Making Sense of Canine Genetic Information: Lessons for Scientists and Dog Lovers
Norine E. Noonan, Ph.D.
School of Sciences and Mathematics
College of Charleston
Charleston, SC 29424
Contact: 843-953-5991
noonann@cofc.edu
Press contact: Mike Robertson
- 843-953-5667
robertsonm@cofc.edu
Why should dog breeders care about the dog genome sequencing project? Why should scientists and veterinarians and other animal care professionals care? Why should folks who just love dogs care? Well, let me begin by telling a story . . . perhaps you've heard it already. . .
When Davy, a blow-dried, fluffed-up Pekingese, waddled past more than 2,000 rivals into the center ring to be crowned the Best in Show at a prestigious dog show, some of the owners of the "losers" were not amused. Rumors wafted through the crowd like a bad smell that all was not as it looked for the Perfect Peke. Gossip had it that Davy's face was surgically "improved" in order to take his place in the pantheon of champions. If this were true, the American Kennel Club was quick to say, Davy would lose not only his titles, but would never set foot (or is it feet?) in the competitive breed ring again. An investigation was launched, and, after a time, his outraged owners were cleared. Davy, it seems, had only had a little throat surgery to improve his breathing, but this did nothing to change his outward appearance.
We know that the development of dog breeds is an ancient process, beginning perhaps 6,000 years ago or more, and it continues today. As we've also heard today, the domestic dog likely originated in East Asia (somewhat of a surprise since the conventional wisdom had the dog originating in the Middle East). Further, the domestication process changed the way in which these canids communicate with humans that may be unique among domestic animals and even higher order primates.
There are about 150 recognized dog breeds in the world and perhaps another 250 (or even more) that are not recognized by any registering organization. Collectively, these breeds represent an ongoing evolutionary "laboratory" that essentially is under the direct control of humans. The range of phenotypes is truly amazing. The weight difference of the average Chihuahua and St. Bernard is about 100-fold. The behaviors of the Basset Hound and the Border Collie lie at opposite ends of the spectrum. The coats of the Norwegian Elkhound and the Whippet couldn't be more different. Yet any dog can be mated to any other dog and, barring some physiological problem, viable and fertile offspring will result. Domestic dogs are also inter-fertile with wolves, coyotes and jackals. To date, what humans have done in domestic dogs is to harness the power of the laws of genetics, short generational times, and relatively large populations to create perhaps the largest number of different phenotypes of any living species, many in response to the needs of humans for assistance with specific tasks.
The "dark side" of all of the attention to breeding dogs over the centuries from those early domesticated canids has been the appearance and perpetuation of genetic defects and diseases. Just as in people, there are many genetic defects and diseases that have been reported in the dog. Table 1 shows a sampling of dog breeds and their genetic problems. This is not a comprehensive list, by far. It simply illustrates that there are a lot of problems out there. It's been estimated that one in every 400 dogs has a genetic disorder. In some breeds, the incidence of one or more of these disorders is much higher. For example, in the German Shepherd dog, there are about 140 genetic disorders that range from conformation "faults" to frank disease. The incidence of hypothyroidism in this breed is about 0.6/100 dogs; cryptorchidism (the failure of both testicles to descend) about 1.2/100 dogs; and overshot jaw about 0.1/100 dogs. For Newfoundland dogs the situation is worse. It is estimated that about 66 percent of the individuals in this breed have defects of one sort or another (Noonan, personal communication). Further, in Doberman Pinschers, 77 percent of the individuals in the breed have the gene for von Willebrand's disease (an bleeding disorder similar to hemophilia that is inherited as an autosomal recessive trait). And lest you think that a "Heinz 57" mixed-breed dog from the local shelter is genetically healthier, there have been more than 200 genetic problems reported in mongrels, more than occur in any purebred breed (Noonan, personal communication). Of the nearly 400 genetic diseases and defects currently described in the dog, the mode of inheritance is known for only about half.
