Editor's Note: From the archives. ShowSight Magazine , May 2016 Issue. Click to Subscribe.
We plan so carefully for each prospective litter. We study pedigrees. We evaluate structure and movement with an eye to what traits might be dominant or recessive in the stud dog and brood bitch. We look at temperament and the performance abilities of both sire and dam lines. But there remains one element that we may not be giving enough importance to—the Major Histocompatibility Complex, or MHC. I know—it’s a mouthful—but stay with me, because MHC truly is crucial to all purebred dogs.
Discoveries about the MHC and how it functions came out of the AIDS crisis. Researchers desperate to find a way to help those dying from that horrid disease began learning much more about the immune system than ever before. This knowledge not only helped in the fight against AIDS, it also began to reveal canine immune system secrets, too, many of which function the same way in both humans and dogs.
The Major Histocompatibility Complex explained
The Major Histocompatibility Complex is a group of genes clustered close together on a chromosome. Their work is absolutely essential to health, to the survival of humans, dogs and all mammals. The MHC governs the functioning of the immune system, enabling it to recognize the invasion of antigens (foreign objects) such as bacteria and viruses. The term “complex” means that this positioning as a cluster virtually guarantees that the genes will be inherited as a unit—called a haplotype. In humans the MHC genes cluster on chromosomes 8 and 6. In the case of dogs, scientists use the term, dog leukocyte antigen (or DLA) to describe the MHC genes, but it’s still the same gene cluster. However, in dogs, the MHC genes have a locus on chromosome 18 with one other haplotype on chromosome 12. All of the combinations of MHC genes are highly specific for each individual species.
The function of the MHC molecules is to sense antigens (such as viruses and bacteria) and recognize them as “foreign” proteins. They do this by binding protein fragments from the antigen onto the cell surface of that invader. Once there, the fragments are recognized by T-cells (a type of white blood cell) that destroy virus or bacteria infected cells and tumor cells.
MHC molecules make it quite difficult for pathogens to avoid an immune response, because they are both polygenic and polymorphic. If you remember, an allele is one of two or more
versions of a gene. An individual inherits two alleles for each gene, one from each parent. Therefore, a wide variety of combinations of MHC genes is possible. These alleles are highly polygenic. In fact, so many alleles exist that most individuals in a randomly breeding population will have unique combinations of MHC genes. In addition to being highly polygenic, MHC genes also have a high rate of mutation—they are polymorphic—because their diversity is so important to species survival. Only identical twins would have exactly the same set of MHC genes and molecules. This lack of similarity is why finding a matching donor for a patient needing an organ transplant becomes so difficult.
However, nature doesn’t provide such an excess of variability in genes without a good reason. Even though an individual has only two MHC haplotypes, the overall population of its species will have hundreds. Whenever a new plague appears—say, Ebola in humans or parvo in dogs—not all the individuals in a species will succumb. Some will survive and carry the resistance for that plague in robust, diversified MHC genes to pass on to their offspring. The individuals who had an inadequate MHC will have died, removing them from the breeding population. This survival set of MHC genes explains why only a small fraction of the millions of indigenous populations of the New World survived the arrival of Europeans. The native tribes lacked any history of coping with measles or small pox, so their MHC had never been challenged and no antibodies existed to protect them from those scourges. Only those lucky few whose MHC genes were robust and heterozygous were able to develop an adequate immune response to defeat the invading pathogen and live. Their high MHC mutation rate guaranteed that there would be generations to come of Native Americans with the ammunition needed to fight future plagues.
Similar canine plague disasters, such as distemper, can decimate a wolf or an African wild dog population too, but thanks to vibrant, diverse MHC haplotypes among those canines, some will survive this genetic bottleneck to continue the species. As an additional safeguard, the high mutation rate within the MHC genes will provide ever more diversity to protect enough individuals from plagues in the future to ensure species survival.
The rise of immune-mediated diseases in dogs
Across the wide range of scientific studies done on the subject of immune diseases in dogs, the data all point to an alarming rise in autoimmune and immune-mediated (abnormal activity of the body’s immune system) disease conditions. This is the “dark side” of the MHC genes. When the MHC lacks the variability in gene combinations to retain the vigor necessary to fight off antigens, a dog’s health suffers. Add to that the possible doubling up of harmful mutations in linebred dogs and the chances exist for inheriting MHC genes that can actually cause dangerous or even deadly genetic conditions.
