Enzyme linked with brain evolution

[Music] Welcome to Science Sessions, the podcast of the proceedings of the National Academy of Sciences, where we connect you with Academy members, researchers, and policymakers. Join us as we explore the stories behind the science. I'm Paul Gabrielson. Sometime after modern humans diverged from the Andertals and Denisovans, a mutation in the gene for the adenillo-sucinate liais or ADSL enzyme, changed one amino acid in the enzyme's protein sequence from an alanine to a veiline. The enzyme helps in the process of synthesizing purine in the body. This mutation appears to have been selected for in modern humans. In a recent PNAS study, Shang Chun-Ju of the Okinawa Institute of Science and Technology, Svante Peibo of the Max Plong Institute for Evolutionary Anthropology in Germany and colleagues, explored in mice how the mutation, the A429V mutation, affects physiology and behavior. The results showed that mice with the amino acid substitution displayed reduced purine synthesis and a build-up of substrates of purine in their bodies. The results also showed interesting behavioral advantages and further questions to pursue. Shang Chun, let's start with some background. For those who may not be familiar, tell us about the significance of ADSL and purine in biochemistry. The purines are very important molecules, building blocks for DNA, RNA, and storage of NH. So ADC encodes one of the six enzymes and conducts two reactions in the purine-bicyndesis pathway. So in humans, ADC deficiency caused by mutations in this gene is a real or some more recessive disorder of purine metabolism. It often leads to significant neurological symptoms, such as mental retardation, intellectual disability, and developmental disorders. Svante, how was the A429V substitution discovered? And why is it important? So what our laboratory has done over the past decade and a half is to generate genomes from our closest extinct relatives, the Neanderthals and the Nisovans. And one of the things that we were very interested in there was to find genetic changes that occurred on the human lineage since we separated from the common ancestor with Neanderthals and the Nisovans about half a million years ago. And particularly those changes that occurred there and exist in everybody today or almost everybody. Because in some sense we imagine that that is a recipe for being a modern human and maybe behind traits that sets us apart from Neanderthals and also from the apes. So we made sort of a catalog of such things and we're particularly interesting in those that changed amino acids in proteins. And one of those proteins was this enzyme ADSL which is crucial for purine biosynthesis. We had done another study where we looked at the concentration of small molecules in the brains of humans of apes and of monkeys and looked for molecules that changed their concentration, particularly in humans relative to the apes and monkeys. And one thing that stood out there was actually purines or humans have lower levels of purines in the brain than in the apes. What did you do to explore the evolutionary significance of the A429V substitution? We found it is in a chromosome region that has evidence of positive selection in modern humans. So we made the mice humanites for this gene by converting the aligning to valine at the position 429 of its protein sequence. So when we looked at the substress of the enzyme in both brain and non-brentissue such as muscles and labor long hot to using liquid chromatography mass spectrometry, we found the brain was especially affected. Also showing the highest concentrations of ADSL substress. Moreover the amino acid change affected females, more than males. So humanites females have higher substress in the brain. This enzyme is expressed in every organ in our body but we see the effect particularly in the brain and we think we know why and that is because the level of expression of this enzyme is lowest in the brain. We are interested in a gene and say where may it be active in our body? We tend to look at where is its most highly expressed because that's where it should be particularly important. But in this case when you tweak the activity of the enzyme it may actually be like in this case where it's most locally expressed that's where the cells are most sensitive for a change in it. What happened to the mice with the substitution? What did you find? We then tested that the behaviors both male and female mice using an automatic tracking system called IntelliCage. So by housing multiple mice, maximum 16 of different genotypes but the same sex within the same cage and gradually reducing the water availability within a day, all mice become so state. So everyone wants to drink water immediately as long as the water pot is open. So this is known as a competition task. We observed that more femium mice expressing the humanized adhesio were able to access the water pot earlier than the white type of lithiumase. So suggesting that this ameliosate change or reduce the adhesio activity may provide a competitive advantage for femium mice when the resources are limited. It's sort of very interesting why this affects only females and not males. When we looked at the amount of enzyme that is made, indeed females actually express less of this enzyme than males. So our idea is that not only is brain most sensitive because it expresses less of the enzyme, but females express even less than males and maybe that's why we see the effect in the females. What is the takeaway from this study regarding the role of the A429V substitution in human evolution? So at the biochemical level we could say that this substitution causes this reduction in purines in the brains and humans compared to apes and now we know all the tiniander calls. What we get from this study I think is a hint, but it also have effects for behavior, but we don't understand of course what those things are really in humans. So we sort of just know that female mice carrying this modern human-like substitution compete better for a scarce resource against wild-type litter mates. What this would translate to in humans we really don't know. We have some little hint perhaps and that is that if we look indirectly at genetic variants in our genome that reduce the amount of these purines or part of these purines in the brain, they also affect human intelligence but very little significantly but it's a very small change but suggesting that it could be some cognitive effectiveness. This illustrates also that it's a very hard task to understand what makes human special particularly behaviorally and cognitively. It will for sure be many different changes and we feel quite confident that this change in ADSL in this enzyme will sort to be part of that story but it will only be part of it for sure. How does this paper fit into the landscape of studies on human evolution that you've published? Can you comment on its relative significance in relation to other discoveries on this topic? We have studied a number of changes in genes that have this characteristic that they are wearing everybody today and not in the undertones or the apes. Several of those earlier ones we studied in the model systems where we have little brain organoids that are human stem cells that we modify to look ancestral with respect to these changes and we then study early stages in brain development and we found for example a set of changes that made the segregation of chromosomes when early brain stem cells divide more accurate in humans but in those cases we have no clue if it has any effect in the adult individual in the mature brain and this is the first one really where we in the adult mice see a very clear behavior of effect in the females so to me this is exciting because it have an effect in the model system but in the adult brain. What are the caveats or limitations of this study? We work in a model system mice and mice are not humans so we don't know of this translates to they behavioral or cognition in humans. What we really need are association studies I would say in humans where we study then other subtle changes that affect this enzyme or its expression in humans and how it affects behavior. So the molecular and cellular mechanisms please change the behavior effect that is something we still don't know and also why did this MS change effect the competitive behavior only in female mice this is also something we don't know. We have around 100 MSAs as a chain fix they modern humans. So what is the combined effect of these? Emeralds a change. This is something amazing and we want to address a scene. Thanks for tuning into science sessions. You can subscribe to science sessions on iTunes, Spotify, or wherever you get your podcasts. If you like this episode, please consider leaving a review and helping us spread the word. [Music]