What a Difference an Enzyme Makes 

The difference between Homo sapiens and their extinct cousins might lie in a tiny change to a single enzyme – one that subtly altered brain chemistry and, possibly, behavior. 

In a new study, an international research team zeroed in on the gene for adenylosuccinate lyase (ADSL), an enzyme that is key for making purines – the molecular building blocks of DNA, RNA, and other vital compounds.  

Nearly all humans alive today share a version of ADSL that extinct hominins, Neanderthals, and Denisovans didn’t have.  

The only difference is that out of its 484 amino acids, one has been swapped: An alanine in the ancient version was replaced by a valine in ours. That small swap makes the enzyme less stable, a change researchers suspected might influence the brain.  

To explore this theory, they used a CRISPR gene-editing technique to insert the modern human ADSL gene into mice.  

In an experiment in which mice had to learn to get water, female mice with the human version proved better at snagging a drink when water was limited.  

“It’s too early to translate these findings directly to humans, as the neural circuits of mice are vastly different,” said first author Xiang-Chun Ju in a statement. “But the substitution might have given us some evolutionary advantage in particular tasks relative to ancestral humans.” 

Rare mutations in ADSL can cause severe neurological problems in modern humans, including autism-like symptoms, seizures, and cognitive impairments. This link intrigued the researchers, as it suggested even mild changes could have behavioral effects. 

The study also found other genetic tweaks in modern humans that further reduce ADSL activity, especially in the brain.  

“This enzyme underwent two separate rounds of selection that reduced its activity… while keeping it active enough to avoid ADSL deficiency disorder,” added co-author Shin-Yu Lee. 

The authors and other researchers noted that while the findings don’t claim this gene alone explains our species’ success, they add a big clue to the mystery of why H. sapiens dominated. 

“I am quite convinced that there is some fundamental difference between modern humans and other earlier forms of human,” Svante Pääbo, another of the study’s authors, told the Washington Post. “The fact that Neanderthals and Denisovans never became more than a few hundred thousand people at any one time… (while) modern humans in just a hundred thousand years spread all over the planet, became millions of people and developed technology and culture that changed so rapidly.”