By Carol Beuchat PhD
The development of ever better and cheaper tools for the analysis of DNA have driven the development of a genetic testing industry that allows breeders to identify potential genetic defects before breeding. Through pedigree research and careful selection of tested animals, breeders can now produce a litter of puppies that is essentially guaranteed to be free of particular genetic disorders that plague the breed.
Breeders have adopted routine genetic testing with enthusiasm. Nevertheless, purebred dogs are in a bad spot. The list of genetic disorders is growing faster than the canine geneticists can identify the responsible genes, and the development of tests lags even further behind. DNA tests are powerful tools - they can reliably identify the presence of particular mutations, but it sure doesn’t feel like we’re winning this war. Is all of the effort and expense being invested in DNA analysis and testing actually improving the health of our dogs?
Every dog has many mutations, most of which we have no tests for - in fact, we don’t even know they exist unless they cause a problem in some dog. For recessive mutations, this means they can be passed harmlessly from generation to generation like any other allele, and as long as they don’t meet up with a second copy (to become homozygous) in a dog they have essentially no effect.
The genes that we can test for are only a tiny fraction of all of the mutations in a population or even a single dog. So the genes we test for are really just the bit of iceberg that sticks out above the water. The much larger list of defects we don’t know about is out of sight, out of mind. We can carefully navigate around the dangers we can see, but lurking below just out of sight is a much larger mass that can destroy the navigator who cuts it just a bit too close around the edge.
What do we actually accomplish with genetic testing? Most of the tests currently available are for specific recessive mutations. For these, breeding a carrier to a carrier has a 25% risk of producing an affected puppy. (Get out your Punnett square if you need a refresher.) So by testing, a breeder can completely eliminate the chance of producing a puppy with a particular disorder. The level of disease risk that a breeder is avoiding with this type of testing is 25% - one chance in four.
But what about all those other mutations we don’t know about? The DNA tests we’ve done tell us nothing about them, and they work the same way as any other recessive mutation - a puppy that gets two copies of a mutation will be homozygous and therefore “affected”. This is the part of the iceberg under water that we can’t see, and if we don’t properly navigate around it there could a serious consequence - a genetic disease. How can we avoid these mutations if we don’t even know what they are?
We need to navigate in a way that will minimize the risk of a puppy inheriting two copies of the same recessive mutation. Dogs that are closely related are more similar genetically than dogs that aren't, so the probability of producing offspring that inherit the same allele - good or bad - from both sides of the family is higher in dogs that are related. We can estimate the liklihood of a puppy inheriting two copies of an allele from an ancestor on both sides of the pedigree with a statistic called the “coefficient of inbreeding” (COI). A COI of 25% means that there is a 1-in-4 chance that a puppy will inherit identical copies of the same allele from both the sire and the dam. This is the same as the risk we talked about earlier that a breeder avoids with DNA testing.
So think about this. Breeders can reduce the possibility of puppies affected with a particular genetic disorder from 25% to 0% by means of a DNA test. But if a breeder diligently runs all available DNA tests to prevent known genetic disorders, then does a breeding with a COI 25%, all they have done is swap the risk of known problems for the equally high risk of problems from those unknown, unseen mutations lurking beneath the surface. DNA tests should definitely be used as a tool to prevent known genetic disorders in puppies.* But it is pointless to be reducing the risk of one genetic disorder with one hand (and paying for the test to do it), only to be increasing the risk with the other hand by pairing two dogs with a high liklihood of sharing recessive mutations because of their shared ancestry.
This is the road we’re on. Breeders run the available DNA tests to avoid known carriers, then line breed on that terrific dog a few generations back to double up on some of those genes - mutations included. Or breed two dogs with lots of common ancestors to get the “look” of that line, without considering the probability that even if the dogs are “health tested” for known mutations, they nevertheless can both carry some of those unknown mutations, and the more ancestry they share the greater the risk. It’s a self-defeating cycle - DNA testing to eliminate the possibility of homozygosity for a known mutation, do a breeding with a significant risk of producing homozygosity for unknown mutations, produce puppies that have a genetic disorder, commission a laboratory to identify the offending mutation and develop a test, then add this new silver bullet to the list of disorders you can avoid through testing in the next litter. The future of the DNA testing companies is assured.
