Practical Genetics, Step 3:
Having made a reasonable guess about inheritance pattern is all very well, but then how do you go on to use this guess in your actual breeding program?
I) Dealing with a Dominant:
a) Unaffected dogs are clear and need not be removed from the breeding program. This is true even if a parent or full sib is affected. The trait status of parents and sibs is irrelevant – unaffected dogs are still clear.
This is worth emphasizing: let me say again that there is no need to remove the full sib of an affected dog, or the offspring of an affected dog, from your breeding program if the trait you are working to eliminate is dominant. If the sib is unaffected, or the offspring is unaffected, then they are clear and can safely be bred regardless of the degree of relatedness they have to the affected dog.
Lack of complete penetrance can lead to mistakes, however, as a dog that looks unaffected may in fact have an affected genotype. However, if penetrance is very low, you are not dealing with a simple dominant. "Incomplete penetrance" is not a guess that should be used to justify treating complex traits as simple single-gene traits!
b) One of the parents of the affected dog must be affected. If it’s not your bitch, it must be the sire – and vice versa, of course. There are three possible ways you might miss an affected parent:
-- the trait lacks complete penetrance
-- the trait is expressed only in very mild form
-- the trait is late-onset
Any of these situations might make it look as though both parents are unaffected when in fact one has an affected genotype. If penetrance is incomplete, you are going to need to track puppies very carefully to make sure that clear dogs really are clear. This means keeping track of pet puppies as well as show puppies – especially for your bitches, who won’t ever produce many puppies to serve as data points. For mild expression, you are going to need to be hyper-sensitive to suggestions in the phenotype that might be connected to the true trait you are trying to track. For example, could late descent of testicles indicate a mild expression of cryptorchidism? (Isabell has data which suggests this is the case.) In the case of a late-onset trait, you are going to need to keep track of what happens to adult dogs after they have been bred. You may wish to delay breeding a bitch until you can be sure she is clear, although a trait that does not show up until age six cannot be handled this way. You may very well want to breed younger bitches only to older males -- as old as necessary to get ahead of the trait.
c) If an animal is affected by a dominant disease, it’s up to the breeder to decide whether it should be bred. Half the puppies, after all, will be clear of the problem while also carrying on good genes (presuming the dog is otherwise good) for other traits. The other half, of course, will be affected by the dominant problem. None will be “carriers”, a term which makes no sense when discussing dominant traits.
Whether to breed an affected animal therefore depends on how serious the dominant problem is. If the problem will cause no suffering to the affected puppies or serious annoyance or cost to the owner, probably the dog should be bred. If the problem can be reliably spotted in very young puppies, you may wish to breed even if the problem is very serious, and cull affected puppies. And so forth. The key is to decide knowledgeably and get the problem out of your breeding program while maintaining the highest possible genetic quality in your dogs.
d) In the unlikely case of a sex-linked dominant, if it’s your male that’s affected, his sons are almost certain to be normal and can be used freely in your breeding program or anyone else’s. The only way for an affected male to produce an affected son is to be bred to an affected bitch – if the problem is a sex-linked dominant. Don’t hold your breath. Few if any sex-linked dominant traits are known.
The only dominant problem that Padgett reports for Cavaliers is Ehlers-Danlos syndrome, a problem with loose and fragile skin that is excessively subject to injury. This is very rare in Cavaliers, I expect, as I've never heard of it actually occurring. Some (many) diseases do get into the literature without actually being problems for a breed. Other problems that are thought to be dominant exist but have not been reported for Cavaliers. These include goiter, lymphedema, thrombopathia, benign familial pemphigus, lentigo, and a severe reaction to halothane anesthetic (“malignant hypothermia”). There aren’t very many known dominant traits, but since most genetic diseases have unknown modes of inheritance, this list will certainly grow as their modes are determined.
