The Harry M. Zweig Memorial Fund for Equine Research

Horse Genome Project

Dr. Douglas F. Antczak

Objective: The goals of this project are 1) to continue to develop new methods for characterizing the genome of the horse, and 2) to apply information from the horse gene map in studies of equine performance and disease. The first generation equine gene map developed during the past six years is already being used by equine scientists, clinicians, and horse breeders in the study of normal growth and development, in the diagnosis and management of genetically determined diseases, and in developing new breeding strategies, and there is potential for many more important applications of genetic knowledge of the horse in the future.

Background and Significance: During the past six years (1996-2001) Cornell has participated in and become a leading member of the International Horse Genome Project Workshop. This consortium of 22 laboratories from 12 countries has collaborated to produce the first genetic map of the horse. Advances in technology have greatly improved the efficiency of gene mapping and sequencing, thereby reducing costs and facilitating progress in this area. Moreover, information on the genome structure of other species, notably humans, cattle, and pigs, has been used to speed progress in defining the horse genome.

Benefits have already begun to accrue to the equine industry from genetic studies of the horse. During the 1990s genes causing three of the most important genetic diseases of the horse were identified: Severe Combined Immunodeficiency Disease (SCID) in Arabians, hyperkalemic periodic paralysis (HYPP) of Quarter Horses, and the Lethal White Syndrome of Paint horses. Genetic tests for these diseases are available commercially, and thus breeders and prospective buyers can choose to have their animals tested, so that they can make informed decisions concerning matings or purchases. The identification of mutant genes causing other inherited equine diseases is now underway using the markers currently available in the horse gene map.

A gene map can also help clinicians to diagnose and possibly to treat a variety of conditions caused not by a single gene defect, but by a number of genes acting together (multigenic traits). Many important equine diseases, such as chronic respiratory disease (heaves), laminitis (founder), 'bleeders,' a number of immune deficiency conditions other than SCID, and a variety of musculoskeletal disorders are thought to have a strong genetic component. A detailed genetic map of the horse is necessary to identify the individual genes which contribute to multigenic traits.

Specific Aims: This proposal seeks continued support for Phase II of Cornell's participation in the international collaboration of the Horse Genome Project. Specifically, during the three year period 2002-2004 we propose to work in the following areas:

Part 1) Gene Mapping: We would focus on the sequencing of individual horse genes and assigning them to specific chromosomal locations. It is estimated that the genomes of mammals, including humans, contain no more than 30,000 genes each. It should be possible for the Horse Genome Project scientists to determine sequences from all of the predicted 30,000 equine genes within the next three year period, adding to the equine gene sequences already determined.

Part 2) Performance and Disease Studies: First, we would continue our investigation of imprinted genes that are known to affect growth and development. In these studies we are testing the hypothesis that polymorphic imprinted genes are responsible for the "Maternal Grandsire Effect" long recognized by Thoroughbred breeders. Second, we would intensify our molecular studies of selected genes of the equine Major Histocompatibility Complex (MHC). The MHC genes have been demonstrated to be associated with susceptibility to skin tumors in horses, and with other diseases involving the immune system.

Plans for 2002: Part 1) Gene Mapping: Of primary importance will be our new effort to determine the DNA sequences and chromosomal location of a large number of horse genes (target for the Cornell laboratory of 1000 gene sequences for 2002). This would be accomplished using well-defined strategies and techniques used successfully in other species. The research would be part of a co-operative project involving several laboratories of the Horse Genome Project.

Part 2) Performance and Disease Studies: We continue to investigate horse genes which show parent-of-origin effects. These so-called imprinted genes behave differently from all other genes described during the past 100 years—their activity varies depending upon whether they are inherited from the paternal or maternal parent. Such genes could explain the pattern of performance inheritance shown in certain Thoroughbred lines. Secretariat, for example, although an outstanding performer himself, enjoyed much less success as a sire of performers. However, Secretariat is considered a leading sire of broodmares—that is, inheritance of his positive performance traits is manifest primarily in his daughters' offspring. Our hypothesis is that the activity of certain performance-enhancing genes is determined by the parent of origin. Imprinted genes behave in this way, and many of them control processes of growth and development, which could explain their effects on performance. We are testing selected imprinted genes for variation that might explain the Maternal Grandsire Effect. In other studies we are characterizing in detail the DNA sequence and chromosomal structure of genes of the equine Major Histocompatibility Complex that have been implicated in the development of sarcoid skin tumors and other diseases of the equine immune system. Finally, we continue to collect samples from Arabian Foals born with 'Lavender Foal Syndrome.' Various efforts have been made to raise awareness of this syndrome among breeders and establish Cornell as a collection center.

Progress in 2001: At the level of the Horse Genome Project workshop, the 100+ Cornell microsatellite genetic markers continue to be positioned on the linkage map. These markers are proving useful in several studies designed to identify disease causing-genes in horse families. On the Maternal Grandsire Effect project we have begun to characterize four horse genes known to be imprinted in humans and mice. Related work by a Swedish laboratory has shown recently that the imprinted Insulin-like Growth Factor-2 (IGF-2) gene we are studying can affect the size of heart and muscle mass in pigs. These clearly are traits of interest to horsemen.

Dr. Helen Bird (postdoctoral associate) has continued to work in our laboratory with Ms. Rebecca Tallmadge (PhD student) and Mr. Donald Miller (technician), along with four undergraduates, including one Honors student who will attend veterinary school next year, and a Cornell Presidential Undergraduate Scholar.

The Havemeyer Foundation has pledged support for the Horse Genome Project that will continue for at least three more years, and probably longer, depending upon progress of the Horse Genome Project. Havemeyer funds support the Horse Genome Project Workshop meetings, and they are also used for certain types of supplies that are widely used by the participating laboratories. A comparable level of support is also provided by the US Department of Agriculture through the National Animal Genome Project for centralized facilities and special resources. Finally grants to other participating Workshop laboratories from local and regional agencies such as the Zweig fund provide crucial support for technicians, graduate students and supplies required by each participating laboratory.

The horse genome project continues to attract media attention; following last year's London Times article, the New York Times ran a piece earlier this year. This has stimulated wider public interest, so much so, ABS News featured our project in an item for the World News Tonight which ran on Saturday 9th June, just after the running of the Belmont Stakes.

Conclusions: During the past six years the Horse Genome Project has achieved far more than was of the anticipated when it began in 1995. Cornell's participation in this project has made horse genetics a flagship program of the College of Veterinary Medicine. Through this collaboration the results of Cornell's research are immediately available to the other participating laboratories, and the shared resources of the Horse Genome Project are available to the equine research programs at Cornell. Continued support from the Zweig Memorial Fund is critical to future applications of horse genome research.