By Carol Beuchat PhD
There's a paper just out about two autoimmune disorders, hypothyroidism and symmetrical onychomadesis, in Gordon and English Setters. Hypothyroidism is inadequate levels of thyroid hormone in the body, which can often be managed with appropriate treatment. Symmetrical onychomadesis (SO) results in the loss of the nails over the course of a few months. In some cases the nails grow back but in others euthanasia is the result. Obviously, both disorders are better avoided.
The study is easy enough to read and I've put a link to the pdf download below so you can read it yourself.
But it presents an opportunity to address the widely-believed notion that genetic disorders in dogs can be eliminated simply by getting rid of the offending genes. The argument is that inbreeding can be used as a tool to expose recessive mutations, and affected and carrier dogs can simply be eliminated from the population. It is true that breeding related dogs will unmask hidden recessives. Unfortunately, it is not true that breeding healthy dogs is a simple matter of eliminating all of the bad genes from the gene pool.
Just from an understanding of basic genetics, there are some obvious reasons why this won't work. First of all, you can't select for or against genes a la carte. Each dog comes pre-packaged with a collection of genes, and if you select against some specific gene it carries, you are also selecting against all of the genes it carries. And to complicate things, there is something called genetic "linkage", in which groups of genes tend to get inherited together as a block. If you select for a particular gene, the linked genes get selected for too. If some of the genes in a block are "good" genes, and some are "bad" genes, there is going to be some serious frustration. And if linkage wasn't itself a big enough problem, inbreeding tends to increase the size of the blocks of linked genes, something called "linkage disequilibrium". So while inbreeding might expose those recessive mutations, the resulting linkage disequilibrium is likely to frustrate your attempts to purge the mutations without collateral damage to the gene pool.
There is usually no dissuading the advocates of mutation-purging as the strategy for improving health in dogs. So, this study is the perfect illustration of the problem. They looked at the genes in the immune system, called "dog leukocyte antigens" (DLA), and found that a particular DLA haplotype was associated with both autoimmune diseases, hypothyroidism and SO. But most inconveniently, this DLA haplotype, which was associated with SO in Gordon Setters, was protective for hypothyroidism; a dog could be hypothyroid, or suffer from SO, but usually not both. Clearly, this DLA haplotype is associated with both of these disorders (one positively and one negatively), but there must be other genes involved that are yet to be identified. They might be closely linked genes, or genes that interact in a particular way, or who-knows-what? But the suggestion from this study is that selecting against the DLA haplotype that is associated with SO could increase the risk of hypothyroidism, trading one autoimmune disorder for another.
They conclude with advice to breeders:
"It is important to state that selection of breeding animals supported by DLA haplotypes/alleles could only be used if taking into account also potential associations to other autoimmune disorders in a dog breed as well as how it influence (sic) the genetic variation in the breed".
Of course, we know nearly nothing about associations of DLA haplotypes with specific autoimmune disorders, so fixing autoimmune disorders through selection of DLAs is likely to be a lot harder than putting Humpty Dumpty back together again.
So what are breeders to do? Good question. But for Gordon Setter breeders, trying to get rid of the offending gene is clearly not the way out of this one. If your breed is not already struggling with autoimmune disorders, keep it that way. Protect the genes in your gene pool that are playing well together, and manage the problem genes instead of trying to eliminate them. The immune system is extremely complex and we are far from understanding everything about how it works. If we break it, making it right again isn't going to be easy because we really don't know how to fix it.
Ziener ML, S Dahlgren, SI Thoresen, and F Lingaas. 2015. Genetics and epidemiology of hypothyroidism and symmetrical onychomadesis in the Gordon setter and English setter. Canine genetics and epidemiology 2:12. DOI 10.1186/s40575-015-0025-6. Download pdf.
There's a paper just out about two autoimmune disorders, hypothyroidism and symmetrical onychomadesis, in Gordon and English Setters. Hypothyroidism is inadequate levels of thyroid hormone in the body, which can often be managed with appropriate treatment. Symmetrical onychomadesis (SO) results in the loss of the nails over the course of a few months. In some cases the nails grow back but in others euthanasia is the result. Obviously, both disorders are better avoided.
The study is easy enough to read and I've put a link to the pdf download below so you can read it yourself.
But it presents an opportunity to address the widely-believed notion that genetic disorders in dogs can be eliminated simply by getting rid of the offending genes. The argument is that inbreeding can be used as a tool to expose recessive mutations, and affected and carrier dogs can simply be eliminated from the population. It is true that breeding related dogs will unmask hidden recessives. Unfortunately, it is not true that breeding healthy dogs is a simple matter of eliminating all of the bad genes from the gene pool.
Just from an understanding of basic genetics, there are some obvious reasons why this won't work. First of all, you can't select for or against genes a la carte. Each dog comes pre-packaged with a collection of genes, and if you select against some specific gene it carries, you are also selecting against all of the genes it carries. And to complicate things, there is something called genetic "linkage", in which groups of genes tend to get inherited together as a block. If you select for a particular gene, the linked genes get selected for too. If some of the genes in a block are "good" genes, and some are "bad" genes, there is going to be some serious frustration. And if linkage wasn't itself a big enough problem, inbreeding tends to increase the size of the blocks of linked genes, something called "linkage disequilibrium". So while inbreeding might expose those recessive mutations, the resulting linkage disequilibrium is likely to frustrate your attempts to purge the mutations without collateral damage to the gene pool.
There is usually no dissuading the advocates of mutation-purging as the strategy for improving health in dogs. So, this study is the perfect illustration of the problem. They looked at the genes in the immune system, called "dog leukocyte antigens" (DLA), and found that a particular DLA haplotype was associated with both autoimmune diseases, hypothyroidism and SO. But most inconveniently, this DLA haplotype, which was associated with SO in Gordon Setters, was protective for hypothyroidism; a dog could be hypothyroid, or suffer from SO, but usually not both. Clearly, this DLA haplotype is associated with both of these disorders (one positively and one negatively), but there must be other genes involved that are yet to be identified. They might be closely linked genes, or genes that interact in a particular way, or who-knows-what? But the suggestion from this study is that selecting against the DLA haplotype that is associated with SO could increase the risk of hypothyroidism, trading one autoimmune disorder for another.
They conclude with advice to breeders:
"It is important to state that selection of breeding animals supported by DLA haplotypes/alleles could only be used if taking into account also potential associations to other autoimmune disorders in a dog breed as well as how it influence (sic) the genetic variation in the breed".
Of course, we know nearly nothing about associations of DLA haplotypes with specific autoimmune disorders, so fixing autoimmune disorders through selection of DLAs is likely to be a lot harder than putting Humpty Dumpty back together again.
So what are breeders to do? Good question. But for Gordon Setter breeders, trying to get rid of the offending gene is clearly not the way out of this one. If your breed is not already struggling with autoimmune disorders, keep it that way. Protect the genes in your gene pool that are playing well together, and manage the problem genes instead of trying to eliminate them. The immune system is extremely complex and we are far from understanding everything about how it works. If we break it, making it right again isn't going to be easy because we really don't know how to fix it.
Ziener ML, S Dahlgren, SI Thoresen, and F Lingaas. 2015. Genetics and epidemiology of hypothyroidism and symmetrical onychomadesis in the Gordon setter and English setter. Canine genetics and epidemiology 2:12. DOI 10.1186/s40575-015-0025-6. Download pdf.
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