An incompletely dominant (partially dominant) trait is generally one in which a homozygous-affected animal shows the trait in severe form, a heterozygote in moderate form, and a homozygous-normal animal is normal in phenotype. Because phenotype matches genotype, this sort of trait is just as easy to handle in a breeding program as a straight-up dominant, at least theoretically. In practice there are very few genetic diseases that are known to show partial dominance; none have been described in Cavaliers. If you’re breeding merle Collies or harlequin Great Danes, though, this topic is important and you should pursue it.
Traits that aren't diseases may show incomplete dominance. The chinchilla gene which influences the expression of phaeomelanin to give us the chestnut - palomino - cream and bay - buckskin - cream color series in horses is also apparently responsible for creating some of the creams and silvers in dogs -- such as the black-and-silver miniature schnauzer, for example, and perhaps the white Great Pyrenees, among others. There are doubtless other traits that show an incomplete dominance pattern in dogs. I've seen it suggested that ticking may be an incomplete dominant, with heterozygotes showing less ticking than homozygotes. It would be easy to determine whether this supposition is correct by doing a few test-breedings. Likewise, the spotting series (solid color, Irish white, piebald white, extended white) has been suggested to show incomplete dominance between its various alleles.
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II) Dealing with a Recessive:
a) If a reliable test for carriers is available, use it. A carrier bitch may be bred, but should be replaced in your breeding program by noncarrier daughters. If you keep and use several carrier daughters to carry on her line, the overall carrier frequency for your breed will not decline, so if you don't have a test, then replace a proven carrier bitch with a single daughter and your chances of eventually getting rid of the problem in your breeding program is good. Jerold Bell describes in several of his articles why this works. You can produce and keep several daughters as long as you eventually choose only one to carry on the line – in Cavaliers you should not be breeding bitches before they’re about 2 ½ anyway, which gives you time to think about which girl to keep and use.
b) If you have an affected puppy, both its parents must have been carriers. This is 100% certain for a simple single-gene recessive trait. Identifying an animal as the offspring or parent of an affected animal is the only way there is to identify carriers with surety if no test is available. Sometimes, I’m told, a breeder will put the blame for any problem that arises on the stud. Comforting as this may be, unless the problem is dominant, the comfort is illusory. Both parents contributed. If you breed your carrier bitch to other males in the mistaken belief that her genes are clear, you will be increasing the carrier frequency for your breed.
c) If you have an affected puppy, each of its unaffected siblings have a 2/3 chance of being carriers. This does not necessarily mean that you cannot breed those siblings. It does mean that to do so is a risk. However, you can take steps to prevent the production of affected puppies, exactly as though you knew for sure that the sibs were carriers.
d) Do not toss out the baby with the bath water. It is both unnecessary and sometimes tragic to a breeding program – and the breed – to discard normal puppies from the program if they have an affected sibling. Truly excellent dogs should never be spayed or neutered only because a relative has been diagnosed with a genetic problem. Doing so blindly can result in great harm to your line or to your entire breed, as a few breed clubs – dedicated but not sufficiently knowledgeable – have reportedly found subsequent to the development of genetic testing (Bell) The danger is that the club will accidentally reduce the overall quality of their breed and its genetic diversity while also causing some other, previously unidentified, problem to increase in frequency in the breed.
e) Do not use the above saying to excuse your keeping and breeding an animal that represents high risk without sufficient virtues to justify the risk. There is a very powerful urge to believe that YOUR dog will turn out to be clear because it would be so disappointing if she were really a carrier. Decisions about how much risk is acceptable should perhaps be based on how much harm you would be doing to the prospective puppies in the worst case. Cavaliers with iffy hips will probably be able to live perfectly normal, vigorous lives with no clinical signs of pain or need of treatment, ever. In contrast, there is no acceptable degree of syringomyelia.
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What if there is no carrier test for a single-gene recessive problem or trait?
a) If there is no carrier test for a problem, there will be, of course, a risk in breeding a possible carrier. How can you find out whether your bitch is a carrier?
