Part I is here.


PART II: Dogs are not Cheetahs. Or foxes. Or beavers.

Start talking about dogs, closed registries, and the unavoidable inbreeding that occurs, and inevitably someone will bring up Cheetahs. Due to a bottleneck that occurred some ten thousand years ago, Cheetah are not genetically diverse. You can transplant skin from one Cheetah to the next and most of the time there’s no rejection. Their sperm is all messed up, and of such poor quality that if they were another species Cheetahs would be considered infertile. But Cheetahs just keep on keeping on, and right now habitat destruction is a more pressing issue for them than lack of genetic diversity.

Cheetahs have been done to death. They’re boring. Let’s talk about foxes instead. And beavers. And panthers and devils.

Specifically, the San Nicolas Island fox, Urocyon littorals dickeyi. This little fox lives on one of the Channel Islands off the coast of California. The island foxes are really quite fascinating, living on six of the Channel Islands, and each group is considered a separate subspecies. Each subspecies is so distinct, they can be differentiated simply by looking at the skeleton. These foxes live as ‘monogamous’ pairs, although they have a rather loose definition of monogamous; twenty-five percent of their offspring with known parentage are from what is called ‘extra-pair fertilization,’ or sleeping around. Mated pairs are not closely related, even though they live on an island with limited dating opportunities; there is very strong inbreeding avoidance in their mate selection.

The San Nicolas Island fox is remarkable for it’s extremely low genetic diversity. It’s diversity at nineteen microsatellite loci used to measure such things is zero. It’s the least genetically diverse wild population found so far, and it’s conjectured that at some point in the seventies the foxes got down to around five individuals, possibly due to canine Distemper virus. A similar thing happened to the foxes on Catalina Island, which were reduced from a population of greater than one thousand to less than ten individuals in one generation due to Distemper virus in 1999.

The really super fantastically interesting thing about the San Nicolas Island foxes is that despite being so very, very homozygous, they have a heterozygous MHC. It’s not as diverse as foxes that live on the other Channel Islands, but it’s not monoallelic, either. Wow! How can that be? Doesn’t inbreeding reduce diversity in the MHC just like it does with all the other genes? Well, no, not if you’re subject to natural selection.

The San Nicolas Island fox MHC is considered to be diverse due to balancing selection. Balancing selection consists of heterozygote advantage, where the individual with two different genes (AB) is fitter than the homozygous individual (AA.) In theory, the heterozygous individual would be able to recognize and deal with a wider range of pathogens than the homozygous individual. Knowing that the foxes on the other islands practice inbreeding avoidance in their mate selection, the foxes on San Nicolas could also have been practicing inbreeding avoidance right after the bottleneck, by choosing mates with a different set of MHC genes, thereby avoiding homozygosity. Fascinating, eh?

There are quite a few examples of very inbred but evidently thriving wild populations. Since the majority of species exhibit lots of diversity in the MHC, these inbred populations are worthy of study and comment, and can teach us valuable things. One of the other inbred species (besides those boring Cheetahs) that I found frequently compared to dogs in relation to closed registries and inbreeding was Swedish beavers, Castor fiber. Like the foxes, these beavers went through a bottleneck, but unlike the foxes, they have no variation at all at their MHC class I and II loci. None. Around 80 of these Norwegian beavers were released at nineteen different locations in Sweden, and subsequently increased to about 100,000 animals by 1993. They don’t seem to have any sort of extreme disease susceptibility or trouble reproducing.

Contrast the beavers with the Florida panther, Puma concolor coryi. Due to habitat fragmentation, young male panthers are not able to disperse, and end up hanging around and mating with their close female relatives. Inbreeding among Florida panthers produces congenital heart defects, poor sperm quality, and lots of male panthers with retained testicles, or cryptorchidism. (This should sound very familiar to dog breeders in some breeds.) They may also be more susceptible to disease and parasites due to poor immune systems. In 1995, eight female pumas, Puma concolor stanleyana, were sent on vacation from Texas to Florida, to meet some eligible panther males. And lo!, panther numbers increased, heterozygosity doubled, and the number of previously seen defects dropped. This is only a stop gap measure; due to low numbers and the problems with habitat, Florida panthers will have to be extensively managed to survive. They will need to have continual infusions of new blood or they will simply start suffering from inbreeding depression again, and where that blood is going to come from is a big problem.

