Australian Shepherd Health & Genetics Institute

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Muddy Waters: The Confusion Surrounding DNA Health Screening

by C.A. Sharp

Aussie  Muddy Pup MontiFirst published in Double Helix Network News Summer 2008, Rev. May 2013


It all seemed so simple at first:  DNA tests would allow breeders to identify carriers.  Valuable dogs carrying unwanted genes which formerly might have been removed from breeding programs could be bred because breeders could determine the genotypes of prospective mates and eliminate the possibility of producing affected offspring.  We and our dogs would live happily ever after. 

 Scientists warned us it wasn’t going to be that simple.  We are fast reaching the point where we have to face this unwanted fact.  This new realization has muddied our once-crystal waters, causing some to question the value of particular tests, or even DNA health tests altogether.

 These tests are an invaluable breeders’ resource, but a breeder must develop a thorough understanding of what test results tell us, so she can interpret and apply those results for the benefit of her breeding program.  At the moment tests seem to be multiplying like free-ranging dogs but sources of detailed and readily accessible information on applying test results are sketchy.

 Prior to writing this article, I did a Google search on “canine DNA health tests” to see what might be out there already.  I went through ten pages of listings and most were links to various labs offering tests (many for “heritage” tests that have no direct bearing on health.)  I found a few articles aimed at the general public and some links to scientific publications, but nothing aimed at breeders.  There are some resources out there, probably beyond Google’s 10th page, but they are crowded off the higher listings by all the commercial links.  Even the labs offering these tests often provide little or no information on how a breeder should apply them.  It’s pretty much up to breeders to do the digging and educate themselves.

 Calm and Clear:  Recessive, Dominant and X-Linked Trait Tests

 The earlier DNA tests, like the one for Collie Eye Anomaly – Choroidal Hypoplasia (CEA-CH) focused on recessive mutations.  CEA occurs in a variety of collie-type breeds, as well as Lancashire Heelers, Nova Scotia Duck Tolling Retrievers, and Long-haired Whippets.  Dogs with two copies of the mutation have CEA, those with one are normal carriers and those with none are clear. 

When there is a DNA test, all a breeder has to do to make sure he never produces a puppy with a recessive disease like CEA is breed carriers only to mates that have been DNA tested clear.  In this instance the mutation can be viewed as a minor fault:  Preference should be given to clear dogs over carriers in breeding.  Over several generations the frequency of the mutation can be significantly lowered if most breeders take this approach. 

When there is a test for a common recessive disease, all breeding stock should be tested.  If the disease is uncommon, as with the progressive rod-cone degeneration (PRCD) form of Progressive Retinal Atrophy in Australian Shepherds, or if use of a test and careful breeding decisions have markedly reduced the frequency of a formerly common mutation (think what could be done with CEA in Collies,) testing could then be confined to only those dogs with known family history of the disease or with relatives that have been DNA tested as carriers.

There are also tests for simple dominant traits like the form of PRA found in English Mastiffs and Bullmastiffs. (There are multiple genetically distinct forms of PRA.)   Dominant traits pass from an affected parent to its offspring:  Half of them will inherit the mutation if it has only one copy and all of them if it has two.  Dominant traits that are obvious under a year of age are easy to eliminate simply by not breeding affected animals.  However, PRA and some other dominant traits can’t be detected until a dog is already breeding age.  A DNA test enables breeders to identify these dogs before they can be clinically diagnosed and before they are bred.

There are no normal carriers with a dominant mutation.  The dog is either normal (clear of the mutation) or affected.  Fortunately, the frequency of genes for dominant diseases in most breed populations will be much lower than what is typical for recessive traits because there are no normal carriers who might slip unidentified into a pedigree.

All breeding stock should be tested for simple dominant mutations.  Any which have even one copy of the mutation withdrawn from breeding, unless the mutation is so common in a breed that a significant portion of dogs are affected.  After a generation or two the frequency of the mutation will be so reduced that it will only be necessary to test dogs with a known family history of the disease or with relatives that are known, via the DNA test, to have the mutation.  

