It might not make the list of top ten trends in the new millenium, but a growing number of scientists predict human genetics including cancer genetics will go to the dogs in the 21st century. Not figuratively, but literally.
They say the dog, with its many emerging strengths as a genetic model, could join the mouse as the species of choice to unravel the mysteries of mammalian genetics, considered to be the great challenge in biology in the next century.
But, unlike so much of the research conducted on animals, the dog also stands to reap huge and painless rewards from its master's growing curiosity over its DNA. Already, an initial wave of molecular genetic studies in the dog have led to breeding programs that within just a few years have begun to wipe out dread diseases in the Bedlington terrier, Irish setter, Manchester terrier, Shetland sheepdog, and several other breeds.
In fact, some say the great irony here is that the dog will benefit much sooner from advances in genetics than people. According to Debbie Lynch of the American Kennel Club Canine Health Foundation, it is a matter of ethics. "In dogs, you can breed a disease out of a population by rigorous genetic testing and careful breeding," said Lynch. "You really can't do that with humans."
Just One Word
Like the word "plastics" in the 1967 movie, "The Graduate," the mantra in genetics these days has become "function." How does each of the estimated 60,000 or so human genes function individually and as a whole to power our cells?
However, as scientists often say, deducing the function of human genes is easier said than done. Many note that despite all of the progress in mapping genes, the simple fact remains that people are not as amenable to genetic analysis as most other species and organisms.
The problem boils down to three factors. People now live on average well into their 70s, their families are relatively small, and, with the exception of isolated populations such as in Iceland and Finland, humans keep crude genealogical records. All of these factors conspire to make data collection slow, tedious, or sometimes impossible.
Enter the dog. Man's best friend has a much shorter life span, and a bitch can produce
multiple litters with offspring over her life sometimes numbering well into the fifties. With these
large families, dog geneticists have a statistical power to their work that is unheard of in human
studies.
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Some scientists add that these advantages are just window dressing. The most tantalizing aspect of dog genetics is the tremendous variability among the breeds. As most people have marveled during their lives, how can a little Jack Russell terrier and a lumbering Great Dane possibly share the same DNA? Or, how can an obsessive-compulsive border collie and a happy-go-lucky Bernese Mountain Dog possibly have almost the exact same genetic code? And yet, scientists estimate that virtually all domesticated breeds are 99.9% similar on the DNA level.
What has scientists excited is that most domesticated breeds have been produced within the last 250 years. Their rapid rise suggests that the variability among breeds happens quickly and probably involves a relatively small subset of genes. Working out these genetic programs not only will have a profound effect on our understanding of the dog, but on its mammalian cousin at the other end of the leash.
Some scientists also say they are excited about the dog as an evolutionary bridge spanning the well-known biological differences between the mouse, traditionally the favorite mammalian model organism, and people. They note that filling the gap will be particularly helpful in cancer research. "I think this is one of the areas where the dog is going to contribute something that studies of mice won't," said Ostrander. "That is, dogs get lots of cancer. They live in our environment, they eat the food that we do, and they get many, many of the same cancers."
Mapping Dog Genes
The rise of dog genetics is a byproduct of the recent explosion in human genetics. According to Ostrander, as the Human Genome Project evolved during the 1990s and made gene mapping tools more accessible to researchers and less cost prohibitive, a small corps of dog geneticists saw an opportunity to produce their own map. In the mid-1990s, they started the Canine Genome Project.
The dog project, which now involves about 50 laboratories worldwide, aims to create a marker-rich genetic map, the initial step in helping researchers navigate their way across strands of DNA in search of genes. Ostrander, a leading figure in the project, said she and her colleagues have no plans to shoot for the more detailed and expensive full-sequence dog map. In this age of genomics comparing genomes across species she said the full-sequence human and mouse maps will suffice for the dog as a gene-finding resource, noting that the dog genome is about 80% identical to human DNA.
Leslie Lyons, Ph.D., a scientist with the National Cancer Insitute who also works on the dog project, said the map is flying along using 150 distinct sequence markers. Recently, she said a third iteration of the dog map was submitted for publication, and that, to date, the markers are relevant to tracking genes in all breeds.
Meanwhile, scientists have constructed other tools of the trade. Pieter de Jong, Ph.D., and colleagues have created bacterial artificial chromosomes containing a library of dog DNA segments cloned into bacterial vectors, and Francis Galibert and colleagues in France published the first dog radiation-hybrid map in Genomics in December.
