Recent research has revealed the evolutionary path that led to modern humans. Specifically, it zeroes in on the enzyme ADSL, which is essential for the biosynthesis of purine, an important building block of DNA and RNA. The study highlights that a single amino acid change in the ADSL enzyme, occurring at position 429, distinguishes contemporary humans from their ancestral hominins. This change was probably key to shaping modern human brain development and behavior. It happened in parallel with two large evolutionary pressures that worked to decrease ADSL activity.
The enzyme ADSL, which is essential for purine production, an important molecule involved in almost every biological process, including cell signaling and energy metabolism. The research indicates that the modern variant of ADSL differs from its ancestral form by just one amino acid substitution: an alanine is replaced with a valine at position 429. This otherwise unremarkable change has massive ramifications. Their work, combined with the fossil record, helps us understand the biochemical underpinnings that make modern humans different from Neanderthals and Denisovans.
The Distinctive Amino Acid Change
There is only one genetic difference that distinguishes modern humans from their closest relatives, the Neanderthals and Denisovans. This difference is the replacement of alanine by valine at position 429. This adaptation probably evolved after the split between modern humans and the lineage leading to archaic hominins. It occurred prior to their initial prehistory migration out of Africa.
These statistical analyses of ancient genetic sequences from Neanderthals, Denisovans, and genetically diverse populations in Africa, Europe, and East Asia tell a compelling story. Those two results together provide strong evidence that modern ADSL variants have been positively selected in modern humans. At the moment, roughly 97 percent of us hold onto at least one version of the modern variant. This very high frequency is, in part, because people have two copies of the ADSL gene.
This ADSL-mediated reduction in activity during recent human evolution has far-reaching consequences for brain function and behavior. The researchers then performed ADSL enzyme definition experiments measuring concentrations of the protein substrates SAICAr and S-Ado, which rise upon reduction of ADSL activity. This increase in lethargy likely impacted cognitive anxiety and aggression functions necessary for their survival.
“This enzyme underwent two separate rounds of selection that reduced its activity—first through a change to the protein’s stability and second by lowering its expression. Evidently, there’s an evolutionary pressure to lower the activity of the enzyme enough to provide the effects that we saw in mice, while keeping it active enough to avoid ADSL deficiency disorder.”
Implications for Brain Function and Behavior
The studies underscore a need to acknowledge the nuance and complexity of behavior. Dr. Ju further highlighted the importance of conducting longitudinal studies to better explore how ADSL impacts behavior. This type of competitive advantage had only been observed in female mice up until now, due to this enzyme.
We are very successful evolutionarily, but we’re not all that successful in our evolutionary success just due to some really subtle biochemical changes. Indeed, these mutations emerged after our split from Neanderthals and Denisovans roughly 500 thousand years ago. With knowledge of how these adaptations physically alter metabolism and behavioral state, researchers hope to reveal a fuller story about human evolution.
“Through our study, we have gotten clues into the functional consequences of some of the molecular changes that set modern humans apart from our ancestors.”
Professor Svante Pääbo emphasized the significance of enzymes like ADSL in evolutionary changes:
“For example, it’s unclear why only female mice seemed to gain a competitive advantage. Behavior is complex,” Dr. Ju remarked.
Evolutionary Pressures and Future Studies
Scott and other researchers are still working to put together the pieces of the puzzle of human evolution. They admit that much work remains, even “decades of research,” to decipher how multiple genetic mutations work together. Professor Pääbo added,
Professor Svante Pääbo emphasized the significance of enzymes like ADSL in evolutionary changes:
“There are a small number of enzymes that were affected by evolutionary changes in the ancestors of modern humans. ADSL is one of them.”
As researchers continue to piece together the puzzle of human evolution, they recognize that more work is necessary to examine how combinations of these genetic changes interact. Professor Pääbo added,
“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. A next step will be to study what effects combinations of these changes may have.”