Equine Genetics

On June 26, 2000, the President of the United States presided over a news conference at which a dramatic announcement was made: Scientists reported that the human genetic code essentially had been deciphered. At the White House ceremony, the scientists said that they virtually had completed assembly of what they called "the book of life." In essence, that "book" is nature's genetic instruction manual for making and maintaining human beings. Knowing the genetic code, said President Bill Clinton at the news conference, will give science immense power to heal by attacking genetic disease at its roots.

The announcement called attention to the dizzying pace at which progress has been made in the field of genetics. Little more than a decade or so ago, such progress couldn't even be contemplated. To the layman, the whole thing is mind boggling. How in the world can one decipher a genetic code by sequencing (determining the relative order of base pairs) 3.1 billion chemical sub-units of DNA and map their location on chromosomes that exist in all cells?

The human genome project was launched a mere 10 years ago and involved scientists from both the public and private sectors in a number of countries.

While progress in equine genetics has not progressed at the same dizzying pace, many advances have been recorded in that field as well, and the results will benefit horses and horse owners, just as deciphering the human genetic map ultimately will improve health care for people around the world.

Just exactly what form these benefits will take with the horse is not completely known, but some have compared the importance of present-day progress in genetics to the discovery of antibiotics.

Deciphering the human genetic code places science at a new frontier, with opportunities for further discovery stretching ahead in limitless fashion. Now that the gene structure is known, other scientists will work to discover exactly how proteins work in forming and maintaining the human body. They also will seek to understand just how these genes are expressed.

It is understandable that equine research lags behind the human field, but it also lags behind genetic research that has been conducted with cattle, sheep, poultry, and swine. Perhaps this, too, is understandable. The other species listed are part of the food chain, while the horse is economically important as an animal used primarily for recreation and sport.

However, the equine world is in the process of playing catch-up, and it is gaining ground. The present impetus began in October of 1995, when a group of 70 scientists from around the world agreed to take part in a "workshop" to create a gene map for the horse.

A World Apart, Together

Coordinating the effort to decipher the equine gene map from the beginning has been Eugene Bailey, PhD, a professor at the University of Kentucky's Gluck Equine Research Center in Lexington. He is the coordinator of both the U.S. Department of Agriculture's Horse Gene-Mapping Pro-gram and the International Equine Gene-Mapping Workshop. Other leaders include Gérard Guérin of France; Kaj Sandberg and Hans Ellegren of Sweden; Bhanu Chowdhary of Denmark; Knut Røed of Norway; Matthew Binns of the United Kingdom; Kevin Bell and Richard Brandon of Australia; Keichi Hirota, Nobuyoshi Miura, and Telhisa Hasegawa of Japan; and Doug Antczak (Cornell University), Teri Lear (University of Kentucky), Jim Mickelson (University of Minnesota), Loren Skow (Texas A&M University), and Ann Bowling and Jim Murray (University of California, Davis) of the United States. Significant contributions also are being made by scientists in South Africa, Poland, Germany, the Czech Republic, The Netherlands, Ireland, Canada, Switzerland, and New Zealand.

The equine project is a good deal smaller than its human counterpart, and it will cost somewhere in the neighborhood of $3 billion in public and private money.

There is another major difference. In the human genome project, there was competition between private and government-sponsored laboratories. In the horse genome project, says Bailey, there is an atmosphere of cooperation. Each laboratory shares its findings with all other cooperating laboratories.

"Everyone came into this project with different reasons for making the map," Bailey says, "but we all agreed that in order to have a successful workshop, we had to share the necessary elements. We have a project that is larger than one laboratory can do, and we will all benefit by collaborating. If we competed to see who could put the most genes on chromosomes, we would not be easily sharing information."

There is another direct benefit to the cooperating laboratories--a saving of money. Hundreds of thousands of dollars are saved by sharing research results with all of the other laboratories involved. No one has to reinvent the wheel, so to speak. What one laboratory discovers does not have to be researched by another.

The first discussions among scientists concerning an equine genome project began in 1994, Bailey says, but there were limited funds available at that time. However, the workshop was created with a pledge of support from the Dorothy Russell Havemeyer Foundation. With the background of workshop support, the individual programs began to receive extramural funding. For example, the University of Kentucky received grants from the Morris Animal Foundation and the Grayson-Jockey Club Research Foundation. The Havemeyer Foundation is based in New York City and funds workshops on horses. The Foundation committed to five years of funding for travel and meeting expenses. This money supported the first meeting and subsequent meetings in California and Sweden. The next meeting is scheduled for July 2001 in Australia.

