For years, many researchers have been trying to answer the question "What makes us human?" from both a biological and philosophical standpoint. We know that humans and chimpanzees have a high degree of genetic similarity, but there are still about 3,000 regions in the human genome that are very different from our close primate relatives. The unique brain of humans can also provide some physiological insights into what makes us different from closely related species. Scientists have now found that almost half of rapidly evolving portions of the genome called human accelerated regions (HARs) have been involved in changing brain development in people. This work, which was reported in Neuron, may help us understand more about what is special about our species, and how we evolved.
In this study, researchers investigated 3,171 known HARs to identify the ones that could be contributing to changes in the human cerebral cortex over time. The researchers knew that HARs were probably influencing the activity of other genes in the brain, but not when they are expressed during a human lifetime or in which types of cells, noted co-first study author Ellen DeGennaro, who works in the lab of Christopher Walsh at Harvard University.
“Our goal was to fill in these gaps of knowledge about which HARs had important roles in the brain, and how, so that we and other researchers could take the most important ‘brain HARs’ and perform deeper tests of their evolutionary function,” said DeGennaro.
In this study, the researchers created a new method that captures HAR elements and the DNA that's near them with barcoded molecular probes. They were seeking to learn more about how HAR enhancer function is different in humans and chimps.
The team also investigated epigenetic characteristics of HARs in human fetal neural cells. This work aimed to identify HARs that are related to uniquely human brain development processes. Some of the activity this work revealed was only happening in the brain, and in some caases, further restricted to specific types of cells in the fetal but not adult brain.
The study authors suggested that HARs seem to be neurodevelopmental enhancers, and that as humans diverged from other species, the enhancer role of HARs in neurons has increased.
One gene called PPP1R17 is regulated by HARs, and this study indicated that expression patterns of this gene in humans has changed rapidly compared to primates. As neural progenitors move through the cell cycle, PPP1R17 appears to slow their progression. Neurological development is known to be slower in humans compared to non-human primates, and the lengthening of the cell cycle has been shown to slow neurological development.
Many HARs that are important to gene regulation in neurons have now been revealed, and about half of them act as enhancers in neural cells, noted the researchers. The data is also available online at the HARHub; it contains information on rare and common HAR sequence variation in humans.
“Our work provides an important advance in studying many genomic regions at once to help us piece together the very complicated but compelling picture of human brain evolution,” Walsh said. “Our data suggest that evolution of the human brain involved changes in dozens or perhaps even hundreds of sites in the genome, rather than just a single key gene.”