The evolutionary success of our species may have hinged on minute changes to our brain biochemistry after we diverged from the lineage leading to Neanderthals and Denisovans about half a million years ago
Two of these tiny changes that set modern humans apart from Neanderthals and Denisovans affect the stability and genetic expression of the enzyme adenylosuccinate lyase, or ADSL. This enzyme is involved in the biosynthesis of purine, one of the fundamental building blocks of DNA, RNA, and other important biomolecules. In a study now published in PNAS, researchers from the Okinawa Institute of Science and Technology (OIST), Japan and the Max Plank Institute for Evolutionary Anthropology, Germany have discovered that these changes may play an important role in our behavior, contributing new pieces to the great puzzle of who we humans are and where we come from. "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," says first author Dr. Xiang-Chun Ju of the Human Evolutionary Genomics Unit at OIST.
The ADSL enzyme is made up of a chain of 484 amino acids. The modern and ancestral variants of this enzyme differ by just one of these amino acids: at position 429, the alanine in the ancestral form has been substituted with a valine in the modern. In vitro, this change has been observed to reduce the stability of the protein. The team has now shown that in mouse models, this translates to higher concentrations of the substrates that ADSL catalyzes in several organs, especially in the brain.
Given that genetic ADSL deficiency is known to cause psychomotor retardation and cognitive impairments in humans, the researchers explored the possible behavioral effects of this substitution. In an experimental setup where water is made available to mice following a visual or sound cue, they found that female mice with the substitution consistently accessed water more frequently than their littermates when they were thirsty, suggesting that the reduced activity of the enzyme allowed them to better compete for a scarce resource.
The amino acid substitution is absent in both Neanderthals and Denisovans but present in virtually all present-day humans, showing that this change must have appeared in modern humans after they separated from the lineage leading to Neanderthals and Denisovans but before they left Africa. "It's too early to translate these findings directly to humans, as the neural circuits of mice are vastly different," adds Dr. Ju. "But the substitution might have given us some evolutionary advantage in particular tasks relative to ancestral humans."
The team next searched for other related genetic changes that might affect ADSL activity in present-day humans. They identified a set of genetic variants in a non-coding region of the ADSL gene, which are present in at least 97% of all present-day human genomes. Statistical tests involving Neanderthal, Denisovan, and modern African, European, and East Asian genetic sequences provided strong evidence that these variants have been positively selected among modern humans.
Fascinatingly, the researchers found that rather than compensating for the reduced activity of ADSL caused by the amino acid change, the non-coding changes reduce ADSL RNA expression, further diminishing its activity - again, especially in the brain. "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," explains co-author Dr. Shin-Yu Lee of the same research unit at OIST.
"Our results open up many questions," explains Professor Izumi Fukunaga of the Sensory and Behavioral Neuroscience Unit at OIST. "For example, it's unclear why only female mice seemed to gain a competitive advantage. Behavior is complex. Accessing water proficiently involves processing sensory information, learning which actions lead to rewards, navigating social interactions, motor planning, and many other processes. Each of these may involve multiple brain regions. As such, more studies are needed to understand the role of ADSL in behavior."
Professor Svante Pääbo, leader of the Human Evolutionary Genomics Unit, summarizes: "There are a small number of enzymes that were affected by evolutionary changes in the ancestors of modern humans. ADSL is one of them. 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."
