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Posts Tagged ‘Major Histocompatibility Complex’

San Nicolas island foxes (Urocyon littoralis) are thought to be least genetically diverse of all vertebrates. However, they have been able to maintain diversity and heterozygosity of their MHC haplotypes.

On my previous post entitled “Why is inbreeding bad?” I noted that one of the real issues with inbreeding is an impaired immune system as the result of losing diversity and heterozygosity in MHC/DLA haplotypes.

The MHC stands for the Major Histocompatibility Complex.  The MHC is cell surface molecule that is encoded by a relatively large gene family.  The MHC  molecule controls some of the actions of the leukocytes, “the white blood cells.”  As you might remember from your high school health class, leukocytes are the blood cells that act as police, taking out infectious diseases and foreign materials, including cancerous cells.

Possessing a greater diversity in MHC haplotypes allows the organism a heightened ability to control what leukocytes do when exposed to a variety of challenges to the immune system. Reduced diversity winds up restricting the immune system’s ability to fight disease.  Possessing a heterozygous MHC haplotypes also provides greater immune resistance than possessing homozygous MHC haplotypes.

In humans, the MHC is called the human leukocyte antigen system, usually abbreviated as HLA. In dogs, it is called the dog leukocyte antigen system, which is abbreviated at DLA.

One cannot look at an organism and tell what its MHC haplotypes are. It’s not like looking at fur or hair color.

And as a result, these haplotypes are very easily lost within a closed registry system.  Often, the haplotypes not lost entirely within a breed or strain, but because of the popular sire effect and continuous linebreeding  from “the best,” a huge percentage of the population in any one breed can be quite homozyous in its MHC haplotypes.

This has real health and welfare effects.  Autoimmune diseases are becoming more and more common in purebred dogs. Some breeds are highly susceptible to cancer, which might be partially the result of the decrease in MHC diversity of dogs within the closed registry system.  Allergies are also likely implicated to this reduction in MHC diversity and heterozygosity. The MHC also has some effect upon reproductive cells, which is one reason why certain breeds and strains have issues with fertility.

So what can be done?

Well, the easy answer is to do away with rigid closed registry systems and allow the different dog breeds to exist as very genetically diverse populations.

However, it is possible to breed for great MHC diversity in domestic dogs, even within the closed registry system.

To understand how this is possible, we will have to change species again.

Take the San Nicolas population of the island fox (Urocyon littoralis). This population is considered the least genetically variable of all sexually reproducing animals.

However, despite its lack of genetic diversity, this population of island fox has relatively diverse MHC haplotypes.

How does it do this?

Well, a study led by Andres Aguilar (2004)  found that the San Nicolas foxes likely were able to maintain their diverse MHC haplotypes through what is known as balancing selection. Balancing selection occurs when population keep multiple alleles actively maintained at frequencies that are higher than the mutation rate. It almost always happens within populations in better for an organism to be heterzygous for certain alleles than homozygous for them.

As we have seen with MHC haplotypes, it is better to be a heterzygote, so there is a strong selection pressure for the foxes to keep their MHC haplotypes diverse.

One way in which they likely do this is that they choose mates that have MHC haplotypes that are different from their own.

This might sound a little crazy, but even humans have innate mechanisms that are designed to keep our MHC haplotypes diverse.

There is a famous study in Switzerland that asked women which men were most attractive by smelling the shirts the men had slept in for two nights. Almost without exception, the women selected the men who had different MHC haplotypes from their own. The pheromones that are connected with sexual attraction in humans are also giving out genetic information such as what MHC haplotypes a potential mate might have.  And it’s so innate that women are able to obtain this information without understanding exactly what they are responding to.

It’s likely the same way in island foxes, which, like humans, typically reproduce within a bonded pair system. Foxes, like all wild dogs, are pretty particular about their mates. After all, the survival of their offspring is dependent upon having a partner that can provide for them.

Domestic dogs, for whatever reason, don’t seem to be as particular about their mates, and thus, it has been easier to selectively breed them.  Wolves and other wild dogs very rarely inbreed, but it is relatively easy to get dogs to inbreed and to do so for multiple generations.

And as a result, it has been easier for different breeds to lose their MHC haplotypes.

Further, it is not just the mere number of haplotypes a breed possesses. Heterozygosity has proven to be more important in determining immune health than just possessing a certain number of haplotypes.

That means that within an inbred population, there has to be some conscious effort to maintain both diversity and heterozygosity.

