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More on "Simple strategies to reduce genetic disorders in dogs"

12/30/2018

 
By Carol Beuchat PhD

In a previous post, I showed how inbreeding and strong selection increase the risk of genetic disease (via increased expression of deleterious mutations) and diminish overall health (via inbreeding depression). I also explained how we could improve health and reduce the risk of genetic disorders by making some simple changes in the way we breed. I showed why these things happen using a simple path diagram.

(If you didn't read my previous post, you should do that first and return here: Simple strategies to reduce genetic disorders in dogs)
There are other consequences of inbreeding that might be less familiar to the dog breeder but can ultimately be more important because they also feed into the same cycle of "inbreeding -----> genetic disease".
Below is  the figure from my previous blog post, to which I have added another loop (in green). (I have collapsed the loop that was to the left of health consequences and simply replaced it with the word "health".)

Once again we start with inbreeding in a population of dogs. Mating related dogs produces inbreeding, in which a puppy gets identical copies of an allele from both parents, increasing the fraction of genes that are homozygous. To here, we are following the same steps as we reviewed before.

At this point, we will add a new detail to our path diagram. The homozygosity produced by inbreeding might be scattered over the chromosomes, or it can be in blocks of adjacent genes on a chromosome. 

Blocks of homozygosity on the chromosomes are called "runs of homozygosity" (ROH), and they have two important properties.

a) the blocks of homozygous alleles tend to get longer and longer with inbreeding;

b) linkage disequilibrium increases with inbreeding.

We need to define "linkage disequilibrium". We usually think of inheritance as one of the two alleles at a loci that are passed on to a descendant by random chance. This is a simple and useful way to think about inheritance, but in reality it can be more complicated. In fact, the regions of homozygous loci that form runs of homozygosity tend to be inherited together as a block. This non-random inheritance at adjacent loci in a run of homozygosity is called "linkage disequilibrium". 

So, follow along using the chart below -

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​1) inbreeding produces homozygosity

2) "runs" of homozygosity (ROH) increase

3) linkage disequilibrium increases

4) deleterious mutations get trapped in blocks of homozygosity
In step 4, why do mutations get trapped in blocks of homozygosity? Inbreeding removes genetic variation. To breed "away" from a deleterious allele, the alternative (i.e., normal) allele must replace it. When there is inbreeding to increase homozygosity for genes for type, as well as selection to reduce genetic variation, the normal allele can become rare. Homozygosity of the mutation within ROHs will increase. Now it becomes difficult or impossible to remove or even avoid a mutation, and over time the number of mutations that are "trapped" increases.
5) mutation trapping increases the "genetic load", the number of deleterious alleles in the gene pool

6) the expression of recessive mutations increases

This path now joins the main pathway that we discussed previously.
​You can see that the breeder is now trapped. We are trying to improve type and reduce genetic diseases at the same time as we lose the genetic variation needed for improvement. We are also making it more and more difficult or even impossible to breed away from genetic issues because of linkage disequilibrium. Of course, we continue to select strongly for type, which insures that the blocks containing those genes remain homozygous. The mutations in these blocks are trapped forever.

Now this path feeds back into the larger pathway, where we remove affected dogs or entire lines in an effort to get rid of the genes causing problems. But this reduces the size of the gene pool and throws out valuable genetic variation.

​And so it goes, round and round, the quality of the gene pool deteriorating a bit more with every generation.

This is a real pickle if you're a breeder. What all this means is that the more effort you put into breeding for improved health using the usual strategies of inbreeding and strong selection, the bigger the problem gets. This is where we are.

How do we fix this?

If we breed a very inbred dog to one that is not closely related, we can reduce homozygosity (inbreeding) in the puppies. Less inbreeding means smaller blocks of homozygosity, so linkage disequilibrium is reduced. Mutations and other unwanted genes that were trapped in runs of homozygosity are now "set free", so you can breed away from them. There is also new variation that you can make use for improvement of phenotype, so selection will be more effective.