Responsible breeders can test for genetic disorders, but they negate their own efforts if a breeding is likely to pair up unknown mutations. Breeding to eliminate one genetic problem while encouraging another isn’t the road to better health. This is genetic whack-a-mole, and it is potentially endless.
DNA tests will not improve the health of dogs if breeders don’t also adopt breeding strategies that will reduce the risk of producing a puppy that is homozygous for ANY mutation, not just the ones we know about. We will never solve the problem of genetic disorders caused by recessive mutations in dogs until we understand why these mutations become a problem in the first place. And when we understand that, it will be clear why DNA tests are not really necessary to avoid these problems. If breeders reduce the risk of producing puppies that are homozygous for these unknown mutations - and the COI tells us the magnitude of that risk for a particular breeding - the risk of problems from ALL mutations, including those we now test for will also be reduced. The lower the COI, the lower the risk.
What we need here isn’t genetic tests, it’s genetic management - breeding in a way that reduces the risk of all genetic disease to an acceptable level. Breeders can do this by using the information in a pedigree database to compute COI. (Again, we’re talking here only about recessive mutations, which cause disease only when homozygous.) Apparently a 25% risk is unacceptably high, because breeders are paying for tests to avoid this. Would 10% also be too high? What about 5%, or 1%? This might be different for every breeder, and perhaps even every breeding. COI is only a statistical probability, but it is far better than simply crossing fingers after a breeding decision is made, and hoping that the stars are aligned, the karma is good, and that two months down the road you will be cuddling a litter of cute, healthy puppies.
The qualities of “type” are fixed in a breed by reducing the variation in the population for the genes behind those traits. For these, consistency is produced by homozygosity. But homozygosity is also responsible for the high rates of genetic disorders in dogs caused by recessive mutations, so this is the crux of the problem. What we really need is a way to increase homozygosity of the genes we want, without also increasing the homozygosity of the ones we don’t. Is this possible? Can we have both type and health?
The short answer is yes. Breeders of other domestic animals have been doing this for decades. In fact, the breeders of guide and service dogs have been quietly doing it as well. With the right tools and appropriate expertise, breeders can improve type more efficiently than they are doing now, at the same time as they are also reducing genetic diseases. Several European kennel clubs are beginning to implement these techniques, and it is only a matter of time before they are in widespread use by dog breeders. But the longer it takes, the deeper the genetic hole we are digging for our dogs and the harder it will be to turn things around. It will take cooperation among groups of breeders, oversight by clubs or breed organizations, some specialized expertise, the motivation to take the bull by the horns and just do it. I am confident that, sooner or later, this will happen.
But in the meantime, breeders need to understand that DNA screening will prevent producing puppies afflicted with disorders that we can test for, but there is little gained by avoiding the part of the iceberg you can see only to be smashed by the larger, more dangerous part that you can’t. You can navigate far more safely if you use the coefficient of inbreeding to assess the risk of having an unfortunate encounter with mutations that cause genetic disease, both the ones you know about and the ones you don’t.
You can learn more about the coefficient on inbreeding and how you can be using it to reduce the risks of genetic disorders in your dogs, especially those that could be caused by unknown mutations, ICB's 4 week online course "COI Bootcamp".
The development of ever better and cheaper tools for the analysis of DNA have driven the development of a genetic testing industry that allows breeders to identify potential genetic defects before breeding. Through pedigree research and careful selection of tested animals, breeders can now produce a litter of puppies that is essentially guaranteed to be free of particular genetic disorders that plague the breed.
Breeders have adopted routine genetic testing with enthusiasm. Nevertheless, purebred dogs are in a bad spot. The list of genetic disorders is growing faster than the canine geneticists can identify the responsible genes, and the development of tests lags even further behind. DNA tests are powerful tools - they can reliably identify the presence of particular mutations, but it sure doesn’t feel like we’re winning this war. Is all of the effort and expense being invested in DNA analysis and testing actually improving the health of our dogs?
