recessive mutation can spread fairly rapidly through a population before breeders are aware of it, especially if the number of breeding individuals is small. Carriers, who will test Normal all their lives, will be bred and pass the gene to half their offspring on average. If the disease is late-onset, many Affected dogs will be bred unknowingly. An Affected dog, carrying two copies of the mutation, will pass the trait to 100% of its offspring. This spreads the gene even faster. The number of Carriers will rise exponentially with every generation.
At the time that the first Affected dog appears in a pedigree, many of the dogs in that pedigree will be Carriers. For each Affected dog identified, both his parents, at LEAST two of his grandparents, and all his offspring will be carrying the gene. Without a DNA test to identify the Carriers, it is virtually impossible to eradicate a recessive disease from a gene pool. The result is that Virtually all breeds have genetic problems.

Efforts to find the "cleanest" lines and to avoid "dangerous" pedigrees are a waste of time. Reducing a small gene pool by trying to avoid particular dogs in a pedigree will likely only result in the appearance of other, deadlier, recessive diseases and probably won't significantly reduce the risk of producing PRA. Removing the Carriers from the gene pool would be impossible- we'd have very few dogs left to breed except the young and untested ones!
Dogs that are past the age where they may develop PRA themselves, but are documented Carriers, are in fact among the "safest" dogs to breed at this point, as we have no actual Normals yet. These dogs will only pass the gene to half their offspring.

Very young dogs (under two) even if CERFed clear are probably the riskiest, as they may be undiagnosed Affecteds. An Affected dog will pass the gene to 100% of his offspring, which will result in more Affected pups being produced.

An older dog with clear parents, a good number of CERFed offspring and no documented Affecteds to date would be the safest, but these dogs are rare. They qualify as "possible" Normals.

Obviously, no breeder WANTS to produce dogs that will develop PRA. The best any breeder can do is to breed for type, soundness and temperament, perform CERFing annually, and share information on parents, siblings and offspring both with other breeders, so they may also make informed decisions, and with researchers, who will ultimately isolate the gene and develop a diagnostic DNA test. In order to more quickly develop such a diagnostic test, ALL dogs have to be DNA tested. Once a DNA marker is found, the following breeding rules should be followed:

1. No dogs with unknown genotype should be bred. This of course would be an ideal case. Realistically a dog with an unknown genotype should at the very least be only bred to a known Normal.

2. An Affected dog should be bred only to a DNA- tested Normal dog. All puppies will be Carriers, but none will be Affected.

3. The Carrier pups are bred to another DNA-tested Normal dog. Half the litter on average will be Carriers, half will be Normal. All pups must be DNA tested

The Normal pups are then bred to another DNA tested Normal dog. All pups will be Normal. If the dog you start with is a Carrier rather than an Affected, you can omit Step # 2.

If even 10% of the breed tests Normal, there should be enough to work with so that type, soundness and temperament won't be sacrificed. Carriers could be used for breeding until the population is in good shape, at which point the prudent thing to do would be to try and breed only the Normals. But all dogs would ideally be tested, and no one would breed from an untested dog to avoid re-contaminating the population
If all dogs are tested, there would never be another Affected Glen. In breeds where a DNA test for a recessive gene is available, the cost of testing is between $150 and $200. Is there anyone who wouldn't pay that to insure that their dog wasn't going to go blind?

Eliminating PRA is an achievable goal. To date, the gene for PRA has not yet been identified in Glens.
Finally, Ara Lynn in reviewing this manuscript cut right to the point with this succinct observation. Following quote used with Ara’s permission.

“All you need do to avoid creating blind dogs is to make sure that one of the mated pair is truly normal. After that, it is a moot point. As long as you are not creating blind dogs, it truly doesn't matter how long carriers remain in the population. In a theoretical world maybe it would be nice to eliminate the recessive gene, but in the real world you will never get total cooperation towards that goal. There are many many characteristics desirable in Glens. Perfect eye genetics should not be the overriding factor. And remember, even with genetic tests, you may still end up with false positives and false negatives.

We dog breeders and exhibiters are really into perfection and absolute control. There is no such thing on either count.”

Adapted and edited by Bill Amaral, from a web page that no longer seems to be up, with permission to use, from:
http://www.firestormkennel.com/homepage.html

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