Control of Canine Genetic Disease
This is a short "shotgun" article that offers "bullets" on how to cope with genetic disease in dogs. For a general resource, I suggest George Padgett's "Control of Canine Genetic Diseases" as a benchmark reference; as the dust cover says this is a volume that should be on the shelf of every dog breeder. I'm going to borrow a central point from this text to help focus the conversation: from a gene load standpoint, a risk/benefit analysis can be applied to any and all individual dogs and all pedigrees for any characteristic. Thus can the breeder gain control over "genetic" (as in inherited) disease by a careful scrutiny and analysis of the dogs involved for various important inherited characteristics. Before anyone panics at how awesome or technical this sounds, this is akin to a show ring analysis of conformation and something nearly every breeder instinctually understands. This is exactly what you do when you look at the virtues of the dog and measures them against the faults, and place them in context of the pedigree. This just varies in the sense that health issues comprise a separate category from breed ring beauty, and the sort of analysis suggested here can give you as a "breeder X-ray eyes" so you can see traits submerged below the surface of the dog.

First things first; Padgett (and other geneticists) would argue in general that how strongly a disease trait should be selected against largely rests on the impact of the genes in question. If the disease results in a lethal condition, or causes great pain or chronic distress for the dog (and his owner), then a breeder, from sheer humanity, needs to select very strongly against it. From the list in our breed that would include things like heart disease. The practical effect of this is that any “whiff” or suggestion of such deadly problems means a breeder is best to strongly cull (as in decline to breed) and look elsewhere for bloodstock to offer better health. There is really no deal to be made with the devil, and the devil is exactly what such fatal disease represents. It’s a plague on our our breed and we have to work hard to eradicate what is killing our Danes.

If the disease (the trait) is moderately debilitating or has a variable effect that is neither life-threatening or can be controlled clinically, for example, then selection against such disease can be moderate (i.e. less rigorous). This would include something like hypothyroidism, as it is controllable with a simple and inexpensive drug or CHD (hip dysplasia) in all but its most severe forms (which is as it typically presents in the Dane, i.e., as mild disease). Here, a breeder can simply select against actual cripples and use "lesser" individuals from families with reasonable hip health if necessary. This is the compromise that is usually touted as not throwing the baby out with the bathwater. Now if the bathwater is really dirty (i.e. a lot of individuals with disease are showing up), the whole thing might need to be tossed. But usually you can breed away from such moderate level problems, by selecting carriers over those with overt disease, then selecting the less likely to be carriers over those that most likely *are* carriers.

If the disease is simply superficially (not functionally) disfiguring, something that results in the dog being disqualified or otherwise found less than useful for a conscientious breeding program, but still ends in a dog who is a a reasonable pet for example, this isn't a set of traits a breeding program should be centered around & in fact, a certain tolerance here (i.e. for things like poor color or missing teeth or cryptorchidism) should be allowed. Despite common prejudice, logic demands that one simply cannot select strongly again these essentially trivial traits which merely represent minor defects. Rigorous culling (declining to breed certain dogs) should be saved for those who are defective in some significant way. To prioritize otherwise is to, too often, not select strongly enough against more serious threats to a breed/breeding program.

There is a sub-category of actually lethal disease that many would argue needs little or no selection against at all. These would be neonatal or congenital defects that are readily recognizable at birth and so such pups can be humanely euthanized (like megaesophagus). The argument here is that the breeder doesn’t share out the grief of a disease that results in early euthanasia, so therefore there is no need to clutter up a breeding decision by excessive worry about what will manifest in the first month of life. Not all may agree with that as it's an ethical stance with variable positions. But at least itwould logically be reasonable to select more strongly against adult-onset diseases like DCM than ones that manifest before breeding age like “mega,” as it's the adult onset diseases that are so difficult to control. It’s the deadly adult diseases that are so cruel to to many, as they keep finding their way back into the population because the disease isn't obvious until after (often long after) the dog is bred.

So, if you count healthy dogs as important, you learn to live with light eyes or mega to be able to rid yourself of the risk of cardio, and so on. You simply cannot select against everything “awful” all the time and with the same intensity: you have to chose and to chose is to prioritize (in your breeding program) what is most meaningful to your dogs and consequently your buyers. And it's axiomatic that dogs who die young are not a good thing; without a definitive diagnosis otherwise, dogs dead before becoming veterans are best treated as most likely having died of a major and serious breed disease, "proof" or not. It’s just not realistic that most 5-6 year old males who dropped dead were poisoned in a breed where cardio is rife.

