February 21, 2007

C.U. Researchers Help Map Horse Genome

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Thanks to a recent breakthrough by the Horse Genome Project, a horse named Twilight has left her genetic imprint on the history of veterinary medicine. Cornell’s own Thoroughbred mare, Twilight was the donor whose cells were used by Project researchers across the country to assemble the complete sequence of the horse genome. While isolated gene sequences were contributed by a wide variety of researchers, the actual assemblage of the genome was completed by a smaller team led by Kerstin Lindblad-Toh at the Eli and Edythe L. Broad Institute of the Massachusetts Institute of Technology and Harvard University.

Three-year-old Twilight is just one of a small herd of horses stabled at the McConville Barn. This thoroughbred family has been interbred for 25 years for research purposes.

The $15 million price tag for the Horse Genome Project was paid by the National Human Genome Research Institute, one of the National Institutes of Health.

The Horse Genome Project’s achi-evement, the complete sequencing of the approximately 2.7 billion DNA base pairs in the horse genome, has been deposited in public databases for the use of biomedical and veterinary researchers across the globe. The release of the sequence is to be followed by “a publication analyzing the horse genome sequence and its implications for horse population genetics,” according to the National Human Genome Research Institute’s report on the breakthrough.

Horse Genome Project research at Cornell was led by Prof. Douglas F. Antczak, director of the Baker Institute for Animal Health, a part of the College of Veterinary Medicine. Antczak had been involved with the Horse Genome project since its inception ten years ago.

Antczak’s team is focused on horse immunology, particularly the interaction between a mother and fetus during pregnancy. The horses stabled at McConville Barn have been bred for this research.

Twilight is not the only member of her famous family to contribute to genetic research: her half brother Bravo’s DNA was used to create another resource — a bacterial artificial chromosome library. Like Twilight, “his genes are being studied all around the world,” Antczak said. With the success of the Horse Genome Project, Antczak hopes to get closer to discovering why a mother’s immune system does not target the fetus and placenta as invading foreign objects and destroy them.

Other Cornell researchers expect to benefit greatly from the publication of the horse genome sequence. Prof. Maria Julia Bevilaqua Felippe Flaminio, large animal medicine, is one such researcher. She is currently studying a horse immunodeficiency that impairs antibody production and thus heightens susceptibility to bacterial infection. Although Flaminio and her team have traced this immunodeficiency to the depletion of B-cells, which are responsible for antibody production, they have as yet been unable to identify the cause of B-cell depletion. But Flaminio and her team are nearing their goal with the aid of the Horse Genome Project’s research.

“The Horse Genome Project has been instrumental in the investigation of candidate genes that could be involved in the B-cell depletion,” Flaminio said.

Flaminio added that the completion of the horse genome sequence has contributed to a researcher’s ability to replicate naturally occurring antibodies.

“The production of other reagents fundamental to the study of immunology, e.g. monoclonal antibodies, has been expedited by the knowledge of their gene sequences,” Flaminio said. “We hope to have access to tho-se reagents in the near future, in a greater speed than before.”
Antczak in part credits the pronounced dip in the cost of genetic research for this recent breakthrough.

“The price of sequencing has gone down dramatically in the past several years,” Antczak said. The millions necessary for completion of the Horse Genome Project’s efforts were comparatively little; Antczak pointed out that this cost is “much less than $1 billion,” which was the estimated cost of sequencing the human genome, and Antczak only expects the cost of genetic research to go down.

“Scientists are talking about a thousand dollar sequence. It’s not here yet, but it probably will be in about five years,” Antczak said.

Antczak was able to take blood samples from Twilight whenever he needed them, whereas researchers elsewhere were limited to a cell line of fibroblasts, created from a small sample of Twilight’s skin. But according to Antczak, this does not make his team’s research any different from the research of his colleagues.

“It doesn’t change our experiments that much. Because we share so much with other individuals around the world, we’re happy to provide as much tissue from Twilight as we can, without harming her, of course,” Antczak said.

Antczak is quick to point out that the Horse Genome Project is an even more collaborative effort than is evidenced by the involvement of researchers across the country.

“There’s been a grassroots effort by many of the faculty members in the biological sciences to provide support for one another in studies of genetics,” he said. “We’ve formed quite a nice network of individuals … who are producing ways of analyzing genomes and genetic data that makes Cornell a very exciting place in which to study right now.”

Even Cornell undergraduates provided support for Antczak’s research. Work-study students in the animal sciences tended to Twilight and the other horses at the Baker Institute.

“They know how important she is,” Antczak said. “She gets very good care.”

Though Twilight’s genome can be applied to the study of horses in general, Antczak asserts that more genetic research is necessary in order for scientists to have a full perspective on the horse genome.

“We are finding that there is no single answer to, ‘What is the genome sequence of a chimpanzee, or a frog, or a horse,’” Antczak said. “Every individual has a sequence which is considerably different from every other individual.”

“Every individual has a sequence which is considerably different from every other individual,” Antczak said.

Even within Twilight’s limited population, there are a variety of genetic differences.

“With a billion base pairs,” Antczak said, “a one percent difference can be quite a lot.”

Antczak believes that the completion of Twilight’s genome will lead to the sequencing of the genomes of more thoroughbreds and of other horse breeds in a more efficient fashion. According to Antczak, “the advancements in sequencing technology are such that we will really be sequencing not just an individual from each species, but many individuals.”

One might wonder why the National Human Genome Research Institute was willing to supply the funding for horse genetics research. But according to Flaminio and Antczak, horse and human genetics are not mutually exclusive. Though Flaminio acknowledges that the knowledge of the horse genome is not as vast as the knowledge of human genetics, through which “the genetic background of diseases has been identified and characterized repeatedly,” she suggests that breakthroughs in horse genetics may inform the way researchers approach the study of diseases in humans.

“Gene therapy may become a real possibility once we learn about the genes involved in certain diseases. In these cases, horse genetics can bring solutions . . . for diseases that are similarly manifested in humans,” Flaminio said.

To Antczak, horse genome research is an important vehicle for understanding human origins. “Each new species’ sequence is being lined up under the human genome,” Antczak said. “Scientists are using this information to look for patterns . . . how evolution has occurred between these species and what’s driving evolution. And we’re looking for areas of DNA sequence that are conserved among these species. Those are probably very important functions that are critical for survival in all mammals.”

Thus horse genome research serves dual purposes. As Antczak said, “there’s really a lot of bang for the buck.”