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

Discussion in 'Dog Discussion' started by Institute of Canine Biology, Dec 31, 2018.

  1. 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 that are all homozygous.

    The 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 it fact 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 -

    [​IMG]


    1) inbreeding produces homozygosity

    2) this homozygosity can form "runs" of homozygosity (ROH)

    3) ROH increase the amount of linkage disequilibrium

    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 as well as selection to reduce genetic variation, the normal allele can become rare. Homozygosity of the mutation within ROH 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 main pathway in the middle that we discussed previously.

    You can see that we are also now trapped - trying to improve type and reduce genetic diseases at the same time as we lose the genetic variation needed for improvement and at the smake 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 we feed back into the larger pathway, in which 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.

    [​IMG]

    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, if you use the breeding 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 "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 effective 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 you wouldn't take into the ring, 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 put your foot down on popular sires; the last think 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. Don't put two copies of the same mutation together in a puppy. Problem solved.
    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 is not more DNA tests, but genetic management. We know what is causing the 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 will not get us out of the feedback loop that is contributing to the problem. What we are doing is making things worse.

    The solution is sound 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 improve your knowledge and understanding is through one of the courses offered through ICB. This isn't just a shameless plug for my own courses. I believe these courses 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!
    To learn more about the genetics of dogs, check out
    ICB's online courses

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