If the mutation is very common, dogs with two copies should be withdrawn from breeding.  Those with one should be used only with clear-tested mates.  If age of onset of the disease varies, hold off breeding dogs with single mutations until they are past the average age of onset, if at all possible.  Over time, the number of clear dogs available will increase and use of dogs with the mutation can be phased out.

Yet another form of PRA, found in Samoyeds and Siberian Huskies, is X-linked, meaning the gene is on the X chromosome.  All males with the mutation and females with two copies of it will be affected.  Females with only one copy will be carriers; half of their sons will be affected and half of their daughters will be carriers.   Common knowledge indicates that eliminating carrier bitches solves the problem.  However, if an X-linked disease does not arise until an animal is breeding age, even affected males may produce offspring before the disease is identified. 

Any dog or bitch found to have an X-linked mutation should be withdrawn from breeding.  Even though carrier females will be normal, they will produce affected males.  X-linked diseases are rarely common, so diligent use of the test combined with removing dogs with the mutation from the breeding pool should effectively eliminate the mutation from a breed.  Mothers of affected males are obligate carriers so do not require testing.  However, their dams (X-linked mutations tend to occur spontaneously so the dam of a carrier may be clear) and other offspring should be.  If the disease is late-onset, their sires should be tested, too.  Female offspring of affected males should be tested but their sons are obligate clear.


Ripples in the Stream:  Incomplete Dominant Traits

Not every dominant gene follows the simple inheritance pattern noted above.  One of the exceptions is an incomplete dominant, like the Multi-Drug Resistance 1 (MDR1) gene, in which the intensity of a trait is greater when two copies of the mutation are present.  Dogs with two copies of the MDR1 mutation are highly—sometimes fatally—sensitive to a number of drugs.  But even dogs with one copy of the mutation will react to some of these drugs.  This mutation also affects several collie-type breeds, but is also found in German Shepherd Dogs, Long-haired Whippets and Silken Windhounds.

MDR1 is in a different class from other health-impacting mutations in that it does not cause a disease.  If we did not give our dogs pharmaceuticals it would not be a problem at all.  Therefore, having even two copies of the mutation is not a reason to withhold the dog from breeding, though it should be considered faulty and efforts made to breed away from it. 

If tests are developed for relatively minor health issues or for cosmetic defects, as with unacceptable coat colors, dogs identified as having those mutations might continue to be bred, though only with clear-tested mates.

However, if an incomplete dominant mutation did cause a disease, the same breeding and testing advice should be followed as for a simple dominant test, as noted above.


Mud in the Water:  Polygene traits, Genes of Major Effect, and Risk Factors

Science and technology are finally getting to the point where serious molecular DNA studies of gene interactions can be undertaken.  With polygenic traits, multiple genes contribute to the dog’s phenotype (what is observed in the dog.)  At this point there are no tests for polygene traits, but when they are developed breeders will have to understand how each impacts the disease and select mates with a combination of gene versions that won’t produce the disease when mixed with the combination the breeder’s dog has. 

Sometimes the actions of one gene may be more critical than the others that play a role in a disease.  CEA, long thought to be due to a single gene, is actually an example of this.  The mutation we can test for only causes one of the CEA defects but without two copies of that mutation the dog won’t have CEA.  The other (still unidentified) genes only contribute to the trait if two copies of the CEA-CH mutation are present.  Because of this, it is for all practical breeding concerns, a recessive.  However, it is possible that some genes of major effect may usually, but not always, be present in affected dogs.  Until the other genes or factors involved are identified the breeder will have to accept that sometimes the DNA test, though important, will not totally prevent occurrence of the disease.  Genes for diseases like this are often said to have incomplete penetrance.