If your bitch produces 4 normal puppies (*and zero affected puppies*) to an affected male, the chance that she is clear for the trait in question is 93.8%. This would be an example of test-mating: breeding an animal of unknown genotype to an affected animal. Even with only 3 puppies she’s 87.5% likely to be clear. (Padgett has tons of very useful tables in his book that lay out probabilities for various types of crosses.) The surety that test crosses give you may be well worth getting. Even a Cavalier may well produce enough puppies in one breeding to let the breeder make a reasonable guess one way or the other.
If you choose to do a test mating, it surely goes without saying that it's best to choose a really excellent male who also happens to be affected with this problem, because if the puppies are normal, they may be worth keeping in your breeding program – even though they will be definite carriers. As outlined above, a carrier can be bred to a clear dog with no chance of getting affected puppies, and one normal puppy after another kept to replace their mothers in the breeding program in order to dilute the risk of continuing on with carriers. After several generations, the breeder may want to repeat a test mating in order to check and see whether she has successfully gotten rid of the undesirable allele.
b) What if you don't want to take your bitch to an affected male? What if you have your eye on an unaffected male? Is there a way to tell whether he is clear or a carrier?
To do this, you will have to assess his breeding record. Padgett lays out how to do this. If a dog was previously bred to carrier bitches and produced 8 unaffected puppies (*and no affected puppies*), there is a 90% chance he is clear. 10 unaffected puppies? 94.4% probability that he’s clear. 15 puppies? 98.7% probability that he’s clear. He need not have been deliberately mated to carrier bitches – the carrier status of the bitches can be determined after the fact and the information then used to assess this dog’s genetic status. For example, a bitch may have produced unaffected puppies to the dog you are considering, and then at least one affected puppy to a different sire. This would make her a confirmed carrier (and the other sire as well). But each normal puppy she produced to the dog you’re interested in is another data point in his favor, as long as she didn’t produce any affected pups with him. It goes without saying that if he has every produced even one affected puppy with any bitch, he is a confirmed carrier.
This is one reason to consider using a sire who is older and has a fairly extensive breeding record – he will be carrying something (all dogs are), but you are likely to be able to tell what he is carrying if he has a good number of progeny on the ground, as long as his owner is honest with you. The idea is to avoid doubling up on your bitch’s possible problem, not to produce the genetically perfect puppy (that’s not possible).
Incidentally, if a dog was ever bred to a bitch who later was herself found to be affected by a recessive trait, and if with that bitch he produced 4 unaffected puppies (*and no affected puppies*), there is a 93.8% probability that he is clear. 8 normal puppies and there’s almost no chance he’s a carrier.
Obviously the honesty of stud dog owners is paramount in determining the genetic status of a dog for any given genetic trait. You cannot choose a dog to complement your bitch’s genetic traits if you don’t know his. Honesty is essential. So is tracking all the puppies every dog produces.
To sum up, the rules of thumb for handling recessive traits in a breeding program are:
a) If there is a test for a genetic disease, replace carrier bitches in your breeding program with tested-clear daughters.
b) If there is no such test, you can mate possible-carrier bitches to known-clear males to dilute the risk for their daughters. Replace each such bitch with one, just one, daughter. If you keep and use two daughters, you have not improved the carrier risk for your line.
c) alternatively, you can test mate a possible-carrier bitch to an affected male to determine her genetic status. Either remove a confirmed carrier from your breeding program or breed her to a known-clear male and then continue to replace one bitch after another to known-clear males to dilute the risk for successive generations or test-mate possible-carrier daughters until you get a descendant that is clear.
Recessive traits with no reliable genetic test are a pain in the neck, no question about it, especially late-onset diseases. But they can be effectively dealt with in a breeding program – both in theory and in practice, as demonstrated for us by Collie, Portuguese Water Dog, and Malamute clubs. Single-gene early-onset recessive traits are sweet and cuddly, compared to polygenic or late-onset traits.
