This Gene Tweak in Mice Offers Clues to What Sets Us Apart from Neanderthals

Yomiuri Shimbun

5 days ago

Scientists have a new clue in the long quest to decipher what makes us uniquely human: tiny changes in brain chemistry that set us apart from our closest hominin cousins.
In a study published Monday in the Proceedings of the National Academy of Sciences, an international team of researchers scrutinized a version of a gene, ubiquitous in humans today, that is not present in Neanderthals or Denisovans – the hominins that lived alongside our ancestors.
In a lab dish, the modern form of the gene in humans today made an enzyme less stable than the one found in hominin relatives. When researchers introduced that version into mice, they found that in females, it triggered a behavioral change – the mice were more adept at seeking water.
It's an intriguing clue – not an answer – to the question of how subtle changes to brain biochemistry may have meant the difference between hominins that went extinct, and those that persisted and thrived.
In humans today, rare mutations to this gene, called ADSL, can cause brain dysfunction including symptoms similar to autism and seizures. That led the research team to wonder whether a less severe change to ADSL, deep in our evolutionary history, may have conferred a cognitive or behavioral advantage.
'I am quite convinced that there is some fundamental difference between modern humans and other earlier forms of humans,' said Svante Paabo, a geneticist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and one of the leaders of the study. 'The fact that Neanderthals and Denisovans never became more than a few hundred thousand people at any one time, their technology over hundreds of thousands of years hardly changed – and that 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.'
Neanderthal cousins
In 2022, Paabo won the Nobel Prize for his pioneering work on ancient DNA, deciphering the genetic blueprints of ancient hominins.
While our extinct relatives are often caricatured as primitive cavemen, this work revealed that they were not very different from us at the genetic level. They interbred with our ancestors. Much of the human population still has a vestige of Neanderthal or Denisovan ancestry in them – two species of humans that vanished from the planet about 20,000 to 40,000 years ago.
In many ways, this deepened the mystery of why we survived, and they didn't.
Scientists began to look for clues in DNA. Out of 20,000 genes that code for proteins, there were only about 100 changes to the building blocks of proteins between extinct hominins and modern humans. In 2022, scientists intriguingly reported that a version of a gene called TKTL1 found in modern humans and not Neanderthals helps spur the generation of new brain cells and could be responsible for differences in cognitive capacities.
In the new paper, scientists examined ADSL. One building block of the ADSL enzyme found in nearly every human today was different in chimpanzees, Neanderthals and Denisovans. The scientists set out to understand how the function of the gene compared.
Deciphering the function of a gene in mice
Since scientists can't study a living Neanderthal, they used the powerful gene-editing technique CRISPR to insert the modern human version of the gene into living mice. They were intrigued to find that the behavior of female mice distinctly changed.
Mice were put in cages where they learned to drink water by poking their noses into devices in the corners of the cage. When the researchers started restricting water, they found the female mice with the human ADSL gene were much more efficient at accessing water.
'It is still too early to directly translate the behavioral findings in mice to humans, as the neural circuits underlying even similar behaviors may still differ between the two species. However, it is possible that this … change may have given us some evolutionary advantage in particular tasks relative to ancestral humans,' Xiang-Chun Ju, a study author and researcher in the Human Evolutionary Genomics Unit at Okinawa Institute of Science and Technology, wrote in an email.
The researchers also found other genetic changes common among humans today that cause reduced ADSL activity, along with evidence that those changes had been favored by evolution, suggesting that it gave an advantage to the organism.
Brigitte Malgrange, a neurobiologist at the University of Liège who was not involved in the work, said the behavioral change was 'modest' and suggested that additional genomic changes would be needed to see larger effects.
'I can also mention the inherent limitations of the mouse model, particularly the reduced cortical complexity relative to primates, which may constrain the detection of humanlike behavioral phenotypes,' Malgrange said in an email.
Wendy Hanna-Rose, a professor of biochemistry and molecular biology at Pennsylvania State University who was not involved in the study, studies human ADSL deficiencies, in part by modeling them in microscopic roundworms. These simple model organisms allow researchers to probe how genetic changes can affect function; genetic mutations that cause autism-like features, compulsive biting or repetitive motions in human patients can cause profound changes in how worms learn.
Hanna-Rose is not an evolutionary biologist, but said she found the paper fascinating, underscoring what her own research also shows – that the links between the metabolic pathway affected by the ADSL gene and behavior are evolutionarily deep.
'We see it in worms,' Hanna-Rose said. 'It's not surprising to see in humans some kind of tweak on that in our lineage.'