Also it's worth remember that no news in breeding is NOT good news; it's better always to have even ugly and messy details on a dog in your pedigrees than a bright outline that is lacking details. Push for more than an advertising or proud owner picture of a dog. From a cynical standpoint you likely don't have a good enough idea about a dog to breed it unless you know half a dozen negative things about him. Knowledge is certainly power when talking breeding dogs. And ignorance is the prequel to saying "I’m sorry."

Disease in the Dane: from Applied Science into Predictive Inheritance Patterns

Why do we see heritable disease centers around genetic load? Genetic load can become a complex topic, but the pragmatic point here is that some individual dogs are more or less likely to produce disease, and so all breeding stock should be "rated" as to it’s statistical likelihood to carry forward problem genes. All dogs, more or less, for one trait or another, are thus "carriers." These "carriers" have, on a gene level, some undesirable traits. Some are manifest (this dog has vWD), others are not (this bitch carries for DCM), and it's naturally the case that *how* things are passed down becomes a consuming quest. Here is a short internet article, easy to read, that outlines the majors ways traits are inherited called Practical Genetics for Dog Breeders: http://www.chromadane.com/practicalgen.htm

This short article offers an overview of how genes work. Below I've listed out, for various diseases seen in the Dane, the most likely mode of inheritance. However it's not always possible to define exactly each situation, and Padgett had a very good prescription for this which essentially echos older breeder logic: when faced with two healthy parents and pups with disease, treat the situation as one would a simple autosomal recessive. You then consider BOTH parents to be carriers of at least one gene that contributed to disease in the offspring and you assume every littermate has some increased risk also of being able to pass the disease genes onward. This allows the breeder to have enough clarity to manipulate the situation to reduce risk to a reasonable level while affording them to still use valuable animals to best advantage. Below is an outline to manage risk. See also the parent club's Health & Welfare page: http://www.gdca.org/healthandwelfare.htm

1. Diseases found in the Great Dane that are generally considered to be inherited as simple autosomal recessive include the follow and involve the following risks:

Congenital megaesophagus, Wobblers (CVI), vWD von Willebrand's), JRD (juvenille renal dysplasia), hypothyroidism, Addison's disease, most CERF-able diseases (i.e. catarcts), atopy (allergies)*, many other "purebred" diseases & various congenital defects, such as hernias and cryptochidism (sex-limited trait).

With simple autosomal recessives, every affected dog has 2 carrier parents and will, even when bred to a healthy animal, produce ALL carrier offspring. Littermates of affected dogs are likely carriers that have a much increased risk of also producing the disease in question. Affected dogs generally should not be bred. Known carriers should generally be bred only to dogs from "clean" pedigrees and dogs that have a very high probability of not being carriers themselves when serious disease is involved. Ideally known carriers should be replaced with less risky relatives or even "clean" dogs.
The potential carrier status of dogs closely related to an affected should be disclosed to potential breeding partners, and pedigrees should be carefully marked so that the carrier status of the bloodline is noted and this knowledge is not lost. This is to prevent carrier to carrier breedings erupting unknowingly into disease. The standard math here is from two carriers, in the offspring one in four will be affected (i.e. have the disease), and two of the three normal appearing animals will be carriers and so pass on the disease in the same ratio. The solution here is to identify carriers and simply not breed them to each other--or at least to do so only knowledgeably & only generally with less serious/less debilitating disease. Many "protein errors" when one simple coding mistake means a process goes wrong are inherited as simple recessives. This is the MOST likely way many a disease of purebred dogs is inherited simply because unwanted dominants are typically easily screened out. So when in doubt, treat a disease as a “recessive” where it both parents are considered involved. It "Takes Two To Tango" is the mantra of the careful dog breeder.

2. Diseases found in the Great Dane considered to be inherited as polygenic include the follow and involve the following risks:

CHD (hip dysplasia) & joint diseases in general; congenital heart disease (e.g. TVD) as well as SAS (subaortic stenosis)* and ACD (arrythmogenic cardiomyopathy) & possibly atopy/autoimmune disease. Most complex failures of structure are a result of polygenic inheritance.
Polygenic diseases are essentially threshold or cumulative diseases. These problems are a result of accumulating problem genes until there is a clinical problem. For any structural problem from SAS to CHD, think of if this way: you inherit 6 genes to build a thing (heart or hip), and if only 2 of them are "bad" the thing built works anyway. But at some point less "able" genes accumulate and so then the structure fails. These kinds of diseases are hard to eradicate from a breed as most of the dogs in question have some of the genes for the thing, but they can be controlled, because you can reduce the gene load by testing, for example (as with X-raying for hip dysplasia), and then reduce the incidence of actual disease by matching up candidates at a lowered risk with those of value who are deemed to be at a higher risk.

