Human-accelerated regions (HARs) are sections of the human genome that have accumulated an unusually high level of mutations as humans split away from chimpanzees. Given their rapid evolution, some scientists hypothesize that these sequences have an essential role in conferring human-specific traits. But that conclusion is not based on evolution alone. “My personal opinion is that more than half our genome is junk” and sequences that rapidly evolve for the most part “are not doing anything” and “there is no selection to keep them the same,” said Miles Wilkinson, PhD, distinguished professor in the department of obstetrics, gynecology, and reproductive sciences at UC San Diego (UCSD) School of Medicine. “What makes HARs unique is that they are highly conserved in other species.”
Scientists have studied and published data on HARs for nearly 20 years, and to date, over 3,000 have been identified, with about 90% of them appearing in noncoding genomic regions. However, scientists know very little about the biological functions of HARs, and linking these sequences to human-specific traits has been challenging. Now, a recent paper from the Wilkinson lab at UCSD focused on a specific sequence—dubbed HAR123—could get them closer to an answer. Their work, which is done in mice, is described in a Science Advances paper titled “An ancient enhancer rapidly evolving in the human lineage promotes neural development and cognitive flexibility.”
HAR123 is not a gene; rather, it is a transcriptional enhancer. These sequences control which genes are activated, how much they are activated, and at what times they are activated during an organism’s development. Wilkinson’s interest in HAR123 began with his lab’s work on the nonsense-mediated RNA decay (NMD) pathway, whose main function is to reduce errors in gene expression.
“There is a lot of evidence that it’s important for brain function, development, and also the function of adult neurons,” he told GEN. That led them to a simple idea. ”Maybe it evolved rapidly in humans and conferred some unique human neural traits. And so we just simply asked, ‘Are there any HARs in NMD genes?’”
As it turns out, three HARs are associated with the pathway. Two of the three are found in the SMG6 gene—HAR53 and HAR123, which the current research focuses on. To determine whether HAR123 has biological functions in human cells, the scientists used CRISPR to delete both HAR123 alleles in human embryonic stem cell assays. Their analysis revealed “that loss of HAR123 specifically perturbed the formation of neuroectoderm, based on reduced expression there neuroectoderm markers,” the researchers wrote.
Because neuroectoderm produces the neural progenitor cells that give rise to neurons and glial cells, the scientists next evaluated whether HAR123 is critical for that process. The evidence suggests that it is. According to the paper, the HAR123 knockouts caused an “NPC generation defect” as well as “the formation of an NPC cell cluster not found in [wildtype] cells.” There is also evidence that HAR123 “influences the neuron/glia ratio in specific hippocampus regions at both the early and late postnatal stages.”
But “possibly the biggest take-home is our evidence that HAR123 is critical for cognitive flexibility,” Wilkinson said, referring to the ability of the mice used in the study to adapt rapidly to changes in their environments. Both HAR123 wildtype and knockout mice were healthy and performed well on a range of behavioral tests. However, HAR123 knockout mice “are deficient in their ability to learn and/or remember altered information,” the researchers wrote.
For their next steps, Wilkinson and his colleagues would like to run further tests to understand HAR123’s function. The current paper provides “several lines of evidence” that “HAR123 is important for unique human brain characteristics that make our brain different [from the] chimp brain…but we haven’t really nailed it.” A potential study would involve replacing mouse HAR123 with human HAR123 and observing what happens. “At a very obvious level, if our mice become even incrementally smarter, as long as it was statistically significant, I think that would be a lot.”
They also plan to study HAR123’s role in neurodevelopmental diseases and disorders. The sequence’s connection to the brain and cognitive development suggests a possible link to disorders like autism. “The region of chromosome 17 that this HAR is in is a well-recognized disease locus,” Wilkinson said. “It’s in both microdeletions and duplications in this region that are known to cause a whole symphony of problems. Depending on where the exact deletion is, you get different symptoms, everything from intellectual disability to seizures.”
Another line of inquiry would be looking into a possible link between HAR123 and diseases linked to defects in the brain’s white matter, such as multiple sclerosis. To be clear, this link is “purely an association at this point. We don’t know if it’s causal. So we’d like to nail that,” Wilkinson said. He and his team plan to collaborate with colleagues who study these disorders in order to elucidate HAR123’s role.
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