The first workshop of scientists was held in Lexington, Ky., in October of 1995, and it included researchers from the United States, Japan, the United Kingdom, Germany, Australia, Switzerland, Poland, South Africa, the Czech Republic, Sweden, Norway, the Netherlands, France, and Morocco.

To establish a gene map, the scientists set a goal of locating as many gene markers as possible. The horse genome, Bailey explains, contains between 60,000 and 80,000 genes, which are pieces of DNA that code for proteins and enzymes. A marker is an identifiable physical location on a chromosome whose inheritance can be monitored.

While the human project is aimed at sequencing all of the DNA found in a human cell, the equine project is aimed more at identifying as many markers as possible.

"A complete sequence for the horse is not our goal," Bailey says. "The organization of genes is very similar among mammals, so we hope to build on the research done in other species. We will predict the organization of the horse genome by constructing a simple gene map and identifying the zones of similarity (homology) with the human map. We would need to identify between 1,000 and 2,000 gene markers to meet this goal. The cost of developing this kind of map for the horse falls between $5 million and $8 million."

To date, the cooperating scientists have identified 500 markers. A marker is used to shed light on where genes are located. "A marker," says Bailey, "is any measurable inherited difference that shows variation between individuals. The genetic variation scientists use as a marker can be something as small as a change in a single base in the DNA, to a whole deleted section." Three maps containing these markers have been published and shared with all the laboratories involved.

In order to establish markers, DNA samples from horse families were needed to study inheritance. Each laboratory was assigned part of the work. Some provided DNA from equine family members, while others developed DNA markers to place on the map. Laboratories in the United States (University of Kentucky and the University of California, Davis), United Kingdom, France, Japan, and Sweden worked on the physical mapping of genes to chromosomes.

Before that could be done, however, all of the scientists had to be on the same page in language and description. Each gene is a segment of DNA on a chromosome. The first need to be met was to establish a standard to identify and number the 64 domestic horse chromosomes.

A group of scientists, led by Bhanu Chowdhary of Denmark, closeted themselves at the University of California, Davis, for three days. When they emerged, they presented a written description of each chromosome that would be the same for everyone.

The second phase involved getting DNA samples out to 20 of the labs involved. "We became the coordinating laboratory for this," Bailey said. "DNA from 12 families of horses was sent here, and we distributed 460 blood samples to every laboratory."

A "family" includes one stallion and between 20 and 60 offspring. Breeds involved included Thoroughbreds, Quarter Horses, Shetland Ponies, Anglo-Arabs, and Standardbreds.

Each of the laboratories was asked to test at least five markers, and to test all of the families for these five markers. The results of these tests were sent to a laboratory near Paris, France, where the data was (and still is) pooled. The research goes on.

Benefits And Limitations

Does this equine genetic progress mean that in the very near future, we will be able to DNA test our horses and find out everything we want to know about behavior traits and athletic ability? Bailey says no.

"Most of the traits we value in the horse are products of more than one gene, possibly even hundreds of genes. These complex genetic traits will be more difficult to sort out and understand."

However, there likely will be many health care benefits.

"The gene map will help us understand the mechanisms of equine immunity, expose the inner workings of disease-causing organisms, and reveal the physiology that makes some horses more susceptible to developmental diseases, injuries, and infections," says Bailey. "In short, genomic research will mean to the 21st Century what vaccinations and antibiotics meant to the 20th Century."

For those who are not conversant with all of the terms and information available--and I believe they are in the majority--we will provide some basic information in an effort to better understand just what is going on in this exciting field. We must understand from the outset, however, that the very subject we are discussing is extremely complex because so many variables are involved.

To understand that statement, simply look about you the next time you are in a crowded building, street, or athletic stadium filled with hundreds, or even thousands, of individuals. There will be similarities, to be sure, but there also will be great variation. You will not find two people who look and act exactly alike.

It is the same with horses. Walk through a stable or a field inhabited by a group of horses. They all will have many similar features, but it will be impossible to find two that look and act exactly alike.

Yet, if we look at certain horse families, we will find traits that have been passed down for years. I know of one athletic family of Quarter Horses where nearly all members have a signature convex forehead or Roman nose. It is the result of a particular gene being expressed. This is known as a dominant gene.

In some families, certain genes are expressed generation after generation that can have a harmful effect on the horse's ability to perform, such as offset knees, poorly constructed hocks, or some other aspects of poor conformation.