That is pretty hard to do when one is breeding for physical or behavioral traits– and the immune system genes cannot be readily ascertained.

Well, we do have a solution. Genoscoper currently offers an MHC II test, which would allow breeders to see what haplotypes their dogs posess and what to do with them. Mars Veterinary also offers a test that examines the MHC (among other things). It is called Optimal Selection from Wisdom Panel, and it was initially tested with breeders affiliated with the Dandie Dinmont Terrier Club of America (A NEW GENETIC BREEDING TOOL ON THE HORIZON (1)). Over a two year period, this selection tool has allowed Dandie Dinmont breeders to increase their litter sized from 2.75 to 4.0 puppies per litter. Dandie Dinmonts are a rare terrier breed that has issues with genetic diversity, and these tests could be a boon for breeds that have very small founding and effective populations.

So science now allows for us to do with domestic dogs what the San Nicolas island foxes were able to do on their own.  We can maintain relatively inbred populations and still keep the MHC haplotypes diverse and heterozygous.

However, here are some caveats:

First of all, virtually no dogs are bred without some eye to competition. Competition, whether in show or working trials, has a selection pressure of its own, and a breeder has to considered a wide variety of issues before choosing which dog to breed with which other dog. As I’ve noted before, MHC haplotypes are hard to see, so how many breeders would choose diversity and hetrozygosity of MHC haplotypes over the ability of the dog to win in the show ring or in the trial?  I would like to think that very few breeders would choose immune health over ribbons and titles, but that’s probably not the case.  Keeping the MHC diverse and heterozygous is a long-term project, and it requires a bit more dedication and discipline to breed for than physical or behavioral traits.

Further, breeders have to balance a wide variety of issues when selecting which dogs to breed, and MHC haplotype diversity alone should not be the sole criteria.  Other issues with temperament and hereditary diseases have to be considered in light of the MHC.

Finally, many of these breeds have either entirely lost MHC haplotypes or certain haplotypes are very rare within the breed.

You cannot do DIY balancing selection when you don’t have the haplotypes in the first place.

Even if we might have these tools, one should keep in mind that it is much more cost effective and easier to try to maintain genetic diversity within breeds and strains in the first place. It makes much more sense to keep breed registries more open and then operate selective breeding principles within much more diverse populations.  Breeding within much more diverse populations requires some understanding of how different traits are inherited, but one can readily learn these skills. It is not rocket science, but one can figure it out. If people living thousands of years ago0–before there was even a Mendelian theory of inheritance– were able to produce so many different types of dogs, then we surely can.

DIY balancing selection can be a tool within conservation genetics, but I think it has to be paired with a fundamental understanding of how population genetics works.

Otherwise, you’re going to get into silly arguments with people who think that you can just inbreed and inbreed without consequence. No rare dog breed can be saved in the long term if its immune system doesn’t work properly.

It’s really that simple.

In the end, selecting for diverse and heterozygous MHC haplotypes within a limited gene pool is less preferable than trying to maintain genetically diverse strain.  We have intentionally reduced genetic diversity within dog breeds and strains, yet as a population, dogs remain one of the most genetically diverse of all domestic animals. We have the ability to correct some of the errors without resorting to sophisticated genomic technology, but because the dog culture at large values purity and homozygosity at all costs, we are left looking at the only other option available.

Inbreeding requires so much scientific knowledge and acumen to pull off correctly that it really shouldn’t be done. And the validity registry systems that ultimately reduce dog breeds to inbred populations needs to be questioned.

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Why the Ark story can’t be true.

Source.

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Sexual reproduction generates variation that increases the likelihood of survival in a world that generates intense competition.

In the first part, there is an interesting study about these little fish. The sexually reproducing species was better adapted to parasite loads than the asexual reproducers– until the sexual reproducing fish become inbred. Then they can’t handle the parasite load at all. (MHC diversity, anyone?)

Source.

(Click here for Part II, which will take you to the rest).

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Update:  Jess’s post that is discussed here has moved to this address.

It is axiomatic that making analogies from one species to another is often a dubious activity.

We are rightly warned against anthropomorphism when observing animal behavior. We are told to see animals as they are and to do all we can to avoid projecting our human values and cognitive abilities onto other species.

In my hamster-crazed days, I had a hamster escape– as they are wont to do from time to time. One night, I was sitting on the floor watching television, and something crawled up onto my lap. I was bit startled, of course, but when I looked down, I discovered it was my errant hamster.

My 11-year-old mind decided that he came to me because he was bonded to me in the same way dogs were.