Breeders and fanciers have made some effort to control some of the most obvious genetic problems, but it is well to remember that in the dog as in people, phenotype does not equal genotype (especially for "carriers" of a genetic trait). Breeders have sought desirable phenotypes that approach the official breed "standard" via a process known as inbreeding or "line breeding" (line breeding is a bit less incestuous, but a form of inbreeding, nonetheless). In this regard the dog is no different from corn, potatoes, rice or dairy cattle. Inbreeding is essentially cloning the old-fashioned way. It's a time-honored way to rapidly generate a higher percentage of offspring that have "good" traits (in this case, offspring who are "typey" (i.e., approaching the standard) in their looks, movement and temperament). But inbreeding or line breeding is also more likely to result in homozygosity; further, these techniques can't tell the difference between a gene for a thick, beautiful coat in the rough-coated Collie (good) and a gene for "Collie eye", an ocular defect (bad). Genes sort and recombine without regard (mostly) for the phenotypic result (the exception, of course, being lethal gene combinations that result in miscarriages or resorbed fetuses). It is also a basic principle of population genetics that gene frequency, whether normal or defective, does not change between parent and offspring. This is true regardless of the level of hetero- or homozygosity of the parents or whether the mating is linebreeding, inbreeding or outcrossing. Thus, it is the selection of the parent breeding stock that changes gene frequency, not the type of mating.
However, as the level of homozygosity increases throughout the genome, the resulting combinations of genes can result in the unmasking of latent genetic defects. For example, two humans will have about seven in 10 chances of a difference at any single gene locus. Among mongrels this drops to a little less than six in 10, in purebred dogs it=s about two in 10 and in some breeds it's less than one in 10 (Budiansky, 2000). It's also the case that "outcrossing", the opposite of inbreeding, may actually exacerbate the loss of genetic diversity, although breeders sometimes use this technique in the mistaken hope that it will increase heterozygosity and hence reduce the appearance of genetic defects.
Of course, the whole purebred thing is complicated by the fact that a large percentage of genetic traits in the dog, especially behavioral traits, are probably polygenic so that the nice, neat Hardy-Weinberg Law won't work. As far as we know, there is no single gene for "no peeing in the house" or Afailure to chew shoes! These behaviors are probably not genetically based. In addition, there are few, if any, rewards for breeders who advance the health of the breed as a whole by eliminating (not literally, just genetically) or restricting the genes from carrier or affected dogs. In fact, the 'matador effect' is quite prevalent in many breeds today. The 'matador effect' is the reduction in genetic diversity that comes from the use of a small number of popular sires or 'matadors'. These dogs are usually major show winners and highly sought after by breeders to sire litter after litter of puppies. This is inbreeding on a grand scale and the fact that some of those 'matadors' may have latent (or even patent) genetic defects makes no difference to the proud owner of such a dog. However, over time, the reduction in genetic diversity that comes from the matador effect is likely to show at least the major genetic defects that can be traced back to that dog, but by then, he and his offspring could be driving the genetic train of that particular breed. For example, when idiopathic aggression (unpredictable and abnormal aggressive behavior) began appearing in Bernese Mountain Dogs (not in the U.S.), breeders were able to trace this problem back to two 'matadors' imported into that country. Hard decisions and careful screening of pedigrees have succeeded in nearly eliminating the problem (Van der Velden, et. al. 1976). However, unpredictable aggressive behavior in a 100+- pound dog resulted in the euthanasia of many individuals. What a costly and emotionally wrenching price to pay for a puppy from a 'champion'.
Right now, the greatest selective pressures in the dog world are: advertising and gossip. Advertising in publications such as Canine Chronicle, widely read by breeders and judges, identifies dogs with the potential to be 'matadors'. I can name several among Basset Hounds. I see them at our National Specialty show each year. Gossip, of course, is the great leveler and is the basis of most of the current information on the incidence of canine genetic disorders. I should note here that some national and regional breed clubs have been very proactive in trying to eliminate genetic diseases in their breed. For example, the Irish Setter Club of America funded research to develop a genetic test for progressive retinal atrophy (a degenerative eye disease) and now requires that all breeding animals be tested. This has dramatically reduced the incidence of that disease in this breed. The participation of breeders in the screening and grading program of the Orthopedic Foundation for Animals and Penn Hip has reduced the incidence of potentially-crippling (and certainly painful) hip dysplasia in many larger breeds. Tests for Von Willebrand's Disease are available and are being used to identify carriers in many breeds including the Basset Hound. National breed clubs help fund such research through the American Kennel Club Canine Health Foundation (donor advised funds and the Parent Club Partnership Program).
