Horse genetics could unlock breakthroughs in human medicine

A team of scientists has recently uncovered a unique genetic adaptation in horses that may explain their remarkable athleticism. The adaptation, previously seen only in viruses, provides horses with a way to override a premature genetic stop signal.

The discovery, led by Johns Hopkins Medicine, in collaboration with Vanderbilt University’s Castiglione Lab, focuses on a key genetic pathway known as NRF2/KEAP1 and a rare evolutionary mechanism that gives horses an athletic advantage.

Secrets of horse genetics

The NRF2/KEAP1 pathway is found in all vertebrates and plays a critical role in protecting cells from oxidative stress. It also helps regulate metabolism and energy production.

NRF2 is a protein that shields cells from reactive oxygen species – unstable molecules that damage DNA and accumulate during activities like exercise. KEAP1 acts as a sensor that regulates how much NRF2 is available to help cells respond to stress.

“We’ve studied NRF2 and KEAP1 for a long time, because this duo is very relevant to retinal diseases such as macular degeneration and diabetic retinopathy,” said senior author Elia Duh, a professor of ophthalmology at Johns Hopkins Medicine’s Wilmer Eye Institute.

“NRF2 is important for coping with oxidative stress, as well as for mitochondrial metabolism, respiration, and energy production.”

Extremely rare adaptation in horses

Using genetic sequencing, the researchers found a peculiar mutation in the KEAP1 gene in horses, donkeys, and zebras. The mutation introduced a premature stop codon – a segment of DNA that acts like a “stop” sign, usually ending protein production too early.

When such a stop codon appears early in a gene, the resulting protein is often too short to function properly. In humans, these premature stop codons are linked to around 11% of inherited diseases, including conditions like cystic fibrosis and muscular dystrophy.

Surprisingly, horses have evolved a workaround. Instead of halting KEAP1 protein production, their cells recode the stop signal, allowing the gene to continue translating into a full-length, functional protein. This process, known as stop codon read through, is extremely rare in animals and has only been documented in viruses before this study.

Better energy, better performance

Further molecular analysis of horse cells showed that this genetic recoding results in a more efficient KEAP1 protein, one that is highly responsive to reactive oxygen species.

This in turn boosts the activity of NRF2, the protective protein that helps cells generate energy and fend off oxidative damage. The end result: a cellular system optimized for the extreme demands of equine endurance.

The enhanced NRF2/KEAP1 pathway in horses appears to help them meet their intense energy requirements during exercise while also minimizing the cellular damage typically caused by such exertion.

According to the research team, this could explain how horses have evolved such exceptional speed and stamina.

“Not only does our work confirm this genetic evolutionary adaptation, it brings into focus how important this pathway is for chronic disease, age-related diseases, and exercise physiology,” Duh said. “This might give insight into the particular NRF2/KEAP1 interactions we can take advantage of therapeutically.”

Improving human health

The findings on horse genetics do more than offer insight into equine biology – they may open doors to new medical treatments. The same genetic mechanism that allows horses to bypass a premature stop codon could potentially be applied in humans to treat a variety of inherited diseases caused by similar mutations.

By understanding how horses naturally override a genetic stop signal, researchers may be able to design drugs or gene therapies that mimic the process.

“The strategy used by horses to bypass a stop codon could guide ongoing efforts to treat the many inherited diseases resulting from premature stop codons,” Duh explained.

Beyond rare genetic disorders, the study also highlights the broader relevance of the NRF2/KEAP1 pathway in age-related and chronic diseases.

Because NRF2 plays a central role in cellular stress response and energy metabolism, targeting this pathway might offer new avenues for treating conditions like macular degeneration, cardiovascular disease, or even the effects of aging.

Horse genetics and human medicine

This discovery of stop codon read through in horses is a striking example of how evolution can find ingenious solutions to biological challenges. Until now, such a mechanism was thought to be confined to viruses, which use it to produce multiple proteins from the same genetic sequence.

The fact that horses have developed a similar ability suggests this strategy may be more broadly applicable – and more medically significant – than previously imagined.

As the researchers continue to explore the full implications of this evolutionary adaptation, their work is helping bridge the gap between animal biology and human medicine, offering new insights into both performance and pathology.

The study is published in the journal Science.

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