I was wrong. Syrian hamsters have no concept of social bonds. The only social bonds they have are between mothers and their nursing offspring. When they are done nursing, she cares for them not one bit.

This particular hamster had associated me with food. I had often fed him from my hands, and he grew quite tame. (He bit me only a few times, which was saying something for those hamsters). He had spent a few days foraging behind the walls, which I’m sure were not well-provisioned. Hunger set in, and because he associated my scent with being fed, he crawled onto my lap.

Now, it is easy to debunk the assumptions I made when I thought my hamster was bonded to me. Comparing hamsters to dogs is folly. It is what children do.

However, when it comes to the science on inbreeding, it is very common for people to make assumptions based upon different species.

It is just as dubious.

Jess Ruffner at DesertWindHounds writes about this issue  in her latest installment that critiques the closed registry system.

One of the things one often sees in defenses of inbreeding and the closed registry system are quotations of studies that involve other species.

However, dogs have a very different natural history from other animals. Other animals have evolved different ways of dealing with genetic diversity issues. Some animals can handle very, very low genetic diversity and low MHC diversity. Others cannot.

The examples that different apologists misuse, misunderstand, or even misrepresent are fairly common. Cheetahs have low genetic diversity and low diversity within their MHC haplotypes, but because they have evolved through this genetic bottleneck and natural selection has been able to work on them, they are able to continue. It is not an ideal situation, but the cheetahs have been able to survive the past 10,000 years with very low levels of genetic diversity. Dogs in closed registry breeds have not evolved within this framework. Natural selection does not affect most Western dogs, which whelp indoors and get regular veterinary care.

Then there is the island fox (Urocyon littoralis) canard. Supposedly, dogs can do fine with reduced genetic diversity because the heavily inbred population of island foxes still has diversity within its MHC. Well, it turns out that those inbred foxes likely exhibited balancing selection. These foxes, like all wild dogs, have very strong inbreeding avoidance behavior, which would have allowed them to choose mates with different MHC genes. Those foxes that were heterozygous in the MHC were better able to survive over those who were homozygous.w And that process would have continued the diversity of the MHC in these foxes, despite being quite inbred. These animals are also not strictly monogamous, even though they do pair bond. That means that litters sometimes have different sires, which means litters can have littermates with very different MHC haplotypes.

(Many domestic dogs have also have inbreeding avoidance behavior. I remember when Cabbage, the long-legged JRT came in season, and Timmy, her four-month-old son, discovered what his equipment was for. Cabbaged savaged him every time he came near. Even when she was receptive to other males, she wouldn’t let Timmy near her.)

Of course, there are animals that have low diversity in the MHC and low genetic diversity all around. Jess mentions the inbred Swedish population of the European beaver, which has very low genetic diversity and very low diversity in the MHC I and MHC II. The beavers are thriving despite being derived from only 80 individuals.  Although  the European beaver population in Russia is not inbred, there are plenty of examples of beavers inbreeding in the wild. Young beavers do not go far from their parents’ territories, and thus, they often breed with relatives. European beavers lack the inbreeding avoidance behavior of wild dogs, and it is not that unusual to see pairs made up of parent and offspring. Because they have evolved with these behaviors, the animals have evolved a very high tolerance for inbreeding.

Inbreeding tolerance is not universal across species. Each species has its own peculiar tolerance for reduced genetic diversity.

Dogs in closed registries do not have the evolutionary heritage that resembles any of these often quoted examples.

Dogs are derived from wolves that have very strong inbreeding avoidance behavior. All cases of inbreeding in wolves have happened when the breeding female has died and one of the female offspring pairs off with her father. Wolves disperse from their natal packs– usually before they are three– and many individuals travel great distances to find their mates and territories. This behavior lowers the likelihood that wolves will mate with a relative.  Wolves evolved as a high genetic diversity species, as the study that found the Goyet Cave dog discovered. Since the Pleistocene, wolves have lost entire MtDNA lineages. it was once a very genetically diverse species.

And as domesticated animals, dogs have also had a gene flow across vast areas.  The camp wolves of the Pleistocene hunter-gatherer bands likely gave up living in territories, so they could easily follow a ready food source. This change meant that camp wolf genes could spread even more than normal wolf genes. Later, when man became pastoralists, there were gene flows from dogs that were following flocks of sheep and goats over vast distances. After all, shepherds always took their flocks into the high mountains during the spring and into the valleys during the winter. Some of their dogs likely ran off and joined local farm and village dog populations, and in this way, domestic dogs retained an unusually high amount of genetic diversity for a domestic animal.

