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Inbreeding and the immune system: unintended consequences

3/3/2017

 
By Carol Beuchat PhD
Without the immune system, we would be vulnerable to infection by bacteria, viruses, fungi, and parasites. Your body needs to recognize the foreign invader and mount an appropriate response to eliminate it before it does damage. There are zillions of kinds of potentially dangerous beasties out there, so the immune system is necessarily very complex. The immune system must also be able to tell the difference between invaders and your own tissue; failure to do this results in autoimmune disorders. Even cancer cells are targeted by the immune system.

​We're going to talk about the relationship between the inbreeding and the immune system in dogs. Just to make sure you appreciate the complexity of your body's defense system, take a few minutes to watch this little video. You don't need to remember any of this; just notice the number of moving parts and how intricately they are connected.


No doubt about it, your body's defense system is extremely complicated, and all of its magic depends on exceptionally high diversity in the genes that run it. 
One of the consequences of inbreeding and loss of genetic diversity in purebred dogs is decreased diversity in the genes of the immune system. This has lead to weaker immune systems and higher rates of autoimmune disorders.  
To get an idea of how much variation there is in the diversity of immune system genes among breeds of dogs, I've compiled the data for a number of breeds. The genes tend to occur in sets called "haplotypes", and there are two main classes of these, DLA Class I and DLA Class II. (DLA stands for "dog leukocyte antigen", just a fancy name for these particular immune system genes.)
You can see that the breeds with the highest number of haplotypes are the Standard Poodle and the Havanese, with about 40 versions of DLA Class I haplotypes and roughly 30 of DLA Class II. At the other end of the graph are several breeds that have only about 10 of each class of haplotypes (Doberman, Flatcoated Retriever, Black Russian Terrier, and Alaskan Klee Kai). In terms of total diversity (Class I + Class II), the number of haplotypes for these breeds ranges from about 70 (40 + 30) to as few as about 20 (10 + 10). 

(Remember, all of these variations are in the population but not in a single animal.)
Picture
DLA haplotype data from N Pedersen, UC Davis Veterinary Genetics Laboratory.
 
When you're making breeding decisions, you probably don't think much about the genes of the immune system. But there is good evidence that inbreeding and loss of genetic diversity take a toll on DLA diversity. Breed populations with higher levels of inbreeding like the Doberman and Flatcoat have fewer DLA haplotypes, which should compromise the function of the immune system.
 
Picture
Inbreeding coefficients from Dreger et al 2016.

We know that inbreeding produces homozygosity, and this in turn increases the expression of genetic disorders caused by recessive mutations. We know also that homozygosity causes something called inbreeding depression, which is manifested as lower fertility, smaller litter sizes and higher puppy mortality, shorter lifespan, and many other detrimental effects. But inbreeding and loss of genetic diversity also affects how well the immune system does its job. 
Geneticists talk about the importance of genetic diversity for maintaining a healthy gene pool and reducing the incidence of genetic disorders in dogs. We could eliminate every mutation in a breed but this would not produce "healthy" dogs if the immune system has been compromised. Even the breeds with the "best" DLA diversity (Standard Poodles and Havanese) have only a fraction of the diversity present in the ancestral dog, and they have their share of allergies, skin disorders, and cancer. 
The bottom line is that breeders need to protect the DLA diversity that remains in their breed, and as they contemplate breeding strategies to improve overall genetic diversity, they should specifically consider DLA diversity as well.

REFERENCES

Dreger DL, M Rimbault, BW Davis, A Bhatnagar, HG Parker, & EA Ostrander. 2016. Whole genome sequence, SNP chips and pedigree structure: building demographic profiles in domestic dog breeds to optimize genetic trait mapping. Disease Models & Mechanisms 9: 1445-1460. doi:  10.1242/dmm.027037


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