Every dog has many mutations, most of which we have no tests for - in fact, we don’t even know they exist unless they cause a problem in some dog. For recessive mutations, this means they can be passed harmlessly from generation to generation like any other allele, and as long as they don’t meet up with a second copy (to become homozygous) in a dog they have essentially no effect.
The genes that we can test for are only a tiny fraction of all of the mutations in a population or even a single dog. So the genes we test for are really just the bit of iceberg that sticks out above the water. The much larger list of defects we don’t know about is out of sight, out of mind. We can carefully navigate around the dangers we can see, but lurking below just out of sight is a much larger mass that can destroy the navigator who cuts it just a bit too close around the edge.
What do we actually accomplish with genetic testing? Most of the tests currently available are for specific recessive mutations. For these, breeding a carrier to a carrier has a 25% risk of producing an affected puppy. (Get out your Punnett square if you need a refresher.) So by testing, a breeder can completely eliminate the chance of producing a puppy with a particular disorder. The level of disease risk that a breeder is avoiding with this type of testing is 25% - one chance in four.
But what about all those other mutations we don’t know about? The DNA tests we’ve done tell us nothing about them, and they work the same way as any other recessive mutation - a puppy that gets two copies of a mutation will be homozygous and therefore “affected”. This is the part of the iceberg under water that we can’t see, and if we don’t properly navigate around it there could a serious consequence - a genetic disease. How can we avoid these mutations if we don’t even know what they are?
We need to navigate in a way that will minimize the risk of a puppy inheriting two copies of the same recessive mutation. Dogs that are closely related are more similar genetically than dogs that aren't, so the probability of producing offspring that inherit the same allele - good or bad - from both sides of the family is higher in dogs that are related. We can estimate the liklihood of a puppy inheriting two copies of an allele from an ancestor on both sides of the pedigree with a statistic called the “coefficient of inbreeding” (COI). A COI of 25% means that there is a 1-in-4 chance that a puppy will inherit identical copies of the same allele from both the sire and the dam. This is the same as the risk we talked about earlier that a breeder avoids with DNA testing.
So think about this. Breeders can reduce the possibility of puppies affected with a particular genetic disorder from 25% to 0% by means of a DNA test. But if a breeder diligently runs all available DNA tests to prevent known genetic disorders, then does a breeding with a COI 25%, all they have done is swap the risk of known problems for the equally high risk of problems from those unknown, unseen mutations lurking beneath the surface. DNA tests should definitely be used as a tool to prevent known genetic disorders in puppies.* But it is pointless to be reducing the risk of one genetic disorder with one hand (and paying for the test to do it), only to be increasing the risk with the other hand by pairing two dogs with a high liklihood of sharing recessive mutations because of their shared ancestry.
This is the road we’re on. Breeders run the available DNA tests to avoid known carriers, then line breed on that terrific dog a few generations back to double up on some of those genes - mutations included. Or breed two dogs with lots of common ancestors to get the “look” of that line, without considering the probability that even if the dogs are “health tested” for known mutations, they nevertheless can both carry some of those unknown mutations, and the more ancestry they share the greater the risk. It’s a self-defeating cycle - DNA testing to eliminate the possibility of homozygosity for a known mutation, do a breeding with a significant risk of producing homozygosity for unknown mutations, produce puppies that have a genetic disorder, commission a laboratory to identify the offending mutation and develop a test, then add this new silver bullet to the list of disorders you can avoid through testing in the next litter. The future of the DNA testing companies is assured.
Responsible breeders can test for genetic disorders, but they negate their own efforts if a breeding is likely to pair up unknown mutations. Breeding to eliminate one genetic problem while encouraging another isn’t the road to better health. This is genetic whack-a-mole, and it is potentially endless.
DNA tests will not improve the health of dogs if breeders don’t also adopt breeding strategies that will reduce the risk of producing a puppy that is homozygous for ANY mutation, not just the ones we know about. We will never solve the problem of genetic disorders caused by recessive mutations in dogs until we understand why these mutations become a problem in the first place. And when we understand that, it will be clear why DNA tests are not really necessary to avoid these problems. If breeders reduce the risk of producing puppies that are homozygous for these unknown mutations - and the COI tells us the magnitude of that risk for a particular breeding - the risk of problems from ALL mutations, including those we now test for will also be reduced. The lower the COI, the lower the risk.
