HybridVigor

After splitting genetically from wolves about 135,000 years ago, dogs have followed humans through every step in their cultural and social development, from hunting and gathering to agricultural societies, from the farm to the city and suburb. The dog has helped domesticate sheep and cattle, served as a guard, beast of burden, guide, and companion capable of easing the pain of loneliness. So closely entwined are their lives that a number of evolutionary biologists argue that dogs and humans have evolved together. Over the past decade, a loose-knit band of scientists in laboratories in the United States and abroad have worked diligently to bring man's esteemed friend into the postindustrial age of the genome. Compared with the Human Genome Project, the dog effort resembles a poorly capitalized cottage industry, strung together with occasional grants rarely amounting to more than a few million a year. But researchers have recently begun to speed the search for disease-causing genetic mutations in dogs, which often have human counterparts. "We are a small group of people who want to map the dog genome for a variety of reasons, including the study of human genetic diseases," said Dr. Gregory M. Acland, a research scientist at the James A. Baker Institute for Animal Health at Cornell University. "The dog might also be the best model for looking at the genetics of behavior. Beyond that, most of us just like dogs." The dog seemingly changed little in appearance from the wolf until some 15,000 years ago, when it began to move with humans into more permanent settlements, according to Dr. Robert K. Wayne, an evolutionary biologist at the University of California at Los Angeles. Since that time, through conscious and unconscious selection, humans have created more than 400 breeds with greater variability in size and shape than any other species, with the exception of humanity itself. Breeders have traditionally relied on the "founder effect," mating popular sires to numerous females to spread their characteristics rapidly, and inbreeding, mating related descendants of that dog to fix the traits they want, said Dr. Donald F. Patterson, a professor of medicine and medical genetics at the University of Pennsylvania. If a popular sire also carries a genetic defect, it too spreads rapidly through the line. For the past 20 years, Dr. Patterson has maintained a database now listing 370 genetic disorders in dogs, with 5 to 10 new ones added each year. (By comparison, there are some 5,000 identified human genetic disorders.) Like behavioral and physical characteristics, those canine diseases and the responsible mutations tend to segregate according to breed, with many prone to more than one affliction. Thus, progressive retinal atrophy, a form of hereditary blindness, is caused in different breeds by a mutation to any one of at least seven different genes, according to Dr. Gustavo Aguirre, a professor of ophthalmology at Cornell's Baker Institute. In 1998, his research team, including Dr. Acland, located a marker for the gene causing heredity blindness in Labrador retrievers, Portuguese water dogs, poodles, American and English cocker spaniels, and possibly five other breeds. (Because of hybrid vigor, mixed breeds suffer from genetic disease far less often than their purebred cousins.) Progressive retinal atrophy is the equivalent of retinitis pigmentosa in humans. In fact, nearly 60 percent of the genetic disorders in dogs correspond to genetic diseases in humans, Dr. Patterson said, including epilepsy, cancer, deafness, blindness, autoimmune disorders, congenital heart disease, skeletal malformations, neurological abnormalities and bleeding disorders. "The closed gene pools and extensive pedigrees of purebred dogs make them ideal for mapping genetic diseases that have been intractable in humans," said Dr. Elaine Ostrander, head of the human genetics program at the Fred Hutchinson Cancer Research Center in Seattle. Dr. Ostrander is studying the genetics of breast and prostate cancer. In 1991, Dr. Jasper Rine, a genetics professor at the University of California at Berkeley, and Dr. Ostrander, then a staff scientist in his laboratory, conceived of using the dog to examine how genes shape behavioral and physical characteristics, as well as disease. In the process, they would establish a genetic map that could be linked to that of humans, with whom dogs share 80 to 90 percent of their genetic code. The project's initial goal was to study inheritance of the Newfoundland's perceived love of water and the border collie's habit of herding sheep. So the researchers crossed a border collie and Newfoundland but abandoned that program after two generations. Dr. Rine is no longer involved, but Dr. Ostrander has continued as coordinator of the Dog Genome Project. She and a core group of 15 researchers from laboratories in the United States and Europe have created and are rapidly expanding several different maps showing the location of hundreds of signposts, or markers -- genes and microsatellites, which are repetitive strands of genetic code, with an unknown meaning, that are useful for tracking familial inheritance of genetic traits and finding the genes. They have also created a database containing cloned stretches of dog chromosomes. At any one time, 50 to 100 laboratories are drawing on it and contributing new data, Dr. Ostrander said. Reviewing progress for the March 2000 issue of Trends in Genetics, Dr. Ostrander and her co-authors, Dr. Patterson of Penn and Dr. Francis Galibert of the University of Rennes in France, estimate that most of the dog genome is now assigned to its corresponding part of the human map. But assigning the markers used in the mapping to specific canine chromosomes, an essential process to exploiting the data's full potential, has proceeded more slowly. Although the canine genome, like that of humans, is estimated to have three billion base pairs of DNA and 100,000 genes, they are distributed over 78 chromosomes, compared with 46 in humans. To date, only about two-thirds of the dog chromosomes have been identified, many of them by the Animal Health Trust in England, and fewer than half of the existing markers have been assigned to chromosomes. Incomplete as it is, the material that does exist has opened a new season in the hunt for defective genes. Since 1989, scientists have identified and characterized 21 specific canine disease genes, half of them since 1996, and markers have been found for others, according to Dr. Patterson. Among the most spectacular was the discovery in 1999 of the gene and mutations responsible for narcolepsy in Doberman pinschers, Labrador retrievers and dachshunds by Dr. Emmanuel Mignot, an associate professor of psychiatry at the Stanford University School of Medicine. "The dog unlocked the mystery of narcolepsy in humans so that we can now work to develop new treatments and better understand sleep," Dr. Mignot said. Given the pace of discovery, Dr. Acland predicts that "all single-gene disorders in the dog will be eliminated through genetic testing and selective breeding within the next 20 years." The American Kennel Club's Canine Health Foundation and 60 breed clubs are supporting much of that work. Even disorders caused by unknown combinations of genes may soon be better understood. Dr. George Brewer, a professor of human genetics and internal medicine at the University of Michigan, believes he will begin to unravel the genetics of hip dysplasia, a disabling form of osteoarthritis that afflicts many breeds, in the next year or two. Encouraging as those advances are, the Dog Genome Project has yet to contribute significantly to its initial goal of understanding morphology and behavior. Dr. Rine said that with the human and mouse projects drawing to a close, it was time to sequence the entire dog genome. That would not only accelerate the search for individual genes but help scientists understand more complicated questions about the nature of the dog, its incredible talents and the origin of breeds. Copyright 2000 The New York Times