The Harry M. Zweig Memorial Fund for Equine Research

Horse Genome Project

Dr. Douglas F. Antczak

The goals of this project are to continue to develop a genetic map of the horse and to apply information from the gene map in studies of the effects of imprinted genes on performance traits. The first generation equine gene map developed during the past 4 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 important applications of genetic knowledge of the horse in the future.

During the past 4 years (1996-1999) Cornell has participated in 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 have been 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 autosomal recessive diseases can now be attempted 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. 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 musculo-skeletal disorders are thought to have a strong genetic component. A genetic map of the horse is necessary to identify the individual genes which contribute to multigenic traits.
This proposal seeks continued support for Phase 2 of Cornell's participation in the international collaboration of the Horse Genome Project. Specifically, during the three year period 1999-2001 we are undertaking the following investigations: 1) We continue to contribute to the cooperative gene mapping effort of the Horse Genome Project Workshop through identification, characterization, and testing of equine microsatellite markers that form the backbone of the horse gene map. 2) We are also investigating polymorphism in 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.

During the coming year we would continue to map the 204 new microsatellite markers that we have identified during the past four years. The immediate goal for the Horse Genome Project Workshop is to complete a 300 marker linkage map by the year 2000. In our new studies we are also investigating horse genes which show parent-of-origin effects in mice and humans. These 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. In the coming year we would complete the development of gene probes for four major imprinted genes which have been shown to control growth and development in other species. These probes would be tested for imprinting of the target genes using equine tissues. If the genes prove to be imprinted, they would subsequently be tested for variation within Thoroughbreds as candidates for genes controlling the Maternal Grandsire Effect.

During the past year there has been much progress in the Horse Genome Project, both here at Cornell, and at the level of the international Workshop. At the Baker Institute we have continued to characterize equine microsatellite markers for their utility in gene mapping. As of this writing we have fully characterized and published 100 new microsatellite markers for the horse. This total makes us the leading laboratory world-wide for the identification of this important type of genetic marker. These markers have also been mapped to individual horse chromosomes through collaboration with the Veterinary Genetics Laboratory at the University of California at Davis. This information greatly increases their utility. The markers are also being linked to other genes on the Horse Genome Project's half sibling reference families and on the unique full sibling horse family developed by my long-time collaborator, Prof. W. R. Allen of Cambridge University in England.

On the Maternal Grandsire Effect project we have begun to characterize four horse genes which are imprinted in humans and mice. Related work by a Swedish laboratory has shown recently that the imprinted Insulin-like Growth Factor-2 (Igf2) gene we are studying can affect the size of heart and muscle mass in pigs. This is clearly a trait of interest to horsemen.

The Horse Genome Project has continued to attract outstanding students. Over the past year two students from the Veterinary College's summer Leadership Program and an undergraduate honors student have worked on this project. Ms. Amanda Murphie (1998 Leadership student and final year veterinary student at the University of Sydney, Australia) was first author on a report describing 20 of Cornell's new horse microsatellite markers. Ms. Kim Costello (1999 Leadership student and first year veterinary student at Virginia Tech University) is spending this summer working on the imprinting project. Ms. Leah Ruth (Howard Hughes Undergraduate Scholar from Cornell) worked on horse microsatellites for her undergraduate Honors project, which was submitted in the spring of 1999. Ms. Ruth will enter graduate school in equine genetics at the Univ. of California at Davis in the fall of this year.

The Dorothy Russell Havemeyer Foundation, Inc. continues to support core activities of the Workshop, and this $50,000 per year commitment will continue beyond the initial 5 year project begun in 1995. In 1997 the horse was accepted as a member species of NRSP-8, the National Animal Genome Research Project, along with cattle, sheep, pigs, and chickens. This USDA funded Regional Project was renewed in 1998 for a second 5 year term. It provides $45,000 per year in new funds for centralized facilities and special resources for the horse gene mappers. When considered with the Havemeyer Challenge Grant, this new grant doubles the available central funds which facilitate the efforts of individual laboratories of the Horse Genome Project collaboration.

Finally, here at Cornell, a major campus wide program in genomics has been initiated. This program will link the research of scientists with interests in plants, animals, humans, and microbes, and it has already brought new technology for gene mapping and sequencing to Cornell. I have served as a member of the Cornell Genomics Task Force since its inception.

Momentum for horse genome research continues to build, and the success of the international collaboration among participating laboratories continues to attract new resources to this project. During the past 4 years the College of Veterinary Medicine at Cornell emerged as a leading participant in the Horse Genome Project, and progress in Cornell's laboratory continues to accelerate. Support from the Zweig Memorial Fund has been critical to this success.