Genetic Juggling

How to manage polygene traits in your breeding program

by C.A. Sharp

First published in the Fall 2009 issue of Double Helix Network News

 

Traits with simple, single-gene inheritance are easy for breeders to deal with.  We all know how to get merle pups in our litters if we want them—or not, if we don’t.  But when it comes to complex traits, those that are governed by multiple genes and also sometimes have environmental components, the effort to maintain or avoid them can cause breeders endless frustration.

Many desired traits are polygenic.  Some behavioral traits like the working stockdog’s ability to move livestock, or aspects of conformation like dentition or the front end assembly, are the result of polygenic inheritance.

Experts agree that multiple genes are involved in hip dysplasia and that exercise levels and nutrition are contributing environmental factors.  Autoimmune diseases are genetically predisposed, with genes setting the dog up for illness and environmental factors making the final determination on who gets sick and who does not.  Even coat color, which we tend to think of one gene at a time, is actually polygenic.  If you are breeding Pomeranians or Chihuahuas and want to breed away from merle, if you not be able to determine whether your yellow or sable dogs have the merle gene.

What’s a breeder to do?

The first step is to use whatever phenotype screening tests may be available for traits of concern:  Hip or elbow x-rays, eye exams, etc.  Screening exams will tell you what version of the trait the dog exhibits.  Knowing your dog is OFA Excellent is a big check mark in his favor, but it isn’t the whole picture.  For that you would need to know his genotype—what genes he has—and therefore what he as potential to produce.  For that you need a DNA test and, as this is written, there are no DNA tests that will give you your dog’s genotype for most or all of the genes involved in any polygene trait. 

But sometimes there is a test that will give you part of the picture.  In the case of hip dysplasia, researchers in Germany have recently discovered that there is a gene of major effect, a gene with a significant impact on the phenotype, one version of which is highly associated with dysplasia and, interestingly, more so for one hip than the other.  There isn’t a test yet available, but if one is eventually offered, knowing your dog’s genotype for this particular gene can help you make informed choices when breeding him.

The phenotype of any one individual isn’t sufficient.  You also need to know something about her family history for the trait in question.  What do you know about her parents, grandparents and other ancestors?  Equally important, what do you know about near relatives that are not directly on the pedigree – her siblings, aunts and uncles, and cousins?  Dr. Jerold Bell, a Gordon Setter breeder and veterinarian who teaches veterinary genetics at TuftsUniversity, has said, “The most important factor in selecting against a polygenic disorder like hip dysplasia is to seek breadth of pedigree.”  By “breadth of pedigree” he means the status of these collateral relatives.

Do you know where your puppies are?

Offspring are an important source of information.  Check in periodically with the owners of puppies you have sold or placed so you can stay up-to-date on how they are shaping up and whether any problems have arisen.  If you are seeing something frequently, good or bad, in half siblings it indicates that the common parent dog has a higher than average collection of genes for that trait.  If the trait is a good thing, you can list it among the dog’s virtues as a breeding animal.  If it isn’t, the knowledge will help you make better choices in who he should or shouldn’t be bred to.

Information gathering is an ongoing process.  Develop a method of recording information on traits you feel are important so you can readily retrieve the information when you need it.  The best way to do it is by utilizing pedigree software that allows you to append notes to a dog’s record.  That puts the information right where you need it as you research pedigrees.   Be sure you develop a systematic way of searching your database that will allow you to retrieve the information you have on the collateral relatives, too.  Over time and with cooperative information sharing among breeders, you can gather significant amounts of data to review when you are considering potential crosses.

Finding Fault

Both parents contribute to a polygene trait, so there is no future in he did/she did finger-pointing game if an unwanted polygenic trait comes up in a litter.  Both parents passed genes to the pup that allowed it to happen.  However, the contribution may be unequal.  Some dogs will only occasionally produce something like HD, others will have multiple affected offspring.  The dog that produces the trait more often, especially with multiple mates, carries a heavier load of genes for the trait than one that does not.  Recognizing this enables you to a better job of breeding for or away from the trait.

If you want to preserve a polygene trait, you should to start with a pair of dogs that have the trait.  If they also have numerous relatives that exhibit the trait, even better.  Best of all would be that the dogs and their relatives are known to produce the trait consistently.  With this kind of individual and family history the odds are in favor of there being puppies  from your pair that will have the trait you want.

If there is a trait you don’t want, you wouldn’t select breeding stock that had it.  But you must also make sure there is little of that trait in your dog’s family.  If she produces it too often, you might do better to use someone else for breeding.

Setting Priorities 

All traits are not equal.  If you have many good things in a dog that are consistently produced it his family, but there is one consistent trait that you don’t want, you need to look for mates that are not closely related to your dog (because you know the problematic genes are there) which are clear of the trait, have not previously produced it, and have little or no family history for it.  Such a mating will reduce the risk of getting the unwanted trait in the litter.  Even if everything is perfect with the litter, at least some of them will carry the problematic genes, so those which are bred will also need careful mate selection to reassembling the polygene set and producing the unwanted trait.

