NEW HAVEN, Connecticut (Yale University) -- A new Yale study provides a fuller picture of the genetic changes that shaped the evolution of the human brain, and how the process differed from the evolution of chimpanzees.
For the study, published Jan. 30 in the journal Cell, researchers focused on a class of genetic switches known as Human Accelerated Regions (HARs), which regulate when, where, and at what level genes are expressed during evolution.
While past research theorized that HARs may act by controlling different genes in humans compared to chimpanzees, our closest primate relative, the new findings show that HARs fine-tune the expression of genes that are already shared between humans and chimpanzees, influencing how neurons are born, develop, and communicate with each other.
Using advanced techniques, researchers also were able to track how HARs interact with genes and human neural stem cells, which allowed them to identify gene targets for nearly all HARs—a significant advance in the study of human evolution.
The discovery adds to the growing understanding of how genetic changes arising during evolution made us human and significantly advances knowledge about what genes HARs controlled, said James Noonan, the Albert E. Kent Professor of Genetics at the Yale School of Medicine, who led the study.
“The results reveal that HARs largely regulate the same genes in both species, particularly those involved in brain development,” Noonan said. “However, HARs adjust gene expression levels differently in humans, suggesting that evolutionary changes to brain function emerged not by reinventing genetic pathways but by modifying their output.”
Noonan’s lab is focused on understanding how HARs contribute to the evolution of uniquely human brain features. In previous work, the team has shown that some HARs alter gene expression in human-specific ways compared with our closest primate relatives. The latest study greatly expands the understanding of the biological changes that HARs may have driven, researchers say.
While the number of HARs in the human genome had been established, there was previously limited knowledge about which genes they controlled; previous studies had only identified gene targets for roughly 7 to 21% of HARs.
That’s likely because the previous studies used less precise methods, Noonan says. And due to the nature of the data, researchers previously were only able to estimate the identity of a small fraction of HAR gene targets, including some which may not have been targets at all.
For the new study, the Yale team used advanced techniques to map the genome in three dimensions in order to track how HARs interact with genes in human and chimpanzee neural stem cells. This allowed them to identify gene targets for almost 90% of all HARs.
“Having a more complete picture now opens up a vast new landscape of things scientists can do,” said Atreyo Pal, a graduate student in genetics at Yale and first author of the study.
Many HAR gene targets are active in the developing human brain and are linked to processes such as formation of neurons and maintaining communication between neurons. Some are also associated with conditions like autism and schizophrenia, highlighting the potential role of HARs both in shaping normal brain function as well as neurological disorders.
“Our findings also show that HAR gene targets are expressed in particular cell types in the developing human brain, including cell types that may have contributed to the increased size of our brain,” Pal concluded.
Noonan added, “Before, we didn’t know what many of the genes that HARs controlled were or what their biological functions were. We didn’t have the full picture. Now, this opens up many new avenues for us to understand how HARs contributed to the evolution of the brain.”