One of the most relevant and interesting questions in neuroscience is: What makes us human? Specifically, what is it about the human brain that differentiates us from our closest relatives? In a recent study, a research team has investigated over 3,000 regions in the human genome that are different from any other mammal to find out what makes us so different.
What are human accelerated regions?
Human accelerated regions (HARs) are a set of 49 segments of the human genome that are conserved throughout vertebrate evolution. These regions are important as they are different to any other mammal, even our closest primate relatives. There are over 3,000 regions that are considered to be HARs. In addition, it has been noted that these are the fastest evolving regions of the human genome. HARs are hypothesised to function as regulatory elements which drive human-specific regulatory programs.
In a new study, published in Neuron, a team of researchers has found evidence that nearly half of these HARs play an essential role in enhancing neurodevelopment in humans. The team set out to identify which of the 3,171 previously identified HARs, were most likely to be contributing to the recent evolution of the human cerebral cortex. The researchers systematically examined the role of these regions using multiple human and mouse cell types and tissues. This study provides important new insights into the genetics of human evolution.
The importance of human accelerated regions in human neurological development
After they identified the regions they were interested in, the team used a new method to capture target sequences that represented entire HAR elements along with their surrounding DNA. This method, called CaptureMPRA, was specifically developed for this study. Using this approach, the team investigated the differences between HARs in humans and chimpanzees. They expanded their investigations by integrating the data collected from the CaptureMPRA with epigenetic data from human foetal neural cells. The aim was to explore the role of HARs on human-specific neural development.
The results demonstrated that many HARs act as neurodevelopment enhancers. The researchers found a specific gene called PPP1R17 that had undergone rapid developmental expression change not only between non-primates and primates but also between non-human primates and humans. The team went on to show that PPP1R17 slows the progression of neural progenitor cells through the cell cycle. This gene specifically increases the cell-cycle length. It is known in both humans and primates that this process forces neurological development to slow down, which is a vital characteristic of the human brain.
In summary, the new findings demonstrate that HARs play a crucial role in human neuronal gene regulatory programs. Interestingly, nearly half of all HARs are shown to enhance activity in neural cells and tissues. The team has now developed an easily searchable online resource named the HARhub, which consists of new data and previously published datasets of common and rare HAR sequence variations. This databank could be used as a resource for scientists worldwide to further our understanding of what makes us human.
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