But the current state of affairs may be about to change.
The canine genome project is intended to produce a map of all of the genes on all of the 78 chromosomes in dogs, which can then be used to create a functional map of the genes causing disease and those influencing morphology and behavior. Just as the completion of the map of the human genome has begun to change our way of thinking about the causes and cures for many diseases, the availability of a full map of the canine genome, thanks to a particularly inbred Boxer named Tasha, may open the vistas for unprecedented progress in canine health and will likely also contribute to human health as well. A framework linkage map has existed since 1997, but thanks to the work of the folks on this panel, this map is rapidly being filled in. Once the Boxer map is finished, the genomes of perhaps 10-20 additional breeds will be 'sampled' that is, a sort of quick pass will be made through those genomes in an attempt to identify breed-specific conditions.
What does this portend for the future? Instead of elaborate record-keeping for pedigrees, genetic information may allow breeders to keep track of the Atags@ that identify a Bulldog as a Bulldog and a Basset Hound as a Basset Hound. Newer breeds are likely to be tougher to identify because of their still fluctuating genetic base. But these 'identity tags' may be useful in tracking both pedigrees and individuals. Further, the inbred nature of the dog should make it easier to identify the genes responsible for specific diseases that are common to canine and human and from there devise therapeutic modalities that might work in either species.
For example, cancer is one of the most prevalent diseases in dogs. Many canine cancers resemble the human counterpart disease more closely than induced cancers in rodents. As a case in point, osteosarcoma occurs 10 times more frequently in the dog than in humans and, although it appears similar, it metastasizes sooner in dogs. For osteosarcoma in a canine limb, amputation is the therapy of choice because of the aggressive nature of this cancer. However, in children with osteosarcoma, new combinations of chemotherapies have enabled limb sparing. Genetic keys to osteosarcoma could improve the odds of limb sparing and life saving treatments for canine disease.
The availability of canine genetic sequence information combined with sophisticated chemo- and immunotherapy (not just for cancers, but for other diseases as well), will define a future filled with opportunities to decode and describe the genes that lie at the center of debilitating conditions or perhaps even negative behaviors.
Already there are both mutation-based and linked-polymorphism-based diagnostic tests to elucidate the genetic status for breeding purposes. Mutation-based testing recognizes the specific change in DNA that causes genetic disease. Of course, this kind of testing will detect both affected dogs and carriers but it requires that the 'normal' sequence of the specific genes be known. Linked-polymorphism-based tests examine variations in areas of DNA close to a gene causing a disorder. Specific polymorphisms must be known and must be linked to the specific disorder for this test to be effective (although it is not necessary to know either the exact mutation or even the gene involved in the defect). This type of screening is most accurate for entire families of dogs where both parents and all siblings can also be tested. Table 2 illustrates a number of genetic tests already available for specific breeds.
Jolly and collaborators (Jolly, et. al., 1981) have outlined several criteria for a successful genetic screening program:
- The genetic defect or disorder is frequent enough to be of serious concern.
- The test for heterozygote 'carriers' is accurate and cost-effective.
- Genetic diversity can be maintained in the breed without carrier and affected dogs being in the breeding population.
- Test and control programs are accepted by breeders and accompanied by education and public outreach programs.
- Breeders can obtain genetic counseling to assist their efforts
- Parent clubs reinforce the importance of and the need for testing for the overall health of the breed (perhaps by mandating testing of broodstock as with the Irish Setter Club.)