Each horse's body contains multitudinous cells. Within each cell is a genetic blueprint for that particular animal. The blueprint, or genetic material, is carried on chromosomes, which are slender, thread-like structures that are paired. A horse has 64 chromosomes, or 32 pairs. At various locations on these chromosomes--referred to as loci or locus--are genes. A gene is comprised of a DNA nucleotide sequence. Just as is the case with chromosomes, genes exist in pairs. The two genes that are paired are referred to as alleles. However, just because they exist in pairs, doesn't mean the pairs are identical. Often they are not.

If the paired genes are identical, the individual is referred to as being homozygous for that particular trait. If the paired genes are not identical, the term used is heterozygous. Homozygous individuals have only one allele to pass on to their offspring. Heterozygous individuals, on the other hand, can pass on either of the two different alleles possessed in their genetic makeup.

When the sperm fertilizes the egg, the paired chromosomes of each parent split, with a single set of 32 chromosomes from each joining to form a new pair for a total of 64 individual chromosomes.

So, now the potential offspring of these two individuals is endowed with a complete set of genes from each parent. The way in which the genes pair up will determine which genes are expressed.

Normally, the dominant gene will always have its way when paired with a recessive gene. Sometimes, however, both parents will pass on a recessive gene for a particular trait; if so, then that recessive gene will be expressed.

A prime example of what can happen negatively when recessive genes are expressed occurred some years ago with a particular beef cattle breed. The breed contained a recessive gene for dwarfism. Anytime a bull and cow were mated with each carrying the recessive gene for dwarfism, the gene would be expressed and the offspring would be a dwarf. The problem was ultimately solved through selective breeding.

If one can remove a negative trait, such as dwarfism, through selective breeding, doesn't it stand to reason that if one were to breed selectively for a single trait, such as speed, that the result would be increasingly faster horses? The answer remains no. There are a great many factors involved in the ability to run fast.

This is known as quantitative gene action as opposed to qualitative gene action. In qualitative gene action, a particular trait is influenced by a single pair of genes, or perhaps by two or three pairs of genes. In quantitative gene action, such as speed in a running Thoroughbred, Quarter Horse, or Standardbred, a number of genes will influence the trait.

The other genetic action might include sturdiness of leg, heart, and lung capacity; coordination; muscle efficiency; strong tendons, ligaments, and joints; and mental traits that govern a horse's will to win.

Bailey is of the opinion that the greatest contribution by geneticists will be on the factors that can indirectly influence this performance, such as disease.

"Breeders are adept at selecting for performance," he explains, "but they are often thwarted by diseases, including those with hereditary tendencies. The mandate for veterinary and animal scientists is to investigate those factors that destroy the athleticism of a horse that would otherwise be a champion. Weaknesses in the leg bones result in life-threatening breakdowns during races or training.

"Infectious diseases can cause abortion of valuable foals or interrupt the performance of competition horses during critical stages of their career. Breeders would like to select for performance and avoid health problems.

"Since we have not had tools to investigate genetics of disease, previous research has been focused on nutrition and other environmental factors that influence diseases. With the advent of genomic research in the horse, we can begin to study the genetics of these diseases. Genomic research can help us to better understand health processes and devise better husbandry methods and therapeutic treatments, or determine whether some aspect of genetic selection is appropriate."

There is another factor involved--and this one is on the negative side--if one attempts to breed for a single genetic trait, such as speed. Breeding for a single trait often is at the expense of other, positive traits.

Genetic Engineering

Theoretically, genetic engineering could lead to the precise insertion of genes that influence important traits. Genetic engineering is the process of inserting DNA for a gene into a cell and altering the function of that cell or even of tissues. Theoretically, this technique could be used to endow a horse with traits not found in its pedigree.

As a practical matter, however, it likely won't work all that well. Bailey explains, "The traits we wish to alter are often the products of not just one gene, but many working in delicate concert," Bailey explains. "Altering one gene destroys the balance. Athletic performance is genetically and developmentally complex, and, therefore, unlikely to be amenable to genetic engineering in the foreseeable future."

Even when genetic engineering is not involved and one concentrates on a single trait, it can be at the expense of others. Broiler chickens are a case in point. It is possible today to buy baby chicks that will grow into three- to five-pound broilers in as few as six to eight weeks. However, it often is at great expense to the welfare of the chicken during its abbreviated lifetime. Many wind up with crippled and grotesque legs because they can't sustain the weight of their rapidly growing bodies. Others drop dead of heart attacks and seizures because the internal organs couldn't handle the stress of such rapid growth.