In actuality, mixed-breed dogs and other species, including humans, have also experienced increases in immune-mediated diseases, so we have to take into consideration non-hereditary causes that all these groups may share. Then we must determine what additional factors might affect purebred dogs.
One non-hereditary factor is our modern emphasis on cleanliness. Of course, cleanliness is the best way to prevent infectious diseases, but that cleanliness also means that young immune systems, be it in children or puppies, do not experience enough minor threats to learn how to function properly. The result has been an increase in immune-mediated diseases. However, it is important to remember that these diseases had genetic underpinnings.
Environmental factors can play a large role in immune-mediated diseases, too. The world that we live in today is suffused with toxic chemicals and combinations thereof in our air, soil and water—with hormones and pharmaceuticals in our rivers and in our drinking water and with pollutants of all kinds in the air we breathe. This is not the world in which our grandparents lived. Many of these toxins have been proven to alter various bodily functions, including the immune system. Humans have rushed forward with technological advancements without giving proper consideration to the environmental consequences. We have only recently begun to assess and address those consequences.
One aspect of such technological advancement is vaccines. They have saved so many human and canine lives and remain a proven and invaluable tool against disease. But—and there is always a “but”, isn’t there?—overly aggressive use of vaccines can compromise immune function.
Autoimmune & immune-mediated diseases in dogs
An immune-mediated disorder occurs when the immune system does not function properly. An autoimmune disease occurs when the body’s immune system attacks its own cells. As with any genetic inheritance, an unfortunate combination of MHC genes can predispose an individual for disease. An autoimmune disease occurs when the immune cells do not recognize the MHC molecules of other cells and begin attacking its own body. In the over three dozen recognized autoimmune diseases, certain MHC genes have contributed to the diseased state. But autoimmune diseases are multifactorial—in other words, several factors go into the actual expression of the disease. First, because of the dog’s faulty MHC genetic makeup, he will be predisposed to develop the disease. Then this genetically predisposed dog must experience an environmental “trigger”. If he never experiences this trigger, he will never develop clinical symptoms of the disease even though he has the necessary genes to do so. A trigger can be any one event or a combination of events. Exposure to toxins, physical or mental stress, viruses, or even fluctuating hormones can serve as triggers.
The over-all canine gene pool probably contains as much MHC diversity as in any independently mating wild species. Humans, however, have divided that gene pool into exclusive sub-sets that we call “breeds” and have closed the stud books of these breeds so that no further outside genes may enter. Therefore, no breed can possibly have the full range of MHC alleles that are present in the entire species. This limiting factor becomes further exacerbated by breeding practices such as inbreeding (which includes line breeding) and the overuse of popular sires. Such restrictions of a breed’s gene pool have left it vulnerable to harmful MHC mutations that can cause multiple immune-mediated and autoimmune diseases.
For example, veterinary researchers know that certain breeds show a high vulnerability to one or more immune compromised diseases. Pancreatic insufficiency in German Shepherd Dogs, an autoimmune disease, has been traced to faulty MHC genes. Canine diabetes shares a link between inherited damaged MHC genes and clinical symptoms of the disease in Samoyeds, Cairn Terriers and Tibetan Terriers. One of the mutated alleles of the MHC is also associated with hypothyroidism in dogs and increases the susceptibility for endocrine immune-related diseases. Canine hypothyroidism is similar to Hashimoto’s Disease in humans, both linked to MHC genes. Doberman Pincers and Labrador Retrievers share a rare haplotype within their MHC genes that causes their version of hypothyroidism. Researchers have also found a clear MHC genetic component to canine thyroiditis in Doberman Pincers, Golden Retrievers, Borzoi, Giant Schnauzers, Akitas, Irish Setters, Old English Sheepdogs, Beagles, Great Danes and English Cockers. The instances of disease rise in closely linebred dogs. Related alleles of the MHC exist in dogs with autoimmune rheumatoid arthritis—the same alleles that are associated with susceptibility to RA in humans. Cancer and allergic dermatitis fall into the immune-mediated diseases, also, but are so widespread that they affect nearly all of the purebred breeds. Obviously, harmful mutations within the MHC of purebred dogs are equal opportunity destroyers, spreading their damage within breeds across the spectrum of sizes, groups or use.