The UK Kennel Club in cooperation with the Animal Health Trust in Newmarket, England, has just undertaken a major survey to get information on the first point, frequency, among more than 70,000 owners with the cooperation of 180 breed clubs in the United Kingdom. The survey is intended to give, for the first time, a realistic baseline picture of canine genetic disease and other health conditions. It is hoped that it may also uncover previously unrecognized defects with a genetic component. Results are expected to be available in the Fall of 2004 and will certainly be useful not only to breeders in the UK, but also in the US and elsewhere. So, gossip and anecdotal information, take heed!
When you put molecular level genetic information together with rigorous and thorough frequency information, all of the breeders, exhibitors, fanciers and people who just love dogs will have both the ability and the responsibility to eradicate diseases and reduce the incidence of genetic defects. There will be no excuses and nowhere to hide. The lesson for scientists is that their work can be of tremendous benefit in improving breeding programs and eradicating canine and human disease. Further, this work can be greatly assisted by close collaboration with owners, breeders and exhibitors. The lesson for dog lovers is that we don't actually have to wait, there are things we can do right now while the ongoing genomic research progresses to reach its full potential. Together we can make real and substantial progress to ensure a future filled with healthy, happy dogs.
As far back as 100,000 years ago, a group of Paleolithic hunters gathered around their fire in the darkness listening to the sounds of wild animals deep in the forest primeval. From the perimeter, a rustling sound and then, inching toward the fire's warmth, a wolf-like animal appears, head lowered and tail down, and cautiously approaches the group. The men reach for their spears, but the animal simply lies down, far enough not to threaten but close enough to feel the fire. In the morning, the animal follows the hunters and flushes game for them. That night they reward their new partner with food from the fresh killed game.
Is this an overly romanticized version of how the companionship between human and dog began? Perhaps, but surely this early relationship was driven by mutual necessity. Perhaps humans followed wolf hunters instead, amazed by the cold efficiency of the pack's hunting skills and scavenging what the pack left behind or perhaps the humans hunted alongside them. The domestication of wolf-like creatures into the aboriginal 'proto-dogs' and then into more recognizable dog breeds was accompanied by a change in the way humans and canids communicate B visual rather than verbal cues can be used to direct the actions of a modern, well-trained dog. Perhaps this stemmed from the need for prehistoric man to use those visual cues so as not to startle herds of game animals as he directed his newly domesticated hunting companion to round them up or chase them down.
So, today the dog is companion, co-worker, protector, therapist, and best friend. 'DOG' is God spelled backward, as a reflection in a mirror. To me this has always meant that dogs are reflections of our best selves, loyal, tolerant, courageous, forgiving, loving us more than they love themselves, they are the way God would want us all to be. Certainly the human-canine relationship is, arguably, the most intense of any except human-human relationships.
The poet John Davies, writing in the late 1500's, said:
AThou sayest thou art as weary as a dog,
As angry, sick, and hungry as a dog,
As dull and melancholy as a dog,
As lazy, sleepy, idle as a dog,
But why dost thou compare thee to a dog?
In that for which all men despise a dog,
I will compare thee better to a dog,
Thou are as fair and comely as a dog,
Thou art as true and honest as a dog,
Thou art as kind and liberal as a dog,
Thou are as wise and valiant as a dog.
I strive to be the person my dogs think I am. Our symposium today has elucidated some of the newest and most important findings about the canine genome and unique canine behaviors. It is our fervent hope that this information will be used to enrich and expand the boundaries of that relationship with a unique and remarkable species.
References
Budiansky, Stephen, The Truth About Dogs: An Inquiry Into the Ancestry, Social Conventions, Mental Habits, and Moral Fiber of Canis familiaris, Penguin Books (2000)
Jolly, R.D., et al., 'Screening for Genetic Diseases: Principles and Practices'. Advances in Veterinary Science and Comparative Medicine. 25:245 (1981)
Van der Velden, N.A., et al., 'An Abnormal Behavioural Trait in Bernese Mountain Dogs (Berner sennenhund): A Preliminary Report'. Tjidschrift voor Diergeneeskunde 101:403 (1976)
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