Crooked legs in Shetland ponies often result from a hereditary disease that leads to disturbed skeletal development and usually requires euthanasia. As such, the condition can cause major problems for Shetland breeding farms. But new genomic research has finally identified the responsible genes, a finding that could ultimately eliminate the disease’s presence altogether.

“Our study has allowed us to discover the exact locations of the responsible mutations in the horse genome,” said Carl-Johan Rubin, PhD, of the Science for Life Laboratory in the Department of Medical Biochemistry and Microbiology at Uppsala University, in Sweden.

“Our hope now is that breeders will use this knowledge to get their breeding stock tested, so that no new individuals ever have to be born with this debilitating condition,” he told The Horse.

The condition, known by scientists as “skeletal atavism,” causes the radius and ulna and/or the tibia and fibula (in the front and hind legs, respectively) to develop as separate bones, whereas in modern adult equids, these two bones are fused together, Rubin said.

Affected ponies are born with splayed, “crooked” legs, which prevent them from moving correctly. Usually, owners have the foals euthanized.

“We’re not sure exactly how common the disease is since we suspect it’s often underreported, given that it’s not something breeders want to publicize about their breeding stock since it’s a hereditary condition,” said Rubin. “But it does seem to happen fairly frequently, resulting in the loss of many individuals.”

In a multinational research project, scientists from Sweden and the United States worked together to map the genomes of affected Shetland ponies and compare them to those of healthy individuals. Their data led them to investigate a region of the genome that carries a gene called the “short stature homeobox (SHOX)” gene. Scientists originally gave it this name because when the gene is absent in humans, it causes people to be shorter than they would be normally.

[image imageid="6684" includeTitle="false" includeSummary="false"]Skeletal atavism causes the radius and ulna and/or the tibia and fibula (in the front and hind legs, respectively) to develop as separate bones, whereas in modern adult equids, these two bones are fused together.[/image]

Deletions in and around the SHOX gene, like those seen in foals suffering from skeletal atavism, might not be strongly related to size but to other aspects of skeletal development, Rubin said. They found that skeletal atavism was consistently associated with a deletion of the SHOX gene, a deletion of the cytokine receptorlike factor 2 (CRLF-2) gene (downstream on the genome from the SHOX gene), or a combination of both.

As a result of their findings, a DNA test is now available worldwide. Rubin said he recommends breeders at least have their breeding stallions tested, because there must be two copies of the genetic deletion (one from each parent) for the disease to appear in the foal. “If the stallion does not carry the deletion, then even if the mare does, there is no risk that the foal will develop the atavism,” he said.

However, the foal could become a carrier if its mother passes on the deletion, he added. So tested mares as well could ensure that the deletion is ultimately eliminated entirely from the breeding stock.

Not to be confused with dwarfism, which is caused by mutations in the aggrecan gene (ACAN), skeletal atavism can also occur in Miniature Horses due to the strong influence of Shetland genes in that breed, said Rubin. A genetic test for dwarfism has been available since 2014.

The research team also included researchers from the Swedish University of Agricultural Sciences, in Uppsala; the Department of Veterinary Integrative Biosciences at Texas A&M University, in College Station, Texas; the Gluck Equine Research Center at the University of Kentucky, in Lexington; the Department of Genome Sciences and the Howard Hughes Medical Institute in the University of Washington School of Medicine, in Seattle; and the New Research Complex at Qatar University, in Al Tarfa, Doha.

The study, “Large Deletions at the SHOX Locus in the Pseudoautosomal Region Are Associated with Skeletal Atavism in Shetland Ponies,” was published in G3: Genes, Genomes, Genetics.