Another type of gene that has incomplete penetrance is the risk factor gene – a gene that will significantly increase risk of having the disease.  A mutation of the HSF4 gene is a major contributor to cataracts, causing a 17 fold increase in risk for hereditary cataract in the Australian Shepherd.  The mutation is dominant and most Aussies with cataracts have it, but some do not.  To further stir up the muck, many dogs with the mutation never develop cataracts. As of this writing, other genes that contribute to cataract formation in Aussies have not been identified.  Some Aussie breeders have expressed reluctance to use the HSF4 test because the result is not clear-cut like it is for the CEA, PRA and MDR1 tests they have grown accustomed to.  This attitude is short-sighted.


Water Clarifier:  What To Do When a Mutation is Found

Screening of related dogs will be necessary if a dog is identified, either by clinical diagnosis or through DNA test results, as having a mutation.  Guidelines for specific types of inheritance have already been discussed, but what should an individual breeder do if she learns there is a problem in one of her dogs?

It isn’t necessary to immediately test every dog in the kennel or every dog the kennel ever produced.  When a rock is thrown into a pool, rings of water move out from the point of impact.  They stop where the water ends.  The search pattern for mutations is similar to those outward-spreading rings.

If a dog has a mutation, all of its full siblings are at risk and any that are potential breeding stock should be tested.  If the trait, as with the MDR1 mutation, presents a serious future health risk, all siblings should be tested.  Once this is accomplished, start to work up and down stream. 

If the originally-identified dog and its siblings only have one copy of the mutation it is probable that one parent is clear and the other has the mutation, but you won’t know which without testing them.  Even if you test one and it has the mutation, the other should still be tested because this does not prove that it is not clear.  However if one parent tests clear, the other parent is an obligate carrier because it is the only one that could have passed the mutation to its offspring.  You won’t need to test it because you know its status. 

When clear individuals are identified, testing of further relatives related to the original dog only through the clear is unnecessary. 

If the original dog or any of its siblings have two copies of the mutation, both parents must have at least one copy.  Whether to test them or not will depend on whether they are still active breeding or if results will indicate a serious health concern for the dog itself.  In either of these cases it will be important to determine if the dog has one copy of the mutation or two. 

A similar approach applies to offspring of any dog known to have at least one copy of a mutation.  If it has one copy, roughly half of the offspring will have inherited it; if it has two, all of them will.  Whether to test just breeding stock or all dogs will depend on the health impact of the disease. 

Continue outward testing siblings then parents and/or offspring as outlined above until clear dogs are identified or the dogs are deceased or owned by someone else.  In the latter case, you should inform the owners of their dogs’ potential for having the mutation and suggest that they test it.  Even with deceased dogs, it may be possible to determine status by using frozen semen as a test sample if the laboratory involved will accept it.  Semen from deceased dogs is a limited resource, but if the mutation in question can cause a serious disease, anyone using that semen needs to be aware of the dog’s genotype.

Another way to be sure you have sample material available to test after your dog is gone is through the Canine Health Information Center’s DNA Repository. 


Clean Water Acts:  Best Practices for DNA Test Application

DNA screening tests, even for complex traits, provide concrete information about the genotypes of tested dogs.  This data is far more valid and useful that assumptions drawn from pedigree data alone.  Recognizing this, the Orthopedic Foundation for Animals will register the results of many DNA health screening tests. 

While the acts of individual breeders can help improve breed health through the use of DNA screening tests, the best results can only be reached through teamwork.  This can be on the level of cooperating breeder groups, but will be most effective if applicable DNA tests are viewed to be as necessary as hip and eye evaluations.  Ideally, breed club Health and Genetics committees should develop recommendations for what tests breeders should use and how to apply them.  The Australian Shepherd Health & Genetics Institute, Inc. has developed a health screening protocol that includes DNA tests along with the more traditional health exams.

DNA tests are not a panacea and they may not always give us easy answers.  Even so, they provide a much more effective tool for making informed breeding decisions than the process of educated guesswork that has prevailed up to now.  If breeders and breed clubs start now to clear the waters surrounding this new technology, our dogs will be better for it.