Key Genetic Changes in a Brain Enzyme (ADSL) Discovered to Have Driven Human Evolution and Behavior
- Aug 5
- 3 min read
Our remarkable evolutionary journey might have hinged on minute genetic shifts in our brain biochemistry, occurring after we diverged from the lineage leading to Neanderthals and Denisovans approximately half a million years ago. New research, conducted by scientists from the Okinawa Institute of Science and Technology (OIST) in Japan and the Max Planck Institute for Evolutionary Anthropology in Germany, sheds light on these subtle, yet impactful, modifications, specifically genetic changes in a brain enzyme ADSL.
The findings reveal that two of these tiny genetic changes affect the stability and expression of adenylosuccinate lyase, or ADSL, a crucial brain enzyme involved in the biosynthesis of purine, one of the essential building blocks of DNA and RNA. These discoveries, published in the journal PNAS, suggest that these variations may have played an important role in our behavior, adding key pieces to the puzzle of human identity and our origins. Dr. Xiang-Chun Ju, the study's first author, emphasizes that the research has provided "clues into the functional consequences of some of the molecular changes that set modern humans apart from our ancestors".
One of the key differences in the ADSL enzyme is a single amino acid change: the ancestral alanine at position 429 was substituted with a valine in the modern form of the enzyme, which reduces its protein stability. In mouse models, this alteration translates to higher concentrations of the substrates that ADSL catalyzes, especially in the brain. Given that genetic ADSL deficiency in humans is linked with psychomotor retardation and cognitive impairments, researchers explored its possible behavioral effects. In an experiment, female mice with this substitution consistently accessed water more frequently than their littermates when they were thirsty, suggesting that the reduced enzyme activity allowed them to better compete for a scarce resource. This substitution is present in almost all current humans, but absent in Neanderthals and Denisovans, indicating that it appeared in modern humans after divergence, but before their migration out of Africa, and could have conferred an "evolutionary advantage in particular tasks".
The study also identified a second set of genetic variants in a non-coding region of the ADSL gene, present in at least 97% of all present-day human genomes. Fascinatingly, researchers found that rather than compensating for the reduced ADSL activity caused by the amino acid change, the non-coding changes further diminish its activity by reducing its RNA expression, again, especially in the brain. Dr. Shin-Yu Lee, co-author, explains that the enzyme underwent "two separate rounds of selection that reduced its activity". This indicates an evolutionary pressure to modulate the enzyme's activity enough to provide the effects seen in mice, while keeping it active enough to avoid ADSL deficiency disorder.
Although Professor Izumi Fukunaga points out that many questions remain unanswered, such as why only female mice showed this competitive advantage, and Dr. Ju cautions that it's "too early to translate these findings directly to humans" due to differences in neural circuits, these discoveries are a giant step forward. Professor Svante Pääbo summarizes that ADSL is one of the few enzymes affected by evolutionary changes in our ancestors, and "we are beginning to understand the effects of some of these changes, and thus to puzzle together how our metabolism has changed over the past half million years of our evolution". This study brings us closer to understanding what makes us unique and how small genetic adjustments could have shaped the path of our species.
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