Dogs did not evolve to have closed registries. They evolved to have diverse and dynamic gene pools, and that is why we have so many issues with inbreeding in this species. It has relatively low tolerance for inbreeding.

It was once thought that wolves did fine with low genetic diversity. The wolves of Isle Royale were trumpeted as the best example of a healthy population of wolves that had thrived in spite of a genetic bottleneck that came from being founded by a small founding population that wandered across the ice to colonize the island. However, inbreeding has exposed what is likely a deleterious recessive gene or series of genes that causes bone deformities. The majority of wolves on the island  nowhave these deformities, and they are now having a very hard time killing moose.

But wolves can put up with more inbreeding than dogs can. That is because dogs are a domestic species and are not subject to natural selection. The wolves of Isle Royale might be able to make it if the ones with the deformed backs die off, but if the remaining wolves are all carriers in some way  for that deformity, then it natural selection cannot save them in the way that it did for the cheetah. Because dogs are typically born in houses and well-cared for in the West, dogs with genetic disorders or even weird conformation that prevent them from surviving in the wild are capable of surviving long enough to reproduce.

The natural selection effects on cheetahs cannot happen to domestic dogs– unless you want to risk animal cruelty charges. They can be mimicked by breeding dogs outdoors, but it still doesn’t do much for their MHC diversity.

Finally, some animals are able to survive inbreeding because they evolved within very narrow range that has only so many different pathogens. The pathogens and the organism are able to co-evolve. That why species that have very small ranges don’t need a diversity in MHC genes.

I don’t have to tell you that doesn’t apply to either dogs or wolves. Wolves once had a vast range in Eurasia and North America (perhaps also North Africa). Dogs were domesticated somewhere in Eurasia and then spread throughout the rest of the world. They need diverse MHC genes.

So one must be very careful when reading articles about the viability of inbreeding in domestic dogs– especially when they make comparison to relatively successful wild populations that have experienced a genetic bottleneck. Each species has its own peculiar tolerance for inbreeding that results from its own peculiar evolutionary history and behavior.  Comparing closed registry domestic dogs to cheetahs, island foxes, or beavers is simply not valid.

It is as bad as comparing a friendly domestic dog that comes to you for an ear scratch to an escaped hamsters that comes you for a sunflower seed. The difference in behavior of the two is the result of how these animals have evolved.

And as it is in behavior, so it is for inbreeding tolerance.

Anyone who makes claims otherwise is either misunderstanding the concept or is misrepresenting it.

See also:

MHC, DLA, WTF?

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How do we breed dogs with stronger immune systems?

Also, see this post at DesertWindHounds. (Don’t freak. The background has changed. It is the same blog.)

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Twenty years ago, things seemed great for the Tasmanian devil.

The species had rebounded from several decades of intense persecution. It was originally believed that Tasmanian devils were a major threat to sheep, and from about 1830 to 1936, they were relentlessly hunted, trapped, and poisoned. Bounty systems were implemented, and their number did drop during that time period.

In 1936, Tasmania offered full protection to the Thylacine, which had become quite scarce in the wild. Because the devil was also quite uncommon, protection was offered to that species in 1941.

From 1941 until the 1960’s, the devils were allowed to exist without any sort of hunting pressure. And the numbers began to increase again. Occasionally, poisoning permits were issues to control devils in sheep production zones, but the animals were still officially protected.

By the 1970’s, there were concerns that the devils were overpopulated.  In 1975, the population crashed, but it then rebounded. It continued to grow until 1987, when another crash happened. These sorts of boom and bust growth cycles exist in virtually all wildlife species, and it was assumed that the devils were developing along healthy lines.

Tasmania allowed permits to cull devils until the early 90’s.

Then in 1996, all hell broke loose for the devils. A contagious form of cancer was discovered. Called devil facial tumour [tumor] disease, it was originally believed to be caused virus. It is now founded to the result of a clone of malignant cells. It is transmitted with the devils fight over carcasses, which they are so famous for doing.

The devils are highly susceptible to this cancer. Since 1996, the devil population has crashed by 80 percent. Almost all of the loss is attributed to this disease. It is estimated that if the disease continues as it is now, the Tasmanian devil will be extinct in 25 years.

Why would the devils be so susceptible to this unusual cancer?

Well. It was always noted that devils were unusually susceptible to other forms of cancer. Cancer has always been a major cause of death in the populations that have rebounded since the devil was protected in 1941.