With these diseases it's especially important to consider the status of littermates as well as the specific dogs in question to be bred, as how many have been checked is likely to tell you how many "bad" genes are circulating in any one family. Most close relatives are going to have some after all: i.e. you have to consider the so-called “horizontal” pedigree, and not just boast of “Excellent” parents, but outlined if the siblings are Excellent, Good, Fair…or some kind of fail. It’s the family average that speaks to your real risk. And it goes without saying that it's always best to have an intimate knowledge of ALL the dogs in at least a three-generation pedigree, but with complex diseases inherited in a complex way, this becomes even more critical to be able to reasonably assess risk. You cannot be satisfied with haphazard or isolated information on a pedigree when complex inheritance is involved. When in doubt, again, the simplest way to deal with disease is to essentially treat them as simple recessives: both parents contributed at least one gene to the disease, and so on.

3. Diseases found in the Great Dane considered to be inherited as X-linked include the follow and involve the following risks:
"Classic" DCM (Dilated Cardiomyopathy ( potential X-linked recessive).

This is a different situation to that above. X-linked means the disease lies on the X chromosome. And although one can have X-linked diseases that are dominant, this isn't much seen and it's not relevant to this discussion. The kind of X-linked disease to be discussed is a recessive. But since the gene is on a sex chromosome, males are especially then at risk. Females have two X chromosomes, so the normal gene protects them typically from the disease. The males have only one X (the other is a Y, to make them male), so they are normally the ones who are diseased. The way this sort of thing is inherited is tricky for this same reason. Males get the Y from their sires, the X from their dams, so it's the *DAM* who was the carrier of the X-linked disease. In the same way males give their defective X only to their daughters, but they give it to all of them, every time. So males who have DCM had dams that carried it down, often 2-3 generations, from a sire who gave them the defective X gene. And daughters of DCM males often, again, carry this down, unseen, for a generation or two. Since the males die of it, they get tracked, but the hard part for breeders is to get used to looking at the normal females that surround him as the source of the disease. To read more, go to this link & read the links at the bottom of the page: http://www.gdca.org/health/cardio.htm Not all heart disease is inherited this way bear in mind, and not all defects of the heart muscle are even necessarily X-linked, but this way of inheriting things does have meaning in Danes and in dogs, so it’s "odd-ball" presentation should be learned.

4. Diseases found in the Great Dane considered to be inherited as autosomal dominants include the following and involve the following risks: Polycystic kidneys, various MHC (immune) diseases, SAS (possibly)*:

Were these diseases simply "dominant" and deadly--disease that is caused by a single gene in every individual--they would winnow themselves out without a breeder's help obviously. Most cases of autosomal dominant diseases in dogs are considered a result of reduced penetrance and/or incomplete dominance, meaning essentially the gene doesn't have the same deadly effect on every individual as it (in various ways) works with other genes in concert. This is problematic as it may mean a parent appears healthy but still donated a disease gene to their offspring, and so there may also be healthy-appearing animals in the litter that also are capable of carrying this gene onward and producing again, in later offspring, this same deadly effect. The reason such diseases are considered dominants is they typically do NOT trace down both parts of a pedigree, but typically come through one parent, who has the disease behind them (somewhere); and it can be actually documented the disease hasn't appeared on the other side of the pedigree. That's clearly often hard to do, given the state of records on dogs--even scientists cannot be sure as they'd like to be at times. And sometimes these diseases are argued to be polygenic, as with SAS. So this is murky water, and it's never incautious to treat such things as Padgett suggested is best in general when unsure: assume both parents as likely contributors, both had a hand in the disease in question, and assume that all littermates are at increased risk to carry down the disease. Bottom line is don't linebreed back on suspect regions of the pedigree our out to dogs whose families have also experienced the disease in question. And use the less likely carriers vs. the ones directly related to dogs that are actually diseased.

In summary, the breeder has more control over disease than is often exercised. Most heart diseases and other complex structure diseases are polygenic (with the exception of "classic" Dane DCM which seems to come from a simple mutation of heart muscle, not of structure). These and the autosomal dominants are best treated by first casting a wide net to find out as much as possible on family members to assess family risk. Most diseases that "skip a generation" are simple recessives, and the result of a single mutation that is often breed specific. These are the “takes two to tango” situations, and can be easily controlled and can also be prioritized as to the level of threat the disease represents to the breed and the individual dog. Many, many purebred dog diseases are inherited this way. Most gene tests to date are for such diseases. Linebreeding particularly brings such disease into view, and careful breeding can control them so that the carriers don't meet and create diseased individuals. It simply requires careful record keeping and appropriate disclosure to other breeders.