As an example of an extremely poor outcome due to inbreeding, the Tasmanian Devil, Sarcophilus harrrisii, stands alone. The Devils get a form of cancer which is really freaky, basically a cloned tumor, transmitted by biting, which the devils do a lot of. Put simply, the Devils are transplanting tumor cells into each other via bite wounds. Remember what I said in part one about the MHC being very key in most transplants? Those Class I MHC genes have got to be pretty close between the donor and the donee, or you get rejection. Now, dogs have a similar tumor, canine transmissible venereal tumor (ick!) which passes from dog to dog by fooling the immune system into ignoring it so it can grow. But that is not what’s happening with Devil facial tumor disease. Devils have very little variation at their Class I loci, so the tumor, which emerged around ten years ago, isn’t recognized as ‘other’ by their immune system and it takes hold. It is possible that the Devil facial tumor disease will eventually evolve to be non-fatal, like CTVT, but the Devil population is so small that there may not be time for that. Without DFTD, Tasmanian devils would be on the mend. With it, who knows what will happen?

So, what gives? Why do some species with no diversity survive and thrive, and others just keel over? First, you need to look at whether the population has been historically diverse. If it has undergone a bottleneck in the distant past, like the Cheetah, it may well have evolved inbreeding tolerance in the intervening time; it has evolved to tolerate inbreeding and does not experience depression. Deleterious genes have been purged from the population, those animals simply not surviving to reproduce, or the founder population may have had very few bad genes to begin with. Second, you look at the environment. If the animal is living in an optimal environment, it may not need diversity, it has evolved (there’s that word again) an immune system adequate to whatever the environment can throw at it. How well a species tolerates inbreeding is extremely variable and dependent on a lot of factors. No wild species lives in a vacuum, it is continually responding to the environment and the pathogens it encounters. A species in a fairly static environment would need less diversity than one in an ever-changing environment where new pathogens are encountered on a regular basis. In the latter case, this is called coevolution, and it could account for the diversity in the MHC that we see in most species.

Coevolution is basically a never-ending race between evolving pathogens and evolving hosts. Given a sufficiently large population, coevolution will maintain a large degree of diversity in the MHC. Pathogens come along, the hosts with the greatest fitness respond to the pathogen, and those host genes become prevalent in the population. New pathogens arrive, or old ones change, and the host with genes specific to those new or different pathogens becomes the fittest, so previously rare genes become more common. Extremely fit genes may persist for a long time; there are HLA genes that predate the split between humans and chimpanzees. It’s a very dynamic system. Hosts which may have evolved in an environment with limited pathogens, where they didn’t need ultra diverse immune systems will be vulnerable to newly introduced pathogens. Like the island foxes and canine Distemper. Or Tasmanian devils and DFTD. Species with limited diversity, like Cheetahs, and the Norwegian beavers, may be stable now, but a novel pathogen that their immune system is not adapted for, and cannot adapt to, may spell doom for them. Or at least a very bad time, like the island fox.

In the process of researching this article, I reviewed a bunch of species that lack diversity but are apparently thriving, or at least surviving without intervention. Moose, mountain goats, beavers. Not a single one can be honestly compared with purebred dogs. Dogs are not subject to natural selection, balancing selection, or coevolution. No one stands hip deep in a lake, deciding which male beaver gets to mate with which female. No one picks only one or two foxes from each litter to carry on the next generation. Even in species which lack diversity and have adapted well to that lack, the consensus regarding conservation is clear: what diversity there is should be maintained, using all the available genetic data, including the MHC. Continued reduction of diversity, loss of genes, serves no conservation purpose and may reduce fitness. The function of background genes, genes not belonging to the MHC, to the immune system should also not be ignored. The animal needs to be considered as a whole, a product of it’s environment and adaptation to that environment, not just as an expression of this gene or that gene or this other set of genes.

So what, you’re wondering, do foxes and beavers and their genetic diversity or lack thereof, and how they got that way, have to do with purebred dogs in closed registries? Doodly-squat, that’s what. It’s intellectually dishonest to compare dogs to wild species. Dogs are not wild animals, they aren’t subjected to the same selection pressures as wild animals, and their relationship to humans is nothing like that of a wild species. Even if you wanted to persist with that argument, it doesn’t fly, because if we look at dogs across the species, they are very diverse. This current diversity argues for historical diversity as well. Closed registries are a tiny blip in the long history of the dog. Technically, modern purebred dogs are closer to Florida panthers, with limited carrying capacity in the environment and limited access to unrelated breeding partners, than they are to Scandinavian beavers, which were basically left alone to succeed or not. 