Another key project is unfolding in England where researchers at the Animal Health Trust are developing reproducible strategies to number the notoriously hard-to-label dog chromosomes. This work is especially important because the dog has 38 pairs of chromosomes, plus the X and Y. This translates to almost twice the number of chromosomes found in people, although dog chromosomes are much smaller and more asymmetric. To date, only the first 21 dog chromosomes have been numbered.
Another key factor in the growth of canine genetics has been the breed clubs. In most cases, their motivation seems to arise from a growing concern for the health of their animals.
The record bears out the need for concern. There are over 300 well-documented inherited diseases that crop up in the 150 recognized purebreeds, with most diseases typically affecting several breeds.
Most of these inherited diseases are rooted in what the clubs call "bad breeding." The issue is breeders, in their quest to create the perfect show dog, may elect to narrow the breed's gene pool by inbreeding prized specimens to maximize a desired trait. But along with the desired trait, garbled disease-susceptibility genes often slip into the breed's gene pool.
The results of bad breeding can be devastating as in the case of progressive retinal atrophy, or PRA, in Irish setters. PRA, which also affects several other breeds, is an inherited deterioration of the eye's retina that typically robs an Irish setter of its vision by its first birthday. "I'll tell you, there are a lot of diseases that are heartbreaking in dogs, but a blind Irish setter has to be right at the top of the list," said Lynch.
Traditionally, breeders have dealt with the problem by performing a test mating. If by the 1-year mark, the puppies still were sighted, then the thumbs up was given for further mating. According to Connie Vanacore, chairperson of the Irish Setter Club of America's Health Committee who lives in Mendham, N.J., this approach had its obvious limitations when puppies had PRA. "It was a terrible, agonizing thing to do," she said.
During the 1980s, the roughly 1,800-member Irish Setter Club of America began working with Gustavo Aguirre, Ph.D., now of Cornell University's James A. Baker Institute for Animal Health in Ithaca, N.Y., hoping his group could pinpoint the gene responsible for PRA in Irish setters. Raising an estimated $150,000 to support the study, the Irish Setter Club of America got its answer in 1994 when Aguirre and his colleagues identified the responsible gene and mutation.
In the meantime, Vanacore and her colleagues already had gone to work in the club's quarterly newsletter. "Every issue, we told them that we were going to have a gene test, and we hoped that they would use it," she said. "We explained how it works, what to do, and how to do it. We hammered away at them."
Peer Pressure
With this bombardment of information and a lot of peer pressure to use the test, Vanacore said the disease has almost 6 years later been bred completely out of Irish setters. "You never see a blind dog anymore," she said.
For some breed clubs, however, the promise of genetic research is more complex. Take the flat-coated retriever, a relatively rare breed that a growing body of evidence indicates has a cancer incidence that is more than three times higher than the general canine population. Put another way, the lifetime risk of cancer for an individual "flat coat" might be as high as 40%, particularly for histiocytoma and osteosarcoma.
Though the evidence is still far from concrete, flat-coat fanciers face a tough decision. By funding research on the problem, they risk that their beloved dogs will be stigmatized as being a cancer breed. But to ignore the issue, they risk the future vitality and survival of the breed.
For members of the Flat-Coated Retriever Society of America, known as one of the most progressive breed clubs in the country, the choice has been to fund the research. "Anybody who has watched one of these dogs die of cancer knows it's not a pretty thing," said Teri King, Ph.D., a flat-coat fancier and a genetic epidemiologist at the University of Texas M. D. Anderson Cancer Center in Houston.
To lay the groundwork for future research, King said she and colleagues at Ohio State University have established a flat-coated retriever tumor registry. Since 1992, King said, the registry has compiled a library of over 300 tumor samples.
King noted that if a genetic test ever hit the market for flat coats and cancer, the club also might face an even tougher choice. "If it's monogenic [involving one gene] and dominant, I don't think we could breed it out without completely corrupting the population genetics because the flat coat gene pool is so small, " she said. "From my studies, about 30% of the dogs are bred. So, every time that you have a generation that is bred, you're talking about reducing the gene pool that much."
But Ostrander said genetic testing in general does not require that breeders make immediate and absolute decisions. She said in many cases, the correct choice for breeders will be to limit the mating of gene carriers. "Breeders are aware that they are going to have prized dogs that epitomize everything that is great about their breed, but that do carry a deleterious mutation," she said. "The only way to keep them in and the deleterious mutation out is going to be by judicious breeding of carriers. The key is to try and dilute the gene from the breed."
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