Draw the chemistry of the brain through the family tree of humanity

The evolutionary success of our species can have taken up tiny changes to our cerebral biochemistry after we have diverged from the line leading to Neanderthals and Denisovans about half a million years ago.

Two of these tiny changes that distinguish modern humans from Neanderthals and Denisovans affect the stability and genetic expression of enzymatic adenylosuccinate, or ADSL. This enzyme is involved in the biosynthesis of the purine, one of the fundamental constituent elements of DNA, RNA and other important biomolecules.

In a study published in PNAResearchers from the Okinawa Institute of Sciences and Technology (OIST), Japan and the Max Planck Institute for evolutionary anthropology, Germany have discovered that these changes can play an important role in our behavior, contributing new pieces to the big puzzle of who we are humans and where we come from.

“Thanks to our study, we have obtained indices in the functional consequences of some of the molecular changes that distinguish modern humans from our ancestors,” explains the first author, Dr. Xiang-Chun Ju from the human evolutionary genomic unity of the OIST.

The ADSL enzyme is made up of a chain of 484 amino acids. The modern and ancestral variants of this enzyme differ by only one of these amino acids: in position 429, Alanine in the ancestral form was substituted by a valine in the modern.

In vitro, this change was observed to reduce the stability of the protein. The team has now shown that in mouse models, this results in higher concentrations of substrates that catalyze ADSL in several organs, especially in the brain.

Since ADSL genetic deficiency is known to cause psychomotor delay and cognitive impairments in humans, researchers have explored the possible behavioral effects of this substitution.

In an experimental configuration where water is made available to mice according to a visual or sound benchmark, they have found that female mice with substitution have constantly accessed water more frequently than their litter companions when they were thirsty, which suggests that the reduction in the activity of the enzyme has allowed them better competition for a rare resource.

The substitution of amino acids is absent both in Neanderthals and Denisovans, but present in almost all current humans, showing that this change must have appeared in modern humans after their separation of the line leading to Neanderthals and Denisovans but before leaving Africa.

“It is too early to translate these results directly into humans, because the mouse neural circuits are very different,” adds Dr. Ju. “But substitution could have given us an evolutionary advantage in particular tasks compared to ancestral humans.”

The team then looked for other related genetic changes that could affect ADSL activity in current humans. They have identified a set of genetic variants in a non -coding region of the ADSL gene, which are present in at least 97% of all current human genomes.

Statistical tests involving genetic sequences of Neanderthal, Denisovan and Africa, European and Asian of Europe have provided solid evidence that these variants have been positively selected from modern humans.

In a fascinating way, the researchers found that rather than compensating for the reduced activity of the ADSL caused by the change of amino acid, non -coding changes reduce the expression of the ADSL RNA, further decreasing its activity – again, in particular in the brain.

“This enzyme has undergone two distinct selection cycles which reduced its activity, first by a change in stability of the protein and the second by lowering its expression. Obviously, there is evolving pressure to reduce the activity of the enzyme enough to provide the effects that we have seen in mice, while keeping active enough to avoid the ADSL research disorder”

“Our results open up many questions,” said Professor Izumi Fukunaga of the ILO sensory and behavioral neuroscience unit.

“For example, we do not know why only female mice seemed to gain a competitive advantage. Behavior is complex. Access to water implies in -depth sensory information, learning actions lead to rewards, navigation of social interactions, motor planning and many other processes. Each of them can involve multiple brain regions. The role of ADSL in behavior. “

Professor Svante Pääbo, head of human evolving genomic unity, summarizes: “There are a small number of enzymes that have been affected by evolutionary changes in ancestors of modern humans. ADSL is one of them.

“We are starting to understand the effects of some of these changes, and therefore bringing together how our metabolism has changed in the last million years of our evolution. A next step will be to study the effects that the combinations of these changes may have.”