That an abnormal MHC can cause a wide range of physical diseases is not difficult to accept, but here’s a whole new area of discovery—how the MHC can affect the brain. Researchers into human mental illnesses have recently learned that mutated alleles in the MHC of patients with schizophrenia and bi-polar disease greatly resemble each other in form and in their altered function. These genes normally destroy useless synapses in the brain, allowing for adaptive learning and removing “clutter”. The abnormal MHC versions destroy perfectly good, useful synapses, mostly in the frontal lobe of the brain where our cognitive ability resides as well as all that make us humans. [See side bar.] We share so many of our genes with dogs. Does this new discovery hint at a possible cause of Canine Dementia? Will veterinary researchers begin to look for these abnormal MHC genes in the brains of elderly dogs with symptoms of dementia to look for a biological, inheritable link? This is an intriguing new field of study that will be exciting to follow its developments.
It’s a given that we cannot shield ourselves or our dogs from all of the harmful toxins in our environment. We can feed them wholesome food without chemicals, avoid the toxic mix that traditional lawn care products contain, make sure their bedding is free of chemical taint, avoid over vaccinating and take great care with the flea and tick prevention products that we use on our dogs. But that’s not all.
The additional factor that breeders must consider in maintaining strong immune systems in their dogs is the Major Histocompatibility Complex. Genetic diversity becomes essential in producing dogs with robust immune systems, especially in light of those many environmental toxic exposures that today’s dogs confront. To achieve that diversity in the wild, animals will avoid or significantly limit the amount of inbreeding in their breeding choices as long as they have enough habitat to do so. I could not find any academic study on this subject in dogs, but numerous anecdotal accounts exist of bitches that refuse to mate with closely related stud dogs. Even a few stud dogs can be choosey about which bitches they service.
Remember that scientists use the term “inbreeding” for all line breeding and, as such, humans have practiced inbreeding on their domestic dogs for more than a century. Inbreeding works quite well with traits that can be observed and measured, so it does what breeders want—effectively “fixing” those traits that set breed type and are deemed desirable. On the other hand, inbreeding fails to work as well on complex traits or behaviors such as temperament, or performance drives. Even worse, inbreeding has led to the inadvertent loss of MHC diversity within purebred dogs. Add to this effect, the genetic bottlenecks due to the two world wars on European breeds, a loss of popularity (Terriers, for example), other drastic population-reducing events (distemper prior to a vaccine) and the extensive use of popular sires and the MHC diversity falls to a critical level.
The whole issue of “closed stud books” exacerbates the lack of heterozygosity within the MHC. Many of our purebred dogs are the result of a mixing of two or more breeds to create them. As the gene pool shrinks and the breed’s MHC vitality becomes compromised, it may well be time to infuse the purebred line with healthier MHC genes from one of those founding breeds. I can hear the outraged protests right now, but in the hands of skilled breeders, this move could help save some of our more threatened, immune-compromised breeds. Of course, the glacial speed at which the AKC moves would threaten the success of introducing outside breeding stock, because the powers that be would refuse to register the progeny. We can always hope that enough scientific evidence will soon exist to convince our registering body that this is a valid path to increased health and vigor in purebred dogs, because the alternative is simply too damaging.
One example of the result of an inadequate level of diversity was a resistance to the parvovirus vaccine in Rottweilers. Perhaps, this is because their MHC genes are incapable of recognizing the parvovirus antigens. Before the immune system can mount a response to an antigen, the antigen must first be broken into pieces inside its cell by histocompatibility molecules of the MHC. Then these bits of antigen are transported to the cell surface by the MHC genes where T-cells recognize them as foreign antigen and destroy the invader. In Rottweilers, the early parvo vaccines did not work, because the MHC genes did not recognize the parvo antigens. This recognition failure meant that those genes would not break up the antigen into pieces nor could they transport those bits of antigen to the cell surface. Therefore, the T-cells were prevented from doing their job. Fortunately, newer improved vaccines do protect them now, but that situation should have set off alarms for Rottweiler breeders that the breed had developed an inadequate immune system.
Using inbreeding coefficients to plan breedings
The over-use of popular sires has an especially pernicious effect on the MHC, earning them their moniker, “matadors”. A sire can have only two MHC haplotypes which is only a tiny fraction of the hundreds that exist in the canine genome. When a significant portion of a breed descends from one individual, those descendants will lack a robust MHC and will carry within them susceptibility to infectious disease and/or to an autoimmune disease. Although no way exists for a breeder to determine what haplotypes a sire has, there is a tool available help breeders make more informed decisions in their breeding programs. That tool is the coefficient of inbreeding, or COI. Scientists have discovered a strong correlation between the COI and the MHC heterozygosity. The COI measures how inbred an individual is. Animals with low COIs are less inbred and are more likely to have two different haplotypes, reducing the chances for disease and an impaired immune system.