By concentrating on speed only, one might be able to breed a faster horse, but it also might self-destruct before ever reaching a fraction of its speed potential because traits for durability were lost.

By the same token, however, one can use genetics as an ally in breeding a horse which will remain sounder and healthier by breeding positive characteristics to positive characteristics.

The hope here would be that positive characteristics, such as good legs, lungs, heart, and temperament, would be achieved via expression of dominant genes, and that breeding a stallion with those traits to a mare with the same traits would improve the odds of having those genes expressed and winding up with a strong, sound foal. The age-old horseman's adage of "breed the best to the best and hope for the best" perhaps does have some merit, although no guarantee.

The racing and show horse industries frequently have been guilty of overlooking this aspect of genetics. Far too often, we see a horse retired because it sustained an injury. In many cases, the injury might have been related to genetics because the horse was born with a weakness that predisposed it to a certain type of injury. Yet, when that horse is forced from competition because of the injury, it very often winds up in the breeding shed and produces offspring with the potential for identical problems.

While a sound and consistent breeding program can help reduce problems in our horses, there is no sudden genetic fix for anything.

For example: Let's assume that you have a mare that is 14 hands in height and a stallion that is 18 hands tall. You decide that the correct height for your particular interest is a horse that is 16 hands tall, midway between the tall stallion and the short mare. Does this mean that if you mate the two, you will achieve that goal? Very likely not. Either the tall gene or the short gene will be expressed and represented in the size of the foal.

It is possible that if you mate the pair year after year that you will get a variety of offspring. One foal might have the gene for height expressed while in the next one, it might be the mare's gene for being short that is expressed. This does not mean that if the tall gene is expressed, the offspring would be the same exact height as the stallion. Again, we are dealing with quantitative gene action with many variables being involved. That is why there often is a vast difference between full brothers and full sisters in regard to looks and ability. It all depends on which genes were expressed quantitatively.

The Thoroughbred stallion Northern Dancer was a tremendous racehorse. He was relatively short himself, but he often sired tall horses when bred to tall mares. He also sired horses which were sprinters, and those which excelled at distances of a mile or more. A number of his sons also became great sires in their own right.

Compare him with another Thoroughbred stallion, Secretariat. He was one of the greatest racehorses to set foot on the track. He had an awesome stride and blinding speed. Yet, relatively few of his offspring came close to duplicating his accomplishments and relatively few of his sons have established themselves as great sires. In contrast, much of his positive genetic influence was on the female side.

We can assume that Northern Dancer was loaded with a great many dominant genes that were expressed more often than not in his offspring, and that Secretariat was not. He inherited the genetic potential to be as great as he was, but apparently was unable to pass along those same traits consistently.

Environmental factors can muddy the waters a good bit when we are attempting to understand the role that genetics plays. If the offspring mentioned above in the tall stallion-short mare scenario should inherit the stallion's genes for height, it does not necessarily mean that it will achieve that potential. The offspring might have the genetic capability to reach 17 hands, but if it is not fed properly and is stunted during its early years, it might be shorter.

A horse also might inherit all the right genes for well-conformed legs, but if he is sent pounding over hard surfaces before the bones, muscles, tendons, and ligaments have a chance to develop, the horse could be crippled, without a chance to achieve its genetic potential.

There can be a case where two horses inherit, generally speaking, the capability to perform at matching levels in a given discipline. Yet, if one horse receives better training for that particular discipline, it might reach its genetic potential while the poorly trained horse does not.

Genetic and environmental factors become even more entwined when we attempt to learn about behavioral traits. Does, for example, a foal inherit more from its dam than its sire in the way of temperament? Is environment a prime influence? Is the foal merely mimicking its mother's behavior, with environment overriding genetic influence?

If a mare is a stall weaver and her foal follows suit, does that mean the foal inherited the tendency, or is it merely copying its mother's action? In some cases, both genetic and environmental influences are involved. Perhaps the mare passed on that tendency for stall weaving and solidified it by providing the foal with a daily example.

Sometimes nature intervenes and dictates when expressed genes can go into action and reach full potential. In a noteworthy experiment at Colorado State University, a pony mare was inseminated with semen from a draft horse stallion. Had that foal's genetic potential been even partially realized in the uterus, it would have run out of space and never reached parturition. Instead, the foal remained small enough for normal delivery. However, once out of that confining influence, its genetic potential was realized and it very soon towered over its mother.

