Muscle AMP deaminase activity was lower in Neandertals than in modern humans

Dominik Macak, Shin-Yu Lee, Tomas Nyman, Henry Ampah-Korsah, Emilia Strandback, Svante Pääbo and Hugo Zeberg ()
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Dominik Macak: Max Planck Institute for Evolutionary Anthropology
Shin-Yu Lee: Okinawa Institute of Science and Technology
Tomas Nyman: Karolinska Institutet
Henry Ampah-Korsah: Karolinska Institutet
Emilia Strandback: Karolinska Institutet
Svante Pääbo: Max Planck Institute for Evolutionary Anthropology
Hugo Zeberg: Max Planck Institute for Evolutionary Anthropology

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract The enzyme AMPD1 is expressed in skeletal muscle and is involved in ATP production. All available Neandertal genomes carry a lysine-to-isoleucine substitution at position 287 in AMPD1. This variant, which occurs at an allele frequency of 0–8% outside Africa, was introduced to modern humans by gene flow from Neandertals. Here, we show that the catalytic activity of the purified Neandertal AMPD1 is ~25% lower than the ancestral enzyme, and when introduced in mice, it reduces AMPD activity in muscle extracts by ~80%. Among present-day Europeans, another AMPD1 variant encoding a stop codon occurs at an allele frequency of 9–14%. Individuals heterozygous for this variant are less likely to be top-performing athletes in various sports, but otherwise reduced AMPD1 activity is well tolerated in present-day humans. While being conserved among vertebrates, AMPD1 seems to have become less functionally important among Neandertals and modern humans.

Date: 2025
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DOI: 10.1038/s41467-025-61605-4

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