Cracking the Genetic Code

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New ways to diagnose horse health problems, better treatments for equine diseases, smarter breeding programs, even fresh insights into human health issues—those are some of the benefits that could stem from groundbreaking research into equine genetics. Researchers in several countries have launched a broad-based effort to understand how genes, the chemical code that controls how all living things develop and function, affect a horse’s health and even performance.

This research effort got a huge boost in 2006 when the National Human Genome Research Institute (NHGRI) announced that it would fund a project to sequence the equine genome, the complete collection of genes that make a horse a horse. NHGRI, a part of the National Institutes of Health, sequenced the human genome in 2003 and is investigating genetic similarities between humans and several different mammals. The horse was picked partly because a number of genetic conditions in horses have a similar genetic basis in humans. Scientists suspect many other similarities are yet to be found. Here’s a brief overview of the effort and what it may mean for the horse industry.

DNA DIRECTORY

Inside the nucleus of nearly every cell in the horse’s body is a full set of about 20,000 genes, arrayed on 32 chromosomes. The genes are segments of DNA (deoxyribonucleic acid). DNA molecules are made of two twisting, paired strands, a pattern referred to as a double helix.

Each DNA strand is made of four chemical units, called nucleotide bases. The bases—adenine (A), thymine (T), guanine (G), and cytosine (C)—are a sort of genetic alphabet. Their order provides a set of coded instructions for making specific proteins used to build body tissues and carry out body functions. Altogether, the horse’s genome has several billion separate bases. And sequencing the genome means identifying them all.

Scientists at the Broad Institute in Cambridge, Mass., took on the daunting task, using a Thoroughbred mare named Twilight as the representative horse for sequencing. Technology has made short work of the heavy lifting. By late last fall they had analyzed 30 million overlapping DNA segments, each containing about 700 bases. They were on track to complete the sequence—assembling all the pieces in order on each of the chromosomes, and identifying genes—early in 2007.

The Broad Institute team is also examining DNA from a variety of breeds (Akhal-Teke, Andalusian, Arabian, Icelandic, Quarter Horse, and Standardbred) to create a catalog of DNA sequence differences among breeds. These differences, called single nucleotide polymorphisms (SNPs, pronounced “snips”), will be keys in understanding genetic variability in horses. By itself, knowing the genome sequence won’t provide veterinary breakthroughs. It’s like having an aerial photograph of a town—you can see all the buildings, but you have no idea what goes on inside. But the sequence will be a powerful tool for identifying genetic contributions to disease.

GENE HUNT

The Morris Animal Foundation is raising $2.5 million to fund the Equine Consortium for Genetic Research, a collaboration involving scientists from 18 institutions in nine countries. The initial goal is to find genes and mutations (changes in DNA) that contribute a wide range of problems, including joint and musculoskeletal diseases, laminitis, and metabolic and allergic disorders.

Researchers will use the horse genome sequence in two general types of experiments, says Jim Mickelson, DVM, of the University of Minnesota, the lead institution in the consortium. The first is disease gene mapping, in which SNP “markers” (identified in the sequencing) are used to track the association of specific genes with susceptibility to certain diseases.

The work involves collecting DNA samples from horses diagnosed with the specific condition being investigated and from unaffected horses, which serve as a control population. Each sample is then analyzed for its SNP marker distribution. Markers near the disease gene (or genes) will be shared much more frequently by affected horses than the unaffected horses, and those markers are used to “map” the location of the disease gene.

“When we know what small area of the chromosome has the disease gene, and we know which genes are actually present in this region, we can select specific genes to sequence to find the exact mutation that is responsible,” says Mickelson. University of Minnesota researchers will hunt for genes for heritable muscle diseases such as tying-up (recurrent exertional rhabdomyolysis, or RER) in Thoroughbreds and PSSM (polysaccharide storage myopathy) in Quarter Horses and draft horses. They’ll also collaborate with a group in Scandinavia to identify genes linked to OCD (osteochondritis dessicans, a bone disorder) in Standardbreds. Groups at the University of California at Davis, the University of Kentucky, and Cornell University will be examining other conditions in other breeds. Researchers in Ireland and Scandinavia also hope to identify genes that affect racing performance. “It’s a long list, actually,” Mickelson says. A second type of experiment will monitor changes in genetic expression during a disease or a treatment. Only a fraction of the genes in any animal are normally expressed, or “switched on”—that is, actually producing some sort of physical response. Researchers will now be able to see which genes are turned on or off in a particular tissue before and during the development of conditions such as OCD, osteoarthritis, PSSM, or heaves, just to name a few. “The ability to evaluate all the genes at once will reveal pathways among them and the roles they play in these complex processes,” Mickelson says. “We can also determine how a therapy designed to specifically target these gene pathways improves the situation.”

LOOKING AHEAD

One outcome of the research will be better diagnostics and treatments for diseases. For example, veterinarians will be able to find out if a Thoroughbred ties up because of a genetic susceptibility to RER or because of other factors. “Horses known to have an RER susceptibility gene can be managed to minimize their chances of tying-up,” says Mickelson.

Genetic testing may also play a bigger role in breeding. Breeders already test for several previously identified disease genes, such as that for hyperkalemic periodic paralysis (HYPP), a muscle disorder affecting certain Quarter Horses. “Testing is likely to increase as more specific disease genes are identified in each breed,” says Mickelson. Research, he adds, “will likely reveal that all horses have disease genes present, just as humans do. In some cases this will affect breeding schemes and some cases not.” Since horses have been selectively bred for hundreds of years for athletic performance, the research will likely lead to better understanding of the role genes play in exercise physiology and in a host of problems—musculoskeletal, cardiovascular, respiratory—that affect both equine and human athletes. Breed associations, public interest, and perhaps economics will determine how tests are used.

“The Morris Animal Foundation is making a tremendous investment in time and energy” to help achieve these goals, says Mickelson. “They now need the financial support of the entire equine industry.” Researchers also need help from breeders, trainers, and veterinarians in obtaining diagnoses and samples from horses with particular conditions being studied, he adds. “We are trying to move equine medicine into the same realm of possibilities as human and canine medicine, where tremendous advances are being made,” Mickelson says. “We are certain that genetic approaches to improving equine health and well-being will pay off in many ways in the near future.”