Basics Of Diseases

Heredity and environment also become intermixed in some equine diseases. Bailey explains, "Developmental bone diseases are a major cause of unsoundness among horses, and a genetic component is strongly suspected. However, dietary metals, growth rate, planes of nutrition, and conformation clearly have an impact on the occurrence and severity of the condition. Cryptorchidism, conformation, fertility and infertility, response to infectious diseases, and responses to therapeutic drugs are all traits that may have a complex mode of inheritance and strong environmental influence. The solution to these health problems will most likely derive from genomic based research."

Bailey is concerned that horsemen aren't all that enthused about the equine genome project that is underway, although ultimately they will reap definite benefits.

One of the concerns on the part of horsemen might be that they will have to be a geneticist to understand all of the new information that is available or forthcoming. Nothing could be further from the truth, Bailey says.

"A gene map for the horse," he says, "will allow us to investigate the complex hereditary basis of behavior, performance, and disease. But this concept concerns horsemen. One of my colleagues made the unfortunate statement a while ago that in the future, horsemen are going to have to understand molecular genetics. This simply isn't true. You don't have to be a mechanic to drive a car. With this map, geneticists are going to be able to give people in the industry better-quality information to explain why things happen the way they do and how to avoid problems in the future. We are not going to be developing secrets that are going to destroy the industry."

There have been some real accomplishments as the result of genetic research already. Genomic investigation has been used to identify genes that cause hyperkalemic periodic paralysis (HYPP), a genetic disease of Quarter Horses and derived breeds (Paints, Appaloosas), characterized by sporadic episodes of generalized muscle tremors and stiffness accompanied by elevated serum levels of potassium, and severe combined immunodeficiency (SCID), a lethal, inherited disease of Arabian foals, characterized by an absence of T- and B-lymphocytes, in horses.

"In the case of HYPP, work done at the University of Pittsburgh and the University of California-Davis led to the recognition that a single change in the amino acid structure of the gene altered a protein's function, causing the disorder.

"In the case of SCID, researchers at the University of Texas Southwestern Medical Center found a serious deletion of five DNA bases that resulted in a complete disruption of the production of a protein. Although the DNA mutation that caused SCID in horses was different from the mutation in other species, the same gene was affected."

Because science has solved the genetic mysteries surrounding these two diseases, horsemen can take preventative steps to protect future offspring. Breeders know that if both sire and dam have the gene for either of these two diseases and are mated, it is a certain bet that the foal will be afflicted. A simple genetic test is all that is required to obtain this information to prevent such matings.

Another equine malady that is genetically based is overo lethal white foal syndrome. The condition sometimes crops up when breeders mate two overo horses. A Paint horse with a certain overo gene combination will be born white. Although it might appear normal, it is unable to pass food through its digestive tract due to a lack of nerve cells in its intestine, and therefore it soon dies. A gene test is available to detect in advance this potential catastrophe based on work reported from the University of Minnesota, University of California, and from Australia.

In the above three genetic traits, Bailey says, the discovery of the gene responsible for the trait was based on a comparison to a similar genetic trait in other species. Once a candidate gene was nominated, based on a known human or mouse trait, the homologous horse gene was cloned, sequenced, and a genetic variant found that was associated with the appearance of the trait.

Bailey says the future of the horse gene map lies in collaboration, investigation, and application. "We need to promote the map to the horse industry," he says. "We've not done much of that in the last four years because we've not had a product. But now that we have three linkage maps, we need to spend some time explaining to people what it is and how we can use it."

The cooperation of horsemen and veterinarians is essential, he adds.

As with so many aspects of equine health, more research is needed. "We have the bare minimum for markers," Bailey says. "A couple million dollars worth of research across horse labs worldwide would help us flesh out the map. At this point, they have 2,000 markers on the pig and cattle maps, and those scientists don't believe that's enough. Across the maps that have been published, we have a total of 500 markers. We have a way to go."

To monitor the continuing progress of the horse gene mapping program, visit www.uky.edu/AG/Horsemap/.

About the Author

Les Sellnow

Les Sellnow is a free-lance writer based near Riverton, Wyo. He specializes in articles on equine research, and operates a ranch where he raises horses and livestock. He has authored several fiction and non-fiction books, including Understanding Equine Lameness and Understanding The Young Horse, published by Eclipse Press and available at www.exclusivelyequine.com or by calling 800/582-5604.

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