The Neanderthal variant in AMPD1 decreases its enzymatic activity by 25% in lab-produced proteins and by up to 80% in the muscles of genetically engineered mice; the variant is found in all sequenced Neanderthals, but is absent in all other species. It entered the modern human gene pool through interbreeding around 50,000 years ago. As a result, up to 8% of present-day Europeans carry it.
Macak et al. show that a genetic variant inherited from Neanderthals impairs the function of a key enzyme involved in muscle performance. Image credit: Holger Neumann / Neanderthal Museum.
The enzyme AMPD1 plays a key role in muscle energy production and normal muscular function.
Loss of its activity due to genetic mutations is the most common cause of metabolic myopathy in Europeans, occurring at a frequency of 9-14%.
In a new study, Dr. Dominik Macak from the Max Planck Institute for Evolutionary Anthropology and his colleagues compared ancient Neanderthal DNA with modern human genomes.
They found that all Neanderthals carried a specific AMPD1 variant absent in other species.
Laboratory-produced enzymes with this variant showed a 25% reduction in AMPD1 activity.
When introduced into genetically engineered mice, the reduction reached 80% in muscle tissue, impairing enzyme function.
The researchers also revealed that modern humans inherited this variant through interbreeding with Neanderthals, who inhabited Europe and Western Asia before encountering modern humans around 50,000 years ago.
Today, individuals of non-African descent carry roughly 1-2% of Neanderthal DNA.
The Neanderthal AMPD1 variant is carried by 2-8% of Europeans today, suggesting that it is generally tolerated.
“Strikingly, most individuals who carry the variant do not experience significant health issues,” Dr. Macak said.
“However, the enzyme appears to play an important role in athletic performance.”
An analysis of over a thousand elite athletes across various sports revealed that individuals who carry a non-functional AMPD1 are less likely to become top-level athletes.
“Carrying a broken AMPD1 enzyme, the likelihood of reaching athletic performance is reduced by half”, Dr. Macak said.
Although AMPD1 activity appears to have only moderate relevance in contemporary Western societies, it is important under extreme physical conditions, such as those experienced by athletes.
The scientists emphasize the importance of studying genetic variants in their physiological and evolutionary contexts in order to understand their biological effects.
“It’s possible that cultural and technological advances in both modern humans and Neanderthals reduced the need for extreme muscle performance,” said Dr. Hugo Zeberg, a researcher at the Max Planck Institute for Evolutionary Anthropology and Karolinska Institutet.
“Understanding how ancient gene variants affect human physiology today can provide valuable insights into health, performance, and genetic diversity.”
The findings were published on July 10, 2025 in the journal Nature Communications.
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D. Macak et al. 2025. Muscle AMP deaminase activity was lower in Neandertals than in modern humans. Nat Commun 16, 6371; doi: 10.1038/s41467-025-61605-4