I’m going to keep this real simple, so everybody, including me, gets it. To make it easier on myself, I’ve divided this information into sections, so look for more stuff in the coming weeks as I get it done. I’m thinking maybe two more articles in the series. If I get a wild hair I’ll likely get it done faster.

PART I: MHC, DLA, WTF?

Right, so what is the MHC, and why should we care? MHC stands for Major Histocompatibility Complex. Keep that term in mind, because if you use it you’ll sound smart. The MHC is, basically, the gene family that makes up the immune system. In people these genes are called Human Leukocyte Antigens, or HLA genes. In dogs, surprisingly enough, they are called Dog Leukocyte Antigens, or DLA genes. Can you guess what they’re called in cats? CLA genes? Wrong! It’s FLA genes. DLA and MHC as terms are pretty interchangeable.

The MHC is comprised of three regions, which are called Class I, Class II, and Class III. MHC genes regulate the immune response, and help the body to identify foreign invaders (viruses, bacteria, very small aliens), and to recognize the body’s own cells (auto-immunity.) Stuff (antigens) enters the body, and the DLA genes pick it up and wave it around, saying “Hey, look at this! You know what this is! Killitkillitkillit!” Or, in the case of auto-immunity, “Hey, look at this! This belongs here, leave it the hell alone!” The MHC will determine the response to infections, vaccinations, and development of auto-immune disease. It cleans up all the minor little goofs that go on in the body, like messed up cells. The MHC is really, really, really, really important.

Dog have several genes in their Class I region, one of which is very diverse, with lots of alleles. They have three haplotypes, or groups of alleles, in their Class II region, which are called DLA-DRB1, DLA-DQA1 and DLA-DQB1. Each one of these haplotypes is polymorphic, having many variable genes. There are more than two hundred different alleles that can be present in each Class II haplotype, and they find more of them all the time. Class III is much less well studied. 

You are probably familiar with the MHC, even if you don’t know it, because these are the genes that are checked for compatibility in organ transplants. In a human population, one that is a melting pot and not a specific ethnic or otherwise somewhat isolated group, no individuals, except for twins, will have exactly the same genes in their MHC. That is why siblings or parents or clones are preferred for organ transplants, because otherwise, the immune system considers the transplant an invader. Think about how hard it is, and how long it takes, to find a matching donor. That is because the human MHC is incredibly diverse.

Antigens are everywhere, tons of them, all different kinds, so a very diverse immune system is going to be advantageous. In a given population with lots of diversity in the MHC, there is always going to be someone who is immune to a particular microbe. Like when there’s an epidemic, some people won’t die, because they’ve got the right genes. At that moment in time, they have the evolutionary advantage, and their genes will be perpetuated. The MHC actually evolves to fit the local antigens, and vice versa. This is called host-pathogen coevolution, we’ll talk about it a little bit later in regards to natural species (dogs are not natural!) and it makes the science girl in me go “Squee!”.

There are many studies proving associations (risk factors) for auto-immune disease like thyroid problems and diabetes, with certain genes in the MHC. For instance, Gordon setters have a haplotype that is associated with SLO, symmetrical lupoid onychodystrophy, an immune mediated disease which affects the dog’s toenails. Dogs which had two copies of the haplotype (homozygous) were at even higher risk for the disease than the dogs with only one copy. Even more interesting, there is another haplotype, which the diseased dogs didn’t have and which was quite rare, that is associated with protection from developing the disease! Dogs that had both the protective allele, and the disease-associated allele (heterozygous) didn’t have the disease. Cool, eh? What sucks for the Gordon Setter is that the haplotype associated with higher risk of disease is super common, forty-three percent of the dogs in the study had it. Bummer.

This is why scientists just looooove purebred dogs for studying the MHC. Because breeds are basically groups of interrelated individuals, they have a limited number of DLA genes, unlike humans, which have loads of HLA genes, so it is easier to associate disease with specific haplotypes. Dog breeds each typically have four or five different haplotypes that occur frequently in the population. Some breeds have quite a large number of different haplotypes, like Salukis, and some have very, very few. Like in this study, where forty percent of the dogs that were gene typed were homozygous at DLA-DRB1, fifty-two percent at DLA-DQA1, and forty-four percent at DLA-DQB1. That’s out of three-hundred and sixty dogs. These haplotypes are inherited just like any other genes, one copy from mom, one from dad. So if a dog inherits the same gene from both mom and dad, they will be homozygous. Populations that have very few founders, or that went through a bottleneck where only a few representatives lived, will have less variability in their MHC. Purebred dogs are closed populations, descended from few, sometime very few, individuals, and many breeds have gone through one or more bottlenecks. So, purebred dogs have poor DLA gene diversity within breeds.

But wait, you say, didn’t you just tell us that it’s better to have a very diverse MHC? That individuals that are diverse are actually better at countering all the viruses and bacteria and nasty stuff in the environment? That homozygous individuals with less diversity are more likely to have auto-immune problems? Aren’t immune system malfunctions like allergies and food intolerances and cancer pretty common in dogs?

Yes. Yes, yes, yes.

Whoa, you say, are you shitting me? Cancer? You betcha. Cancer cells are normal cells gone awry. When the good cells go bad, the antigens on their surface, which tell the MHC what they are (part of the body), change. That changed antigen tells the immune system, “Hey! Clean up on aisle one!” But what if the immune system doesn’t have a gene that recognizes that antigen, hmmm? Didn’t I say the MHC is really, really, really, really important?

This is why closed registries mean that purebred dogs are going straight to hell in a handbasket. Some are on the express handbasket, some on the slow stop and smell the roses handbasket, but as long as registries remain closed, the only destination for that handbasket is Hell.


To sum up:

The Major Histocompatibility Complex is the genetic basis for the immune system.

The immune system protects us from antigens, like viruses and bacteria, and cleans up biological screw ups, like cancer cells, and recognizes our own tissues so it doesn’t attack them by mistake, and determines response to vaccines and stuff like that.

Diversity in the MHC is good and helps the individual to respond to antigens. There are lots of antigens, so having lots of different DLA genes is advantageous.

Specific DLA genes are associated with risk for certain diseases. Other genes may be protective against diseases.

Dogs have a lot of different DLA haplotypes across the species, which is good.

Individual breeds tend to have only a few haplotypes, which is bad.

Closed registries restrict breeds to only the haplotypes they already have. They cannot shop around for new ones, even if the ones they have are kind of screwed up, or very widespread throughout the breed.

Closed registries + restricted number of DLA genes = handbasket to Hell.

Join us next time when I talk about how the MHC would adapt and change in an open population, why inbred Cheetahs are not the equivalent of inbred dogs, how modern breeding practices actually put the dog into the handbasket, and how judicious use of science can help the dog get out!


Read part II here.