ViaGen Preserving and Multiplying Superior Genetics

Bull’s Eye!

-Cloning takes aim at hereditary diseases by expanding the gene pool of horses that are genetically “clean”.

A revolutionary breeding technique could become a powerful weapon in the arsenal to eliminate equine genetic diseases by broadening the gene pool to include the genetics of top performing geldings that are genetically “clean.” 

Since the first equine clone was foaled in 2003, cloning has been recognized as a tool that enables horses that became outstanding competitors after they were gelded to reproduce as stallions. But as scientists continue to unravel the mysteries of genetic diseases that have plagued the horse industry for decades, cloning could also help eradicate them by increasing the number of sires that are “clean” for the lethal recessive genes that carry the disease.

Like financial experts who emphasize the importance of diversification in personal investments, cloning offers a way for breeders to diversify their genetic portfolios.  Although nine equine diseases have already been linked to genetic mutations, researchers expect to identify more.

That makes breeding options and diversification even more important for breeders who not only want to produce horses that are competitive, but also won’t pass along hereditary defects to their offspring. 

“We’re just starting to peel the lid off this thing,” said Blake Russell, vice president of ViaGen, the Austin, Texas-based commercial cloning and gene-banking company that holds the patent for equine cloning. “We all know there are going to be dozens of genetic diseases out there that haven’t been identified yet. As we learn more about genetics, we’re going to find out that lots of things have a genetic root.”

Founder Effect
Hereditary disease has been found in a variety of horses. Few equine breeds are immune.

The list includes hyperkalemic periodic paralysis (HYPP), a muscle disorder that can cause tremors or paralysis in Quarter Horses, Paint Horses, and Appaloosas. Another disease, a glycogen storage disorder called polysaccharide storage myopathy (PSSM), affects Morgans, Belgians, Percherons and Warmbloods, too.

Severe combined immunodeficiency (SCID), a lethal condition that makes foals susceptible to infections, is inherited in Arabians, while recurrent exertional rhabdomyolyssis, or “tying up,” is suspected to be linked genetically to Thoroughbreds.

Scientists have traced some diseases, such as HYPP and hereditary equine regional dermal asthenia (HERDA), a debilitating condition marked by hyperextensive skin, to a specific sire. In 1992, HYPP was publicly tied to Impressive, the immensely popular American Quarter Horse stallion whose pedigree is the foundation of many halter horses. By May 2008, there had been 366,000 Impressive descendants registered with the AQHA, according to Gary Griffith, who served as executive director of AQHA registration. The report was authored by University of California at Davis geneticist Sharon Spier, D.V.M., and E.P. Hoffman of the Research Center for Genetic Medicine in Washington, D.C. 

In 2004, the western performance horse industry was rocked when HERDA was linked to Poco Bueno, a stallion whose pedigree can be found in many of the world’s top cutting and cow horses.  

HYPP and HERDA are examples of popular sire syndrome, a tendency among breeders to increase their chance of producing winners by crossing mares with proven sires of top performers. While the crosses have resulted in hundreds of champions, the down side is a concentrated gene pool in which negative inherited traits may be amplified over the years.

“Too much breeding to one animal will give the gene pool an extraordinary dose of his genes, and this will include whatever detrimental recessives he may carry, to be uncovered in later generations,” Dr. Spier said.  “This can cause future breed-related genetic disease through what is known as Founder Effect.”

By using genetic tests and reproductive techniques, such as frozen semen, embryo transfer, and cloning wisely, horse owners can effectively breed around a disease and minimize the chance of passing it on. After a genetic test for HYPP became available in 1992, AQHA officially recognized HYPP as a genetic defect and undesirable characteristic. In response to concerns by its members, the world’s largest equine breed registry passed a regulation about HYPP in 1996.

According to Rule 205, foals born in 1998 or afterward that trace back to Impressive have a statement added to their registration certificate that recommends testing for HYPP unless test results that indicate the foal is negative (N/N) for the disease are on file with AQHA.

“AQHA will test any foals that are required to be parentage verified and who trace to Impressive for HYPP prior to registering them,” said Tom Persechino, AQHA senior director of marketing. “This testing will be performed with the same DNA sample submitted to the laboratory for parentage verification.”

AQHA took the regulation one step further in 2007 when it stopped registering foals that test double positive (H/H) for HYPP. An H/H horse, which means it has an HYPP allele from each parent, will pass the gene to its offspring 100 percent of the time.

HYPP is a dominant trait, which means the disease only requires one parent to have and pass on the gene and the disease. Because of this, beginning in 2020, AQHA will not register horses that test N/H for HYPP.  