I had intended to focus on the Cheetah for the purposes of this discussion, but I happened across the San Nicolas fox, which is a much better example, in the most unlikely of places: a paper on hemangiosarcoma that I downloaded from the Golden Retriever Club of American web site. It’s a perfect example of the kind of intellectual dishonesty used to defend the closed registry system:

“There has long been a concern that repeated inbreeding (high COI’s) may result in such significant loss of genetic diversity that highly inbred animals may be extremely vulnerable to infectious and other serious disease. This is of particular concern to conservationists attempting to preserve species that have been reduced to dangerously low numbers. However, as often happens with scientific theories, the data is not always as straightforward as the theory, and it turns out that Nature may have some tricks up her sleeve to preserve essential genetic diversity under even extreme circumstances.

A very recently published study (Aguilar et al, 2004) of the San Nicholas Island fox found surprising results. Approximately 10-20 generations ago (1970’s), the isolated fox population on this island was reduced to under 10 individuals (probably about 5). It has since rebounded and repopulated the island to over 500 foxes, but with an entirely inbred population with extremely high COI’s. It is the most monomorphic population in a sexually reproducing animal ever reported, showing no variation in most of the genetic markers examined. Yet geneticists were startled to find remarkably high levels of variation in the Major Histocompatibility Complex (MHC), which are genes that influence disease resistance. Of course, natural selection guided those breeding choices, not Man, and that is a very significant difference. But this example at least serves to remind us of how much we don’t fully understand yet.”

The implication being that preservation of genetic diversity, specifically of the MHC, in dogs is not and should not be a major consideration, because somehow, these foxes have managed to preserve diversity in the MHC while losing it everywhere else, and they’re just fine and dandy. That inbreeding, as practiced within closed registries, bears no fault in the problems faced by purebred dogs because hey, look at these inbred foxes! EEEENT! Sorry, GRCA. We already know that individual purebred dog breeds are not diverse in their MHC, and that some breeds are very genetically impoverished. We have isolated specific DLA genes as risk factors for disease in dogs. And, as I’ve discussed, we simply cannot compare dogs to wild species. My review of the literature relating to conservation breeding pounds the point home that all aspects of existing genetic diversity within a species should be preserved. But I’ll let the fox study speak for itself, since the GRCA singles it out as an example:

“Finally, our results rekindle the debate concerning the use of MHC and other fitness-related genes in the management of captive and endangered wild populations. Currently, neutral markers are used exclusively in the absence of pedigree information to minimize inbreeding in small populations. With the discovery of the function and importance of MHC genes in natural populations, it was suggested that maintaining allelic diversity at MHC should be an additional goal of genetic management. This notion was debated and largely discredited. Our results, and those showing an absence of association between variation in neutral and fitness-related traits in natural populations, suggest reconsideration of this idea. Preservation of a diverse array of fitness-related genes, along with neutral variation, might be the key to the long-term survival of endangered populations.” (emphasis is mine.)

A closer reading of the paper reveals that even their existing diversity did not keep a novel pathogen, canine Distemper, from devastating populations of both the San Nicolas fox and the Catalina fox. Looks like Nature pulled the wrong trick out her sleeve in that instance, and in order to conserve the foxes, especially in the case of the Catalina Island population, humans had to take up the slack. Maybe island foxes are not such a good example of breeding within a closed population. Whoops. Sorry, Nature.

Like wild species, dog breeds vary in their tolerance of inbreeding, and their responseto lack of genetic diversity. And, like wild species, no one breeding plan is best for all breeds of dog. The management of the Swedish beaver population, for example, would never work with the Channel Island foxes or the Florida panther, which will have to heavily managed if it isn’t to become extinct. Breeding dogs within the closed registry system is like attempting to preserve endangered species by applying the exact same survival plan across the board. It won’t work.

In any case, immunity to bacteria and viruses and the problems with inbreeding depression are not the only reasons we’re so interested in the diversity of doggy DLA genes. The dog has been a model for transplantation research for a long time, and we know a lot more about MHC in dogs than we do about the ones in foxes or beavers. And we’re learning more all the time. There are very clear, emerging reasons for wanting to know exactly what genes your dog has, and for breeding specifically for heterozygosity in the MHC. But you’re going to have to wait until the next installment for that, when we discuss how modern breeding practices have put dogs into a handbasket to hell, and how information regarding the MHC can be used in a breeding program to get them out. Yes, you canbreed closely and still maintain diversity in the MHC. Sound crazy? Like a fox.