What we need here isn’t genetic tests, it’s genetic management - breeding in a way that reduces the risk of all genetic disease to an acceptable level. Breeders can do this by using the information in a pedigree database to compute COI. (Again, we’re talking here only about recessive mutations, which cause disease only when homozygous.) Apparently a 25% risk is unacceptably high, because breeders are paying for tests to avoid this. Would 10% also be too high? What about 5%, or 1%? This might be different for every breeder, and perhaps even every breeding. COI is only a statistical probability, but it is far better than simply crossing fingers after a breeding decision is made, and hoping that the stars are aligned, the karma is good, and that two months down the road you will be cuddling a litter of cute, healthy puppies.
The qualities of “type” are fixed in a breed by reducing the variation in the population for the genes behind those traits. For these, consistency is produced by homozygosity. But homozygosity is also responsible for the high rates of genetic disorders in dogs caused by recessive mutations, so this is the crux of the problem. What we really need is a way to increase homozygosity of the genes we want, without also increasing the homozygosity of the ones we don’t. Is this possible? Can we have both type and health?
The short answer is yes. Breeders of other domestic animals have been doing this for decades. In fact, the breeders of guide and service dogs have been quietly doing it as well. With the right tools and appropriate expertise, breeders can improve type more efficiently than they are doing now, at the same time as they are also reducing genetic diseases. Several European kennel clubs are beginning to implement these techniques, and it is only a matter of time before they are in widespread use by dog breeders. But the longer it takes, the deeper the genetic hole we are digging for our dogs and the harder it will be to turn things around. It will take cooperation among groups of breeders, oversight by clubs or breed organizations, some specialized expertise, the motivation to take the bull by the horns and just do it. I am confident that, sooner or later, this will happen.
But in the meantime, breeders need to understand that DNA screening will prevent producing puppies afflicted with disorders that we can test for, but there is little gained by avoiding the part of the iceberg you can see only to be smashed by the larger, more dangerous part that you can’t. You can navigate far more safely if you use the coefficient of inbreeding to assess the risk of having an unfortunate encounter with mutations that cause genetic disease, both the ones you know about and the ones you don’t.
You can learn more about the coefficient on inbreeding and how you can be using it to reduce the risks of genetic disorders in your dogs, especially those that could be caused by unknown mutations, ICB's 4 week online course "COI Bootcamp".
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ADDENDUM
10 August 2014
Since I wrote this about two months ago, some people have decided that the point of this essay was to say that DNA testing is worthless. That is NOT what I am arguing here. If you do DNA testing then breed to the popular sire and produce a litter with a COI of 37%, you will have dodged a known bullet with DNA testing but signed up for a potential grab-bag of new problems in the litter (the high coefficient of inbreeding reflects the risk of producing a puppy with a disorder caused by a recessive allele) and in the larger population (through the addition of yet more copies of the mutations carried by the popular sire).
YES, DNA tests are an essential tool, but they must be used appropriately within the larger scheme of genetic management or you will simply trade a problem you know for one you don't.
* Yes, breeders should absolutely make use of the appropriate DNA tests available for their breed!
10 August 2014
Since I wrote this about two months ago, some people have decided that the point of this essay was to say that DNA testing is worthless. That is NOT what I am arguing here. If you do DNA testing then breed to the popular sire and produce a litter with a COI of 37%, you will have dodged a known bullet with DNA testing but signed up for a potential grab-bag of new problems in the litter (the high coefficient of inbreeding reflects the risk of producing a puppy with a disorder caused by a recessive allele) and in the larger population (through the addition of yet more copies of the mutations carried by the popular sire).
YES, DNA tests are an essential tool, but they must be used appropriately within the larger scheme of genetic management or you will simply trade a problem you know for one you don't.
* Yes, breeders should absolutely make use of the appropriate DNA tests available for their breed!
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