There are a handful of genetic problems that have been reported for the Cavalier that are thought to be simple recessive traits. These all must occur at a very low frequency in Cavaliers, given that I haven't heard of any Cavaliers with these problems. They include: the simple recessive form of von Willebrand’s disease, ichthyosis, pancreatic hypoplasia, myotonia, a structural defect caused by the premature closure of the ulna, and possibly one form of retinal dysplasia. Padgett (1998) also includes color dilution alopecia in this list, but I take leave to doubt this, as Cavaliers do not have the dilute allele d in their color repertoire. This demonstrates why you should take such lists with a grain of salt. Certainly if this condition is present in Cavaliers it must be very rare. If your puppy is a normal Cavalier color, you don’t need to worry about this problem.
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III) Dealing with a Polygenic Trait:
A good way to get usable information about a polygenic trait out of complicated data is to create a pedigree that looks like the one shown on in this excellent article at the OFA website: http://www.offa.org/hovanart.pdf. This pedigree includes only parents, grandparents, and great-grandparents -- but it also includes the full sibs of the parents, the grandparents, and the great-grandparents. This table is easy to construct and easy to work with, and it gives you exactly the kinds of information you need to know to assess the breeding quality of individual animals with regard to specific polygenic traits. The entire article referenced above is excellent, although you'll also find good articles (and book chapters) by many other authors dealing with this topic if you get interested.
Here are the basic rules of thumb for dealing with a polygenic trait:
a) Assume that both parents contributed to the appearance of an affected offspring, but that their contributions were not necessarily equal. Breeding records may be used to decide how clear a particular animal is for a polygenic trait, but even a sire who is genotypically very sound for an undesirable trait may produce some puppies that show the trait. A genotype like AaBBCCDDEdFF will still pass deleterious alleles along to his puppies -- just not to all of them, nor very many alleles. But if bred to just the wrong bitch, you could get affected puppies from this sire.
b) Assume that severely affected animals are carrying a lot more deleterious alleles than mildly affected ones. Therefore they will pass a lot of problem alleles on to most or all of their offspring and are poor breeding risks. Even phenotypically normal puppies from these parents are probably carrying a good many deleterious alleles.
c) On the other hand, a mildly-affected animal with mostly sound close relatives is probably a better breeding risk than a sound animal with many affected close relatives. The extended pedigree carries information about the genetic potential available in the family. Therefore, it is very important when dealing with a polygenic trait to assess the quality (for that trait) of full sibs, parents, full sibs of the parents, grandparents, and full sibs of the grandparents. This also means that it's very important to track the puppies you sell so you have a record of full-sib information about the puppies you keep to breed.
d) It's not necessary to worry about the soundness of distant relatives. When you're dealing with polygenic traits, the predictive power of relatives falls off fast once you get further away than grandparents, or even parents. It's close relatives that are most important.
d) The breeding record of an animal can tell you a lot, but only if records were kept for all puppies produced and all the bitches to which they were produced. If breeders do not track pets, there is going to be great difficulty assessing the true production records of breeding stock.
Polygenic problems to which Cavaliers are subject include hip dysplasia, patella luxation, MVD and various other heart defects (none nearly as common), quite possibly syringomyelia, and perhaps a form of corneal dystrophy. Type and soundness traits which are polygenic include almost everything. I've been using "disease terminology" because it's very easy to fall into that mode, but if you want to breed for good shoulder layback, good length and angulation of the upper arm, front legs of appropriate length, sound pasterns and good feet -- in other words, if you want to breed for good front construction -- then clearly "a good front" is polygenic and you will be wise to look for a male who has an excellent front but who also has sibs, parents, and uncles and aunts with excellent fronts. It would be nice if he also has a record of producing puppies with good fronts -- especially if his owner also keeps records of front-end construction of all the puppies he has produced, even the pets. And it would be good to know what the dams were like, since his pups were also getting their mothers' contributions, which might have outweighed his, for all you know -- in other words, has he produced good fronts even to bitches with poor fronts? This is where long-term experience in the breed is important, since that's the only way to have at-your-fingertips knowledge of a wide range of animals.
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Inbreeding and the practical breeder --
HWE and the breeding of domestic animals --
More on Punnett squares and probabililty --
Chi-square tests --
Logic traps for the breeder --
Case studies --