To sum up:

Some wild species have extremely low genetic diversity, both in general and in the MHC specifically, but are thriving either in spite of, or due to, this lack of diversity.

Some wild species have terrible problems due to lack of genetic diversity, both in general and in the MHC.

The genetic variability of wild species is molded by natural selection, balancing selection, and coevolution.

Dogs and the way they are bred within closed registries are not subject to natural selection, balancing selection, or coevolution.

Tolerance of inbreeding is variable with both wild species and dog breeds.

Conservation management of wild species must be tailored to the individual species; no one survival plan is appropriate for all.

Conservation of dog breeds must be tailored to the individual breed and even to lines within the breed, no one plan, like closed registries, is appropriate for all.

Existing general genetic diversity and diversity in the MHC should be preserved in both wild species and dogs.

It is dishonest to compare purebred dogs with wild species.

NOTE: Retrieverman has a commentary that may be more clear.

References:

Cheetah

Dating the genetic bottleneck of the African cheetah
Marilyn Menotti-Raymond and Stephen J. O’Brien

San Nicolas Island fox

High MHC diversity maintained by balancing selection in an otherwise genetically monomorphic mammal
Andres Aguilar, Gary Roeme, Sally Debenham, Matthew Binns, David Garcelon, and Robert K. Wayne

Island foxes
The evolution, behavioural ecology, and conservation of island foxes
Gary W. Roemer

Norwegian beaver

Major histocompatibility complex monomorphism and low levels of DNA fingerprinting variability in a reintroduced and rapidly expanding population of beavers
Hans Ellergrebn, Goran Hartman, Maria Johansson, and Leif Anderson

Florida panther

Genetic restoration of the Florida panther.
Johnson WE, Onorato DP, Roelke ME, Land ED, Cunningham M, Belden RC, McBride R, Jansen D, Lotz M, Shindle D, Howard J, Wildt DE, Penfold LM, Hostetler JA, Oli MK, O’Brien SJ.

Cryptorchidism in Florida panthers: prevalence, features, and influence of genetic restoration.
Mansfield KG, Land ED

http://www.panthersociety.org/restore.html

Tasmanian devil

Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial
Hannah V. Siddle, Alexandre Kreiss, Mark D. B. Eldridge, Erin Noonan, Candice J. Clarke, Stephen Pyecroft, Gregory M. Woods, and Katherine Belov

The Tasmanian Devil Transcriptome Reveals Schwann Cell Origins of a Clonally Transmissible Cancer
Elizabeth P. Murchison, Cesar Tovar, Arthur Hsu, Hannah S. Bender, Pouya Kheradpour, Clare A. Rebbeck, David Obendorf, Carly Conlan, Melanie Bahlo, Catherine A. Blizzard, Stephen Pyecroft, Alexandre Kreiss, Manolis Kellis, Alexander Stark, Timothy T. Harkins, Jennifer A. Marshall Graves, Gregory M. Woods, Gregory J. Hannon, and Anthony T. Papenfuss

Conservation breeding and diversity

DNA variation of the mammalian major histocompatibility complex reflects genomic diversity and population History
Naoya Yuhki and  Stephen J. O’Brien

MHC polymorphism under host-pathogen coevolution
Jose A. M. Borghans, Joost B. Beltman, Rob J. De Boer

Low genetic diversity in an endangered species: recent or historic pattern?
Marjorie D. Matocq, Francis X. Villablanca

Genetic diversity and conservation of endangered animal species
Ya-ping Zhang, Xiao-xia Wang, Oliver A. Ryder, Hai-peng Li, He-ming Zhang, Yange Yong, and Peng-yan Wang

Review
The importance of immune gene variability (MHC) in evolutionary ecology and conservation
Simone Sommer

Females prefer the scent of outbred males: good-genes-as-heterozygosity?
Ilmonen P, Stundner G, Thoss M, Penn DJ.

Review
Genetics and extinction
Richard Frankham

Inbreeding and Extinction in Island Populations: a Cautionary Note
Mark A. Elgar and Danielle Clode