Getting the ‘look’
Ironically, the gene for some diseases, such as HYPP and HERDA, appear to give competitors an edge. In fact, the majority of halter horses in the winners’ circle trace back to Impressive, so the marketplace is a powerful incentive for horse owners to breed to them.

After the test for HYPP became available, researchers discovered the number of H/H horses had actually increased, according to a study of data submitted to the Veterinary Genetics Laboratory at UC-Davis from 1992 to 2006. The number of N/H and N/N horses remained the same, said Dr. Spier, an international expert on HYPP who presented the results at the 2006 American Association of Equine Practitioners Convention.

“There has been no decrease in the gene frequency of HYPP,” said Dr. Spier. “Because the gene frequency has not decreased over time, and is higher in elite performance horses successful at halter, this demonstrates that these horses have an advantage in the show ring for the phenotype associated with this disease.”

Successful halter people on the front lines of the industry agree.

“Breeders continue to breed to an Impressive horse because it has more potential to be a better show individual if it’s an N/H horse than if it’s an N/N horse,” said Ted Turner Jr., who has shown 66 AQHA World Champions since he began exhibiting halter horses in the mid-1970s. Turner trains at Turner Bradshaw Ranch in Thackerville, Oklahoma, where he partners with sports broadcaster and four-time Super Bowl quarterback Terry Bradshaw.

“An N/H horse has more potential to have more muscle,” Turner noted. “N/N horses are really nice, but 95 percent of the time they don’t have the cut and that extra little oomph you’re looking for. There are always exceptions to the rule.

“But I would rather have an N/H horse to show. It usually has more potential than an N/N horse to get that look you want. It’s worth the risk.”

Peter J. Cofrancesco III, whose family has bred and shown halter horses for 40 years, concurs with Turner. Located in Sparta, N.J., Peter J. Cofrancesco Jr. Farms has owned 35 AQHA World Champions, and its owner has shown 16.

“All of our horses that have been successful on a national level have bloodlines that trace back to Impressive,” said Cofrancesco, who serves on the AQHA Executive Committee. “Most of the halter horses that are winning today have physical attributes that they normally would not have if they were double negative. Everything has become so specialized and it’s so competitive that everyone is trying to breed that perfectly conformed horse.

“But if someone chooses not to incorporate the HYPP gene into their program, those horses are certainly available to them. There are a lot of mares out there with the HYPP gene, so with AQHA’s new registration rules, those mare owners are going to want to breed their mares to a stallion that is double negative.”

Breeders in every equine discipline are searching for an outcross stallion that can strengthen the breed without contributing negative traits. But that genetically clean individual might already be under the industry’s nose as a gelding that is a proven competitor.

Swimming in the pool
It happens all the time, usually when a colt is a yearling. Perhaps its pedigree isn’t a name brand because its sire is young. For whatever reason, the stallion is gelded, and it goes on to become an outstanding competitor, winning titles and setting records. But because it’s a gelding, its desirable characteristics are lost.

But what if you could bring him back as a stallion so you could propagate his genetics? Cloning provides an opportunity to do that, plus dilute popular sire syndrome, Russell said.

“Cloning is the best tool we have available today to deal with popular sire syndrome. Outstanding geldings that went on to prove themselves in competition were gelded for whatever reasons,” he explained. “Maybe they weren’t the most popular bloodline at the time, but in light of some of these recessive genetics problems, maybe those bloodlines should be resurrected and given another opportunity.

“Or maybe the colt is out of a desirable bloodline that has a negative trait, and it’s gelded because of the indictment that came with the bloodline. You probably don’t even bother to gene-test your geldings. Then the horse goes on and does fantastic. But if that gelding is tested and comes back negative, then by cloning, you can bring that animal back as a stallion.” 

“By offering animals from proven bloodlines that test negative for a disease, those animals could pass along all the desirable genetics of their bloodline without passing the genetic mutations.”

While some geneticists believe cloning will increase popular sire syndrome because it adds more individuals who have the same genetics to the gene pool, Russell maintains the opposite is true.

“My argument is exactly the opposite – the only way you move away from popular sire syndrome is to have more good sires,” he explained. “Cloning offers more options in the market. There are many examples in any discipline where there are geldings that are great candidates to be good sires after they prove themselves.”

Russell cites a clone of Tailor Fit, the two-time AQHA World Champion running horse, as an example. The 1995 bay gelding by Strawfly Special out of Silk Shirt netted $1.4 million in lifetime earnings before he was retired. Tailor Fit’s soundness was as solid as his track record, which he proved by competing through his 6-year-old year. The clone, which Russell co-owns with Betty Jane Burlin, was born on May 1, 2009.