Note that the most useful dogs for an outcross will likely be the ones that are not what you would choose to breed to on the basis of phenotype. The dogs you gravitate to with good type are likely to have all the same ROH you are battling with already, and there will be little to gain. Paradoxically, dogs with more phenotypic variation, especially as it varies away from the extremes in type, will have the most to offer you in terms of escaping from the feedback loop illustrated above. You probably won't get stunning puppies out of a breeding with a dog with mediocre type, but you will escape the loop that is strangling your breeding program and sending purebred dogs towards the cliff.
I can hear a bunch of people complaining that outcrossing will introduce new mutations to your line. Yep, it might. You would probably know about the dominant mutations in a dog you're breeding to, so the new mutations are likely to be recessive. Look again at the feedback loop and you will see that those recessive mutations are completely harmless as long as you don't breed dogs together that have the same ones. And if you keep inbreeding low, you can eliminate those mutations through selection because they aren't trapped in those blocks of homozygosity. Also put your foot down on popular sires; the last thing you want is to produce dozens of puppies that each carry half the mutations found in the favorite dog. Remember, inbreeding is how we ended up with the current problem in the first place. The solution is simple: don't put two copies of the same mutation together in a puppy.
You can fix this problem. You can eliminate health problems in a generation. You can use selection more efficiently. You can add the variation necessary to produce better dogs than you have now. Lives will get longer. Vet bills will go down. Breeding will get easier. Litter sizes will increase. The health and welfare of dogs will improve.
The secret to improving the health of dogs is not more DNA tests, but sound genetic management. We know what is causing the high burden of genetic disorders in dogs, and we know how to prevent this. Trying to eliminate problems by chasing down pesky mutations will not get us out of the feedback loop that is causing the problem. Breeding ever more selectively won't help either. These things make the problem worse.

The solution is genetic management. Understand how the problems are created. Understand the critical importance of genetic variation and reduced inbreeding for improving health. And breed in a way that will be sustainable into the future.
If you learned something useful from this article, there is much more information out there that will improve the health of dogs and make your breeding program more successful. The best way to increase your knowledge and understanding is through one of the courses offered through ICB. These courses are specifically designed for breeders and they truly are the best way for breeders to learn what they need to know to improve the health and well-being of dogs.

The next course is Managing Genetics for the Future and starts 7 January 2019. You can learn more about it and register here -

​https://www.instituteofcaninebiology.org/managing_genetics.html

I hope to see you there!
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Simple strategies to reduce genetic disorders in dogs

12/29/2018

 
By Carol Beuchat PhD

Over the last few decades, the number of genetic disorders in dogs has been increasing at an alarming rate. This is despite the diligent efforts of breeders to breed healthy dogs. Why is this happening?

I have created a very basic flow chart to illustrate how a breeding strategy to reduce genetic disorders in a population will actually have the opposite effect. I will go through each of the steps in the process, and you can follow along on the picture.
1) Let's start with a population of dogs in a closed gene pool like the one in the left circle below. Because all the dogs in the population come from a small number of founders, they are all related. Breeding two together is likely to produce offspring that are homozygous for some loci; that is, they inherit two copies of an allele that originated in a common ancestor of both parents. In the flow chart, the inbreeding step results on average in an increase in homozygosity in the offspring.
​
Picture

2) Every dog carries dozens or even hundreds of recessive mutations. For the most part, these cause no problems if there is only a single copy of the mutation and the other allele at the locus is normal. But if two copies of the mutation are inherited, there is no copy of the normal allele. This is why inbreeding, which results in homozygosity. increases the expression of these recessive mutations.

3) Homozygosity also has more general detrimental effects on function such as reduced fertility, smaller litters, higher puppy mortality, shorter lifespan, etc., which we collectively call "inbreeding depression". Inbreeding also increases the incidence of polygenic disorders such cancer, epilepsy, immune system disorders, heart and kidney issues, and others. 
4) Dogs with genetic disorders are usually removed from the breeding population.

5) Removing dogs from the breeding population reduces the size of the gene pool.

6) Smaller gene pools have less genetic diversity.

7) With less genetic variation in the population, the genetic differences among individuals are reduced and their similarity and relatedness increases.

​8) Breeding related animals is inbreeding, so once again this step results in an increase in homozygosity.
From here, we now have a negative feedback loop that goes back to the top of the list of steps. Again, the increased homozygosity increases inbreeding depression, the risk of cancer, epilepsy, and other polygenic disorders, and the expression of recessive mutations.

The result of this negative feedback loop is the steady deterioration in health of the population over the generations unless there is appropriate intervention.
Let's have a look at the cycle for the population of dogs in the circle on the right in the illustration.

a) Breeders are very selective about which dogs are used for breeding. In general, about 25% of the purebred puppies produced are bred, and typically this is only one or two puppies per litter.

b) Of course, this means that 75% of the puppies are not bred. Removing them and any unique genes they may carry from the breeding population reduces the size of the gene pool.

c) Smaller gene pools have less genetic diversity.

d) If there is less genetic diversity, the dogs in the population are more similar to each other genetically.

e) Breeding dogs that are similar genetically will produce homozygosity in the offspring.

f) Homozygosity increases the expression of deleterious mutations.