X-linked diseases have to be managed by identifying and tracking the carrier females through the generations. This is a sort of "down and dirty" list, granted, but is a reasonable summary to keep in your head when dealing with unknown as well as known diseases. It hopefully helps with a "threat assessment" when someone calls to say X dog has been diagnosed with X disease. And by threat assessment, I mean the disease, not the caller. (This is another topic, but we have to get away from treating disease like some sort of moral failing and deal with it for what it is: a biological reality we all have to face at one time or another.)

Now I truly believe each breeder has to be their own arbiter of what risks to take under what circumstances, and this isn't therefore something one person can legislate or define for another. So this document is NOT meant to be read as a "how to breed right" or even as some personal set of recommendations of mine. It's mostly a "state of the art" message about how the news in genetics can help us breed better dogs, and how a calm, non-emotional and rationally focused analysis of disease is really valuable to that end. We all, as breeders, have to sit down and decide “what comes first” as for all perfection is sought, every living thing is flawed….unique....and to be cherished for their individuality?

I don't have any advice per se for other breeders, just for the record: I am willing to offer analysis, but have no desire to offer judgment. So don’t read this article as an indictment, but more as an incitement for all of us to think more, to do better. These guidelines given above are applied science, not "pure" in any abstract sense, so are also not perfect, but just guidelines. Nothing under the sun, nothing in biology is 100% certain. Biology is a place where perfect proof is more often lacking than not, but action must be taken anyway. So breeders must act in the best interests of the breed without perfect knowledge or absolute proof.

This document is therefore offered to give a breeder the freedom to breed (and hopefully do it well!) by concluding using rational, thorough analysis, the reasonable risk of using any particular dog can be defined and defended. Naturally such an information system is incomplete, and in some ways is always a work in progress. But then the information gathering on any dog is also flawed in most every way, however that doesn’t allow breeders to bury their heads in the sand or say they are waiting for better information. With every breeding, one has made a decision. So to bring lives into this world is to truly commit. To have dogs we all have to act anyway, be it in their care, training or their breeding.

We cannot wait for perfect information, as we are all alive today, and moving into the future. It's just the price to be paid in this field of endeavor? Given we have imperfect information and important decisions to make, I'd think the best motto for dog breeders (when it comes to at least to heritable disease) would be that old saw of pilots who acknowledge the danger of what they love to do when they say: "view with alarm so you can point with pride." It's always best when there are gaps in your knowledge to assume the worst to achieve the best. As Elias Canetti said, "The gaps in our knowledge are always roaming."

I further refer all interested in breeding dogs to Chapter 7 of Padgett's book: "The Interpretation and Use of Pedigrees to Determine the Probable Mode of Inheritance of a Trait." This sort of book in general can help to flesh out the outline given above. I hope this is helpful; it's for now the best I can offer. And one quick thing, for all it's preaching to the choir largely: we have to remember in our love and despair to THINK. The point here is to assess risk, not to assign blame. It's important to put aside the obvious fear and even hurt when trying to objectively assess the accuracy and integrity of the various sorts and sources of information on the dogs in question. Searching for information on the dogs behind your stock should always be done, but it's not a witch hunt. Emotion is best left out of it. It's important also to be critical and careful, and not take information at face value either, for all these are hard things to do. We all have to put away hope long enough at least to face our worst fears. And you can help other breeders do their best by the breed by offering disclosure on your current situation.

Sharing information about flaws and faults, and the concerns of disease risk shouldn't have to be a noble act of sacrifice, but should be a reciprocal relationship with other breeders. We should all be thankful for the information that is shared as it benefits all. It's hard to do, but we must support each other in doing it, as it's critical to gathering up the needed information we all need. And it's actually healing in a way to simply put aside the storm of emotion that comes with disease, and ask yourself if this is more or less likely to be a real problem or not. It also helps you step aside from the desire to believe what is easiest, when it's obviously not always going to be the best belief in truth seeking to hope for what you want to see. In an odd way we love our dogs better by casting such a critical and even cold “unloving” eye over them before we breed them. And if we don't always do a great job at this aspect of breeding, if we don't always talk rationally about disease risk or share information as we should, well, we can only start now...with us…and do better? No point to moaning, let’s roll up our sleeves and get working!

Best Regards, JP Yousha
Chmn., Health & Welfare, GDCA
www.gdca.org/healthandwelfare.htm
danehealth@gdca.org