If the clone proves himself as a sire, he would broaden the gene pool by offering an alternative to other great AQHA running horses like Dash For Cash or Peter McCue.

“Tailor Fit has to prove himself as a sire before he draws some traffic away from those horses. But if he does, then he broadens the potential, and therefore popular sire syndrome is not as big as a problem as it would have been otherwise,” Russell said.

Genetic inbreeding, which resulted in inherited diseases, occurred for centuries before cloning came on the scene.

“People say there is too much genetic inbreeding in horses now, but that was done without cloning,” said Gregg Veneklasen, D.V.M., an equine reproduction specialist who performs the embryo transfers for ViaGen. “There are two ways to eliminate genetic disease. One, breed only to those horses that are N/N, or double negative, for the disease. Or two, breed to clones of horses that are N/N, or double negative.”

Dr. George Seidel Jr., a University Distinguished professor at the Animal Reproduction and Biotechnology Laboratory at Colorado State University, believes cloning can be used to address different needs.

“One of its clear advantages is making a stallion out of a gelding,” he said. “Cloning is often thought of narrowing the gene pool and it can do that, depending on how it is used. But in terms of making a stallion out of a gelding, you’re doing the exact opposite – you’re broadening the gene pool because you’re allowing more genes to be used.”

Cloning could also be used to decrease hereditary diseases in horses, said Seidel.

“I think cloning could have a positive impact on genetic disease,” he said. “It’s a tool that can be used in that direction. I don’t know what impact it would have on the industry, but I think it would help.”

Cloning isn’t a cure-all for genetic diseases, Russell cautions.

“It isn’t the silver bullet that’s going to solve every breeding problem a breeder has,” he maintains. “But in the case of genetic diseases, it’s a technology that broadens the number of options available to breeders. Genetic diseases typically are the result of one or two popular families.

“As they say, ‘Dilution is the solution to pollution.’”

No bull
When a lethal hereditary disease prompted the American Angus Association to stop registering cattle that carried the genetic mutation, some producers turned to cloning to take up the slack.

After scientists tied arthrogryposis multiplex (AM), also known as curly calf syndrome, to a lethal recessive gene traced to a maternal grandsire, Rito 9J9 of B156, the association acted swiftly to eliminate the gene.

According to an amendment approved on Nov. 15, 2008, offspring of registered AM carrier females and bulls born on or before Dec. 31, 2009, must be DNA tested for the mutation in order to be registered. Calves of registered AM-carrier females and bulls born on or after Jan. 1, 2010, must be DNA tested and be free of the mutation to be eligible for registration.

In a nutshell, the new policy allowed animals carrying the gene to be registered through 2009. After that, no animal with the gene could be registered.

“They wanted to get the allele out of the population,” said Dr. George Seidel Jr., a reproductive physiologist at Colorado State University who also raises Angus. “After 2009, you can’t register an animal that is heterozygous (who carries only one copy of the gene). If an animal has two copies, it won’t survive. If you have one copy, you’re still out. You have to do a blood test even if there’s a possibility an animal is carrying the gene.

“The rule wasn’t particularly popular with a lot of people, partly because the heterozygote is a perfectly normal animal. But half of the offspring of heterozygote curly calf syndrome cattle will get the bad allele.”

As a result, some old bloodlines have become even more popular, and breeders have cloned some cattle to preserve their genetics and make them more available. Owners of N Bar Primrose 2424, who died when she was almost 20 years old, have made genetic copies of the cow that had a major impact on the Angus breed.

Primrose 2424′s sons include Pathfinder Sire N Bar Emulation EXT (the leading sire of registered Angus cattle for seven consecutive years), and her daughters, who brought top prices at industry sales, have been key breeding influences around the world.

“Cloned calves of Primrose 2424 are selling at public auction,” said ViaGen’s Russell. “Cloning is playing a role in helping to multiply some of the individuals that were known to be negative for lethal recessives.   

“Primrose 2424 had been owned by several people who had her biopsied, so each of those groups have been cloning her. Cloning is helping to fortify their bloodlines and preserve the genetics of a great cow.”

Express Ranches in Yukon, Oklahoma, has cloned Primrose 2424.

“We recognize the importance of producing high-quality breeding stock that is genetically pure and free from known genetic defects,” said Mark Squires, office administrator of Express Ranches. “We use all proven technologies to meet the needs of our demanding clients”.

“For example, in recognition of the known recessive defects identified in the Angus breed in the past 24 months, we have produced a few clone calves of Primrose 2424, who has a track record of producing high-quality sons and daughters. She is free from these known defects, and any Angus breeder can use more Primrose genetics in their herd.”

Tags: cloning genetic disease, equine clone, equine cloning, HERDA, HYPP