Ultimately, the path feeds into the steps we have already described that form a negative feedback loop that increases the incidence of genetic disease.
The goal of selective breeding is to produce quality dogs. The two breeding strategies we have just described, breeding of related dogs (inbreeding) and breeding "the best to the best", do not result in improvement except in the short term. In the long term, the loss of genetic diversity limits the possibility of genetic improvement because the population has lost the genetic variation needed for selection. Inbreeding depression and increased incidence of genetic disease reduce the quality of the breeding stock, and improvement - or just maintaining quality - becomes more and more difficult. Without intervention, animal populations bred this way will go extinct.
If you understand the downstream consequences of breeding decisions, which are depicted as steps in these flow charts, you can prevent this cycle of genetic deterioration. For example, the simplest action to take is to be less restrictive about which animals are bred. Breeding 50% instead of 25% of the puppies produced will reduced the depletion of the gene pool. Breeding dogs that are less closely related will reduce the risk of producing genetic disorders in the puppies, and it will also reduce inbreeding depression. Replacing genes lost from a population through outcrosses to another population (i.e., through a plan of rotation breeding) or introduction via a cross-breeding program will broaden the gene pool and mitigate the negative effects of selective breeding.

DNA testing is a valuable tool but not the holy grail. By itself, it will not result in healthy dogs. Ultimately, to improve the health of the purebred dog we need to understand basic population genetics and follow a sound strategy for genetic management. Solving the problem requires understanding the cause and how some simple changes in the way we breed can dramatically improve the quality of the dogs we produce.
​
Continue to read Part 2 of this article:
"​MORE ON "Simple strategies to reduce genetic disorders in dogs"
​

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​

Celebrating the Preservation Breeders!

12/24/2018

 
By Carol Beuchat PhD
There are more than 1,000 known breeds of dogs, only a few hundred of which are "recognized" by a kennel club. By any measure, this is a spectacular level of structural, physiological, and behavioral diversity to see in a single species, and we owe a large measure of the development of human civilization to the dogs that have helped along the way.
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There is growing awareness now that many of these breeds are becoming rare and run the risk of disappearing entirely. The UK Kennel Club recognized this possibility a few years ago and created a list of native breeds that are vulnerable to extinction because of declining numbers. In some breeds, the numbers haven't moved much or continue to decline, but in others the heightened visibility has resulted in an increase in the number of puppies produced.

The Dandie Dinmont Terrier is one of the breeds on the vulnerable list, with numbers produced per year hovering between about 80 and 150 per year since 2010. So the birth of a litter of 5 adorable little pups just in time for the holidays is cause for celebration and noteworthy enough to make the news.
​
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Also celebrating are the folks at the Mongolian Bankhar Dog Project. While all is bleak and frigid on the Mongolian plateau, they are welcoming the arrival of 11 new puppies that will be placed in about 2 months with one of Mongolia's nomadic herders. Each will puppy be introduced to the livestock, grow up as a hoof-less member of the herd, and serve as their protector for the next decade or more. The Bankhar Project is bringing these dogs back from the brink of extinction by replacing guns with these traditional Mongolian livestock guarding dogs, allowing the herders to coexist peacefully with the snow leopard, wolves, and other native predators. By the way, that whelping box is not in a cozy abode in the middle of the spare room. It's a hut outside and it's bitter cold. These pups are coming into the world as they have for thousands of years, ready for the weather and with no expectation of napping on the sofa. I haven't verified this yet, but I'm betting that the "fog" you see puffing in the video is the condensation of the warm breath coming from behind the video camera.


​Also in the frozen north, the Norwegian Lundehund Club is readying for the production of the first backcross generation in their breeding program to save the Lundehund from extinction. The dam is Lundhund x Buhund cross and the sire is a Lundehund. The F1 dogs were healthy and very much resembled Lundehunds, retaining almost all of the unique anatomical features of the breed (polydactyly, ability to close the ears, extreme flexibility). The progeny of the backcross should produce pups that are even closer to breed type.

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We celebrate these preservation breeders! They are doing the hard work of making sure that the precious genes in the few remaining dogs of these breeds are preserved - duplicated, recombined, and packaged into a new generation of puppies that will carry the breed forward. Each tiny new nose, while appearing in the depths of winter, holds the promise of a brighter future for a breed.

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