Thankfully for all of us mathematically challenged, several pedigree programs are available that do all of the calculating for us. Here is a sampling of some of the programs:
Tenset: Originally designed for the breeding of zoo animals, a population that is especially prone to low genetic diversity, this program not only offers the COI but also gives calculations on “Gene Diversity” and “Founder Analysis”.
BreedMate: Gives the minimum and maximum generations in which an ancestor appears. Also gives the COI and the COR (coefficient of relationship)
Kintraks: Gives COI
ZooEasy: Another program from the breeders of zoo animals that gives the COI plus relationship percentages.
The inbreeding coefficient is expressed as a percentage value. A low level of inbreeding—such as 3%—reflects a good rate of heterozygosity in the MHC. Although there is no hard and fast rule, levels of 10% or more are considered to reflect too much homozygosity with the possibility of an
Adjacent to the inbreeding coefficient on a typical pedigree program readout will be two numbers that indicate the minimum number of generations in the dog’s pedigree. In brackets beside that number will be the average number of generations in the dog’s pedigree as currently available on the database. Therefore, having a “deep” pedigree with as many generations as possible will result in a more accurate calculation of the inbreeding coefficient.
Inbreeding depression is the term used to describe the reduced performance and viability (or robustness) in animals due to increased inbreeding which has lowered genetic variation. Generally, a dog’s reproductive fitness tends to be affected even more than its performance level. The indications of MHC homozygosity can be as subtle as a dog who is a “poor keeper”, failing to gain fit condition even when put on high quality food. The dog may be sickly, never coming down with anything really serious but catching one minor infection after another. Perhaps, the dog may be unable to rebound from an infection despite diligent treatment.
Below is a list of some of the common symptoms of inbreeding depression:
Reduced fertility both in litter size and sperm viability
Increased genetic disorders
Fluctuating facial asymmetry
Lower birth rate
Higher infant mortality
Depression on growth rate (height, weight and body mass index)
Smaller adult size
Loss of immune system function
Sometimes the symptoms of inbreeding depression become more obvious. Dogs prone to allergies or to severe reactions to their vaccinations can indicate inbreeding depression. Abnormally high numbers of individuals within a breed dying too young from cancer or from the various forms of cardiomyopathy point to inbreeding depression. Autoimmune diseases such as hypothyroidism, irritable bowel disease, systemic lupus, pemphigus or autoimmune liver disease and others that appear far too often in a breed all point to the strong possibility of MHC homozygosity.
What breeders can do
Breeders cannot know what MHC haplotypes their breeding stock possesses, but there are steps we can take to limit the risk of inbreeding depression. First and foremost, dogs that have a chronic autoimmune disease or severe allergies should never be bred. Some careful breeders do not allow either their stud dogs or their brood bitches to be bred until they are four to five years old, by which time most of the genetic problems have appeared. I hear the clamor of complaints already about reproductive problems in bitches if they aren’t bred earlier or the lack of building a siring reputation for their stud dog. Do you remember that the lack of reproductive fitness is one of the first signs of problems with the MHC? How serious are we going to be about returning to a healthy set of MHC genes to our breeding stock?
Weak, sickly or poor keepers must also be removed from the breeding program. If an animal develops one of the many autoimmune or immune-mediated diseases in middle age, do not use it again for breeding and do not use any of its siblings. Genetic disease has spread rapidly throughout a breed whenever siblings of an affected animal were used. Those siblings may not exhibit the clinical symptoms of the disease but they carry within them the alleles for susceptibility for that illness. Of course, if a genetic test is available for a disease that can identify carriers and non-carriers, then siblings tested as non-carriers can certainly be used for breeding.
When planning breedings, one of the key factors in choosing prospective mates should be the resulting inbreeding coefficient for the offspring. Keep it as low as possible while still maintaining the style of breed type you prefer to produce with the structure and movement appropriate for the breed. At all costs, avoid the over-use of any one dog in a pedigree, no matter how fantastic a specimen of the breed he is! Wait for several generations before going back into that particular line. We should be in this breeding endeavor for the long haul, shouldn’t we?
As breeders of purebred dogs, we aim for homozygosity of those breed traits like structure, movement, character. But where MHC is concerned, we definitely do not want homozygosity! We want as heterozygous a MHC as possible in order to prevent immune-mediated diseases in our dogs. Our efforts in this area need to take on a much higher priority. Now we have the knowledge to do so.
Until next time,