Genetic hacks make horse athletes

In a discovery that can change our understanding of evolutionary and genetic diseases, researchers at Johns Hopkins Medicine and Vanderbilt University have identified how horses can escape the outstanding genetic skills previously thought viruses unique to them—they run through the “stop signs” in their DNA.

This evolutionary adaptability occurred millions of years ago among all modern horses, donkeys and zebra ancestors, helping to explain how these animals developed their extraordinary motor abilities.

“Our work not only confirms the adaptability of this genetic evolution, but also focuses on the importance of this pathway for chronic diseases, age-related diseases and exercise physiology,” said Elia Duh, professor of the Wilmer Eye Institute at Johns Hopkins Medicine.

The team identified a mutation in the KEAP1 gene that introduced premature stop codons—generally terminating genetic signals that proteins produce. This premature cessation usually results in shortened, non-functional proteins, accounting for about 11% of all hereditary diseases, including cystic fibrosis and muscle dystrophy.

But horses evolved molecular solutions. Rather than stopping the production of proteins under this genetic “stop symbol”, horses have developed a mechanism to redescribe it, which can produce full-length functional KEAP1 proteins with enhanced properties.

This recoded Keap1 protein interacts with another protein called NRF2 to better detect reactive oxygen-unstable molecules that damage cells during intense exercise. The resulting enhanced NRF2/KEAP1 pathway causes horse cells to simultaneously generate a lot of energy while preventing oxidative damage.

“The horse’s strategy to bypass the stop codon can guide ongoing efforts to treat many genetic diseases caused by premature stop codons,” Duh explained.

This ancient genetic adaptability allows thoroughbred racehors to consume more than twice as much oxygen, which helps explain how these magnificent animals evolved from dog-sized ancestors to powerful runners who changed human civilization. More importantly, it opens the door to potential treatments for many genetic diseases caused by similar premature stop codons.

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