Horse Genome Project Leader Doug Antczak with (l. to r.) project assistants Tatja Hopman, Lea Ruth, and Kitren Nickerson. (Photo: Robert Barker)
Zweig Support Helps Gene Jockeys Map the Horse Genome
Horse Genome Project Leader Doug Antczak with (l. to r.) project assistants Tatja Hopman, Lea Ruth, and Kitren Nickerson. (Photo: Robert Barker)
The term "gene jockey" is bandied about a great deal these days. It was originally coined to refer to biologists who rely heavily on the tools of modern molecular biology for their research. But according to Doug Antczak, D.V.M., Ph.D., director of the James A. Baker Institute for Animal Health at Cornell's College of Veterinary Medicine, it has recently taken on a new meaning in the context of an ongoing international collaborative effort to map the genome of the horse.
The Horse Genome Project began officially in October 1995 when, with support from the Dorothy Russell Havemeyer Foundation, Inc., the world's finest horse geneticists met in Lexington, Kentucky, at the First International Equine Gene Mapping Workshop. There, they divided their workload and agreed to share and integrate their data. The Havemeyer Foundation has continued to provide the umbrella organization under which laboratories from Cornell, California, Kentucky, Texas, England, France, Sweden, Switzerland, and Japan collaborate in this gene mapping effort.
The equine geneticists had their second meeting earlier this spring at the prestigious Cold Spring Harbor Laboratory on Long Island. The reputation of Cold Spring Harbor as a site for important conferences in genetics was built by the former director, Dr. James Watson, who, with Dr. Francis Crick, was awarded the 1962 Nobel Prize for the elucidation of the structure of DNA. The meeting on the genetics of performance in racehorses, convened by the Havemeyer Foundation, was the first equine meeting to be held at Cold Spring Harbor. It attracted not only equine scientists, but also human geneticists, equine clinicians and physiologists, and racehorse owners and breeders.
"This indicates the high level of interest in equine gene mapping in the scientific community and in the horse industry," says Antczak, who organized the meeting with Dr. Ernie Bailey of the University of Kentucky. "Since the initial meeting in Kentucky, there has been enormous progress in gene mapping in horses, and that progress continues at a terrific rate."
Although the mapping of human genes is way ahead of comparable efforts in horses, the horse's slow start in the genetics race has provided unexpected benefits to the horse gene mappers. This benefit comes in the form of comparative gene mapping, the aspect of genome studies which compares the organization of genes on chromosomes between and among species. Antczak reports that a stunning discovery in Sweden two years ago gave the horse genome project a fantastic boost. Whereas patterns of gene order on human chromosomes tend to be very different from those of most other species (except for primates), researchers discovered that the patterns between humans and horses are wonderfully close.
"In other words, there is a very strong conservation of gene order on the chromosomes between the two species," explains Antczak, who is also the Dorothy Havemeyer McConville Professor of Equine Medicine at Cornell. "That means that much of the progress that has been made in mapping human genes can be-and is being-applied to horses. This is a huge boon for equine researchers, saving millions of dollars in time and energy and allowing equine research to forge ahead at an unprecedented rate."
Gene mapping is the decoding of the thousands of genes that line up on the 32 pairs of rod-shaped chromosomes within the nucleus of each equine body cell. The genes determine all the traits and characteristics that are passed down from parents to offspring, such as coat color, running ability, conformation, courage, or genetic defects that trigger inherited diseases.
By having a good comparative map between humans and horses, researchers now know, for example, that many of the genes that are located on human chromosome 6 are on horse chromosome 20. By knowing which genes on which chromosome are linked to muscular or immune diseases in humans, equine researchers can go directly to the corresponding chromosome in horses to look for the disease-causing gene in question.
Although the Horse Genome Project was launched just a few years ago, researchers already have been able to develop genetic tests to identify carriers of three enormously important equine diseases: severe combined immunodeficiency disease (SCID) that runs in Arabians; hyperkalemic periodic paralysis (HYPP) that can devastate quarter horses; and most recently, lethal white disease that can afflict the offspring of overo paint horses.
Cornell's focus, which is supported primarily by the Zweig Memorial Fund, is to contribute to the development of a linkage map for the horse. To develop linkage maps, Antczak and his colleagues are working to first identify as many so-called microsatellites as possible. Microsatellites are anonymous but variable bits of DNA that can be used as markers to identify regions on chromosomes that contain important genes that control traits or functions. They can be thought of as similar to the X and Y coordinates that frame a road map. For example, the coordinates A6 or B19 have no intrinsic meaning on a map of New York State. But they can be very useful in locating specific cities like Syracuse or Albany. Similarly, the equine linkage map can be used to pinpoint particular regions on a chromosome that carry genes for particular traits, such as running speed or disease susceptibility.
As of January 1998, after two years on the project, Antczak's laboratory had identified 145 new microsatellites in the horse genome. When added to those described previously by other horse geneticists, these new markers double the total number of equine microsatellites. Through collaboration with the equine genetics laboratory at the University of California at Davis, 55 of the Cornell microsatellites have already been assigned to locations on horse chromosomes. In addition, 20 are under test at the Animal Health Trust laboratory in Newmarket, U.K., on a unique family of full sibling horses produced for linkage mapping by Professor W. R. Allen's Equine Fertility Unit at the University of Cambridge. Such international cooperation is very rare among scientists, who are often competitive by nature.
"Much of the progress that has been made in mapping human genes can be-and is being-applied to horses. This is a huge boon for equine researchers, saving millions of dollars in time and energy and allowing equine research to forge ahead at an unprecedented rate."
Doug Antczak (Photo: Charles Harrington)
"This cooperation is one of the most satisfying aspects of the Horse Genome Project," says Antczak, whose laboratory exchanges DNA probes and e-mail messages with half a dozen labs around the world each week as part of the project.
Although the horse genome contains thousands of microsatellites, just a few hundred can provide a wealth of information. Already, with just a few years of gene mapping, breeders can use genetic tests to prevent stallion-mare pairings that would result in HYPP or SCID in the offspring. Soon, scientists hope to be able to determine the genetic contribution to conditions such as "heaves" (chronic obstructive pulmonary disease) or "wobbles" (a defect in cervical vertebral formation) and to be able to offer better methods for diagnosis and management.
With gene mapping data, researchers are also learning how multiple genes act together. In the not-too-distant future, this information should allow breeders to not only select for particular traits that are linked to single genes, such as coat color, but also to multiple genes, such as fertility and performance. The microsatellite markers already can be used to provide more precise estimates of inbreeding in horses. This can be particularly useful for choosing matings in certain horse families or in breeds where the total number of individuals is limited. Microsatellites are also being used to study the evolutionary relationships between horses and their close relatives, the donkeys and zebras.
With molecular tests now in hand for three of the most serious genetic diseases that have plagued equine veterinarians and horse owners for years, applications of the Horse Genome Project are not futuristic: they are already off and running with the gene jockeys firmly in the saddle.