The reason for this susceptibility to cancer and to this particular form of cancer is really quite simple. Diversity in the genes in the MHC class I and II in Tasmanian devils is very low.

Devils have very low genetic diversity. There are certain reasons for this low diversity. One of these is that the Tasmanian devil in Tasmania is relict population. The animals were once found throughout Australia, but it is now represented only by population that became isolated on an island.

And this population experienced an extreme genetic bottleneck 10,000 years ago. The founding population that survived that bottleneck could have been as few as 500 individuals. This bottleneck has been exacerbated through intense persecution since Europeans arrived on the island, and because the MHC diversity was always compromised, the devils were often experiencing epidemics.  It is thought that two population crashes that occurred in the first half of the twentieth century were the result of epidemics that rapidly spread through the genetically depauperate devils.

We are no longer talking about devils being overpopulated as they possibly were in the 1970’s and 80’s. We are now talking about possible extinction.

And it’s all because of inbreeding– inbreeding caused by natural causes 10,000 years ago and more recent inbreeding that has occurred because of intense persecution and habitat fragmentation.

This story should be a cautionary tale.

Just because a species has appeared to recover in numbers does not mean that all is well.

We have to pay attention to diversity within the MHC.

Many endangered species are in exactly the same position as the Tasmanian devil. Cheetahs are famously inbred, but thus far, no major disease has popped up that will kill them all. That does not mean that it won’t. It just means that it could easily happen.

And even our success stories might not be so successful.

In the US, we like to congratulate ourselves about the successful recovery of the northern elephant seal. In the early twentieth century, there could have been as few as 100 northern elephant seals left. The Mexican government protected the only surviving colony, and the US soon followed suit. Eventually, their numbers reached over 100,000 individuals. These are harem breeders, which means that only a few males produce offspring every generation. They suffer a definite popular sire effect, which wouldn’t be so bad if they weren’t already so inbred.

No bad diseases have popped up in these animals yet. However, one easily could.

As the devils have taught us, just because a species is particularly numerous does not mean it is not vulnerable. We have to pay attention to genetic diversity, especially in the MHC genes.

Unfortunately, many success stories in conserving wildlife species are likely to be similar to that of the Tasmanian devil. Genetic bottlenecks create small founder populations that may be able to recover in very large numbers, but because these populations have low genetic diversity, they are unable to survive epidemics.

This is why conservationist are so concerned with genetic diversity in all sorts of wild populations and within the zoo breeding programs. Genetic diversity is essential for endangered species to fully recover. Otherwise, they will always be vulnerable.

And if they are that vulnerable, how can we say that they have fully recovered? If one contagious disease can do this to the Tasmanian devil, what can another one do to the California condor, the Florida panther, or the giant panda?

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Jess at DesertWindHounds discusses the importance off genetic diversity in the Major Histocompatibility Complex (MHC),  a gene family that controls immune responses. In dogs, it’s called the Dog Leukocyte Antigen (DLA) system

It’s very important that everyone in dogs understands these concepts.

In fact, it’s very important that everyone interested in conservation of endangered species or in breeding any kind of animal has a full grasp of the problems that can happen with reduced diversity in the MHC.

This angelfish website also partly discusses the MHC. Unlike Jess’s post, it is pro-inbreeding, but the author recognizes the need to bring new blood in.

The problem with dogs is we are operating within a closed registry or a Potemkin open registry system where new blood is not easily brought in.

And with virtually all Western breeds, all individuals within a breed are derived from the same founders.

The is the big problem with line-breeding, inbreeding, and using just a few sires  per generation within a closed registry system. At some point, the breed becomes too homozygous within the MHC/DLA, and it’s screwed when a really bad disease pops up.

My guess is we’re going to hear a lot about the MHC in the near future. Many success stories of recovering endangered species are going to turn into disasters.  Some species have recovered from a very low founding population, and that means that they don’t have much variation at all in their MHC.

That’s bad.

And there is one animal right now that recovered from intense persecution in its homeland. It was eventally protected, and its numbers grew.

But now because of a communicable disease, it may very well go extinct. As a species, it has low genetic diversity and very little variation in the MHC. If it does become extinct, it will be this compromised genetic diversity that ultimately does it in. If it had more diversity in its MHC, then some individuals might have a some immunity to it, but thus far, all have been found to be highly susceptible to this disease.

I’ll reveal that animal and its disease  tomorrow in a longer post.

Until then, read this post and get a good understanding of what the issues are.

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