In many cases, breeders have to do a risk/benefit analysis of proposed matings to capitalize as much as possible on desirable polygenic traits while minimizing risk of getting the undesirable.  But when there is a DNA test available, they can use it to skew the odds in their favor.

Science to the rescue!

At this point we only have single-gene tests available, but some of those are for genes of major effect, genes that are key to how or whether a trait develops, in polygene traits.  One example is the CEA/CH gene.  The gene mutation is the one that causes choroidal hypoplasia (CH,) the most common Collie Eye Anomaly defect.  CH is a relatively minor eye defect; most dogs with it have functional vision.  However, other CEA defects, like optic nerve coloboma and detached retinas, can be blinding.  The more serious defects are caused buy other, as yet unidentified genes.  However, no dog gets CEA at all unless it has a double dose of the CEA/CH mutation.  Because this gene’s actions are so predominant in this disease, CEA can be treated like a single gene recessive even though we know there are other genes that contribute to the phenotype.  And, since we have a DNA test for that key gene, there is no need to remove carriers from the breeding pool so long as we breed them to non-carriers.  Over time, we can give preference to the non-carriers and reduce the frequency of the mutation in the breed.

But most polygenic traits, even those with a test for a gene of major effect, aren’t so cut and dried.   Cataracts in Australian Shepherds are an example.  A dominant mutation in a gene called HSF4 is associated with approximately 70% of the cataracts in the breed.  HSF4 was first found to have a mutation causing a simple recessive form of cataract in Boston and Staffordshire Bull terriers.  In the process, researchers found the Aussie mutation, too.  Not every Aussie with cataracts has the HSF4 mutation and some dogs live out long lives with the mutation and never get cataracts.  Even if you rule out those cataracts caused by environmental effects (injury, infectious or acquired diseases, nutritional imbalance) there are still some dogs without the mutation that will develop cataracts.

State of Confusion

The lack of black-and-white answers from the HSF4 test has lead to great confusion among some breeders, spurring calls to reject the test as inaccurate or useless.   Such opinions are short-sighted.  The breeders who espouse them are rejecting a tool, albeit an imperfect one, that can help them reduce the frequency of cataract in their lines.  The truth is that most of the simple and easy one-gene traits have already been identified.  From here on out, Most of the gene tests developed will be for genes like HSF4 that indicate a risk factor instead of a sure thing.  Even so, the results of these tests put us in a better decision-making position than where we are with most polygenic traits, like the autoimmune diseases, for which we have no DNA tests at all.

The HSF4 mutation in Aussies is highly (70%) associated with cataracts.  It is dominant, so a dog with only one copy is just as likely to develop them as one that has two.  Cataracts are very common in the breed and often, though not always, ultimately blinding.  In general, the best advice is not to breed dogs that have even a single copy of this mutation.  However, the test is relatively new (released in March of 2008) and some breeders have made the unhappy discovery that many of their dogs have it.  So, should these breeders dump all their stock – including animals that have many very find traits – and start all over?  Of course not.

If you find yourself in the unfortunate position of having a breeding program riddled with HSF4, you can take steps that will allow you to hang onto the baby while you drain the dirty bathwater.  Since you can positively determine the HSF4 genotype, breed your best individuals that have one copy of the mutation to clear mates.  Select the best clear offspring from those litters to carry on with.  You will have eliminated the problem in one generation.  If you have the misfortune to have an otherwise exceedingly valuable animal with two copies, breed it to a clear mate.  All the puppies will have one copy of the mutation, but if you breed the best among them to clear mates, and select the best from that second cross to carry forth with, the mutation will be out of your breeding program in two generations.

The HSF4 Aussie cataract mutation is of a type called “incompletely penetrant,”  meaning not every individual with the mutation has the trait.  The penetrance for this one is fairly high, but sometimes penetrance will be low.  Such is the case for the Juvenile Renal Dysplasia (JRD) mutation.

JRD is well-studied in the Tibetan Terrier.  A dominant genetic mutation was found in that breed occurs in all dogs that have the disease.  However, many dogs have the mutation but never become ill.  Since only a small number, estimated at 3-5%, of the dogs with the mutation become ill, there is no point in removing healthy dogs that have the mutation from breeding.  However, those that do become sick often die and those that aren’t killed outright by the disease often have shortened life-spans.  So, what to do?

Decisive Action

The JRD mutation should be treated as a major fault.  It isn’t a fault that will move you to the bottom in a conformation class or get you excused from the performance ring, but it is a fault nonetheless:  One that in a few cases will be fatal to the dog.  The best thing breeders can do if they discover a healthy, breeding-quality dog has this mutation is add that fact to the list of pros and cons for this particular dog.  If the good stuff outweighs the negatives, including JRD, then breed it to something that has tested clear.  As outlined above with HSF4, you can be free of the mutation—and the worry that you might produce a dog with clinical JRD—in a maximum of two generations.

Polygenic traits, both good and bad, can be managed in a breeding program, the key is good record-keeping, doing your homework before you put dog to bitch and, where possible, making educated use of available DNA tests.  We are far from the point where we can guarantee all outcomes in our litters, but the more informed you are the better equipped you will be to work toward the outcomes you want.