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Researchers have now discovered that HAR123, a regulatory gene sequence, is an important factor in human brain development.
Even though humans are closely related to chimps, the slight differences in human and chimp HAR123 suggest something unique in the human version.
HAR123 is also thought to be associated with neurodevelopmental conditions, and may reveal what is needed for more effective treatments in the future.
What is it that makes the human brain distinctly human? What makes it stand out from the brains of other creatures, and even our closest living primate relatives?
Well, it turns out there might be answers hiding in our genome. Human-accelerated regions, or HARs, are segments of the human genome with unusually high numbers of mutations that appeared throughout our evolution. When our ancestors split from chimps about 5 million years ago, the genetic sequences of HARs experienced rapid shifts, which is is why HARs are thought to at least partially explain traits that are singularly human.
HARs are not genes themselves. Rather, they are transcriptional enhancers—DNA sequences that regulate transcription. When bound by proteins, they increase chances of a certain gene being transcribed, which is how they regulate genes for cell differentiation and organ development. And these HARs are especially associated with the brain, as more of them are located in regions involved with regulating neurodevelopmental genes than elsewhere in the body.
Now, a team of researchers from University of California (UC) San Diego have found that there is one particular HAR—known as HAR123—that could be a main factor in molding our brains to separates us from chimps.
“The human version of this HAR confers several properties—both phenotypic and molecular—that differ from the chimpanzee version, raising the possibility that this HAR has played a role in the evolution of human-specific neural traits,” the researchers wrote in a study recently published in the journal Science Advances.
The human and chimp version of HAR123 are orthologs—genes that are passed on to different species that arise from a common ancestor. The human HAR123 acts through the nearby gene H1C1 to promote the formation of neural progenitor cells (NPCs), which will morph into one of two types of cells. The first is neural cells, or neurons, which are the nerve cells that receive sensory input and use electrical and chemical signals to zap messages throughout the body, telling it what to do and when. The second is glial cells, which hold neurons in place and keep them functioning properly. Chimp HAR123 does not lead to the differentiation of as many cells as human HAR123.
To find out whether HAR123 had any special biological significance in humans, CRISPR-Cas9 was used to delete both alleles (different versions of same the genetic sequence) from human embryonic stem cells. This resulted in four clones, all of which developed normally. Closer analysis revealed that removing HAR123 impeded the formation of the neuroectoderm—a thick region of cells from the outer layer of an embryo that will eventually become the entire nervous system—reducing neuroectoderm gene expression.
What is most significant about HAR123 in humans is that it is behind our cognitive flexibility—the ability to either switch from thinking about one concept to the other or to simultaneously think about multiple concepts. This includes being able to overwrite previous knowledge with new knowledge. In animals (like the mice being examined in this study), cognitive flexibility is the changing of behavioral responses in a situation. When this transcriptional enhancer was deleted in mice during a previous experiment, the mice showed less cognitive flexibility, and the ratio of neural to glial cells in their brains changed.
HAR123 may at least contribute to the type of cognitive flexibility that is unique to humans as a species. It could even have something do with neurodevelopmental conditions, such as autism and ADHD, which are already associated with a different ratio of neurons to glia and have been connected to HARs. It is also possible there are the other HARs which also give us our humanity, but have not yet been linked to traits that are exclusively human.
“The finding that the human ortholog of HAR123 differs in some of its properties from the [chimp] ortholog raises the possibility that HAR123 has a role in the originally hypothesized function of HARs—to confer human-specific traits,” the team said. “However, this remains to be determined.’
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