Research results indicate that the reason homo sapiens took a different path from the extinct Neanderthals and Denisovans is due to subtle biochemical changes. It suggests that changes in enzymes involved in human behavior and brain function altered our ancestors about 500,000 years ago.
Svante Erik Pääbo, the director of the Max Planck Institute for Evolutionary Anthropology in Germany and Nobel Prize winner in Physiology or Medicine, along with a joint research team from the Okinawa Institute of Science and Technology (OIST) in Japan, stated on the 5th that "changes in adenosine deaminase (ADSL) have influenced the behavior of modern humans, making it different from that of other archaic humans." The findings of this study were published that day in the "Proceedings of the National Academy of Sciences of the United States of America (PNAS)."
The direct ancestors of modern humans, Homo sapiens, migrated from Africa to the Eurasian continent approximately 70,000 years ago. Prior to this, there were already humans settled in Eurasia, specifically the relatives of humans, the Neanderthals and Denisovans. These two archaic human species coexisted with Homo sapiens for about 30,000 to 40,000 years before they became extinct approximately 40,000 years ago.
Neanderthals left Africa and settled in Eurasia about 400,000 years ago. Denisovans are an archaic human species named after a cave in Siberia where bones were first discovered in 2008, believed to have diverged from Neanderthals about 350,000 years ago and spread into Asia.
The research team noted that the 429th amino acid of the ADSL protein was "alanine" in Neanderthals and Denisovans, but it changed to "valine" in modern humans. ADSL is involved in producing purine, a component of genetic material, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Scientists believe that the change in amino acids occurred about 500,000 years ago.
ADSL contains 484 amino acids. Experimental results showed that even changing just one of them reduced the stability of ADSL and resulted in lower activity. At the same time, the substances that ADSL breaks down in the brain remained unchanged, which led to an increase in concentration. This indicates that a change in one amino acid altered the functioning of the enzyme.
The research team examined whether changes in amino acids affect actual behavior through experiments with mice. In an experiment designed so that visual or auditory stimuli allowed the mice to obtain water, female mice with the alanine amino acid of ADSL changed to valine obtained water more frequently and accurately than other mice. In a state of thirst, they quickly recognized what was needed and acted more efficiently. This may suggest that a decrease in ADSL activity could lead to behaviors necessary for survival competition.
The research team also discovered another genetic variation in the ADSL gene. This change occurred in a non-coding region that regulates gene expression, though it does not directly produce protein. This variation was found in over 97% of modern humans and appears to further suppress ADSL gene expression. It can be suggested that humans evolved to lower the activity of ADSL using variations in amino acids and non-coding regions.
So far, it has been known that a deficiency in the ADSL gene leads to exercise delays or cognitive impairments in humans. The research team explained that "the variations discovered this time likely acted as a regulatory mechanism that moderately lowers the enzyme's activity without causing diseases like ADSL deficiency syndrome."
Izumi Fukunaga, a professor at OIST, noted that "the behavior of mice seeking water requires the cooperation of various brain areas that process sensory information, learning, social interaction, and motor planning," and emphasized that "more research is needed to understand what role ADSL plays in behavior."
Pääbo was awarded the Nobel Prize in 2022 for his contributions to decoding the genome of Neanderthals and discovering Denisovans. He also revealed that traces of archaic humans remain in the genes of modern humans. Pääbo stated, "We are beginning to understand the impacts of changes in enzymes like ADSL," and added, "I aim to uncover how human metabolism has changed during the evolutionary process over the past 500,000 years."
References
PNAS (2025), DOI: https://doi.org/10.1073/pnas.2508540122