The genetic mechanisms attributable to developmental changes responsible for advanced human cognition remain poorly understood. However, researchers from the Yale School of Medicine have data they believe may shed new light on human brain evolution. The scientists revealed that thousands of genetic regulatory elements, acting like “dimmer” switches, were turned up during human evolution driving the development of the human cerebral cortex.     

The investigators used comparative epigenetic profiling of human, rhesus macaque monkeys, and mouse corticogenesis in order to identify promoters and enhancers that have improved activity in humans. The findings from this study were published today in Science through an article entitled “Evolutionary changes in promoter and enhancer activity during human corticogenesis”.

In comparison to rhesus monkeys and mice, the Yale team found evidence of the genetic switches being turned up in humans, which they hypothesize drove the expression of genes within the cerebral cortex, the region of the brain most involved in consciousness and language. This could be a key element in understanding why the structure and function of this brain region is so unique in humans.     

“Building a more complex cortex likely involves several things: making more cells, modifying the functions of cortical areas, and changing the connections neurons make with each other. And the regulatory changes we found in humans are associated with those processes,” said James Noonan, Ph.D., associate professor of genetics at Yale, investigator with the Kavli Institute for Neuroscience, and senior author on the study. “This likely involves evolutionary modifications to cellular proliferation, cortical patterning, and other developmental processes that are generally well conserved across many species.”

With sequencing techniques becoming faster and more cost effective, scientists have become increasingly proficient at comparative genome analysis. However, since human and primate genomes are remarkably similar, Dr. Noonan and his team theorized that the manner in which genes were regulated is what set human neuronal evolution apart.   

Specifically, Dr. Nooan’s team mapped active regulatory elements, using epigenetic modifications as a guide, within the human genome during the first 12 weeks of cortical development. A similar strategy was performed for rhesus monkeys and mice, after which all three were compared, searching for regions with greater activity. What they found were several thousand regulatory elements with significant activity increase in humans.

Using a freely available digital atlas of human gene expression called BrainSpan, the Yale scientists identified clusters of genes with coordinated expression within the cerebral cortex. This aided the investigators in understanding the biological impact of the regulatory changes they found with the comparative sequence analysis. After all of the data was overlaid together, Dr. Noonan and his colleagues identified several biological processes that were associated with a large number of regulatory changes in humans.       

“While we often think of the human brain as a highly innovative structure, it's been surprising that so many of these regulatory elements seem to play a role in ancient processes important for building the cortex in all mammals, stated Steven Reilly, graduate student in Dr. Noonan's lab and first author on the current study. “However, this is often a hallmark of evolution, tinkering with the tools available to produce new features and functions.”