Like treasured recipes that are passed down from generation to generation, there are only certain regions of DNA that evolution dares not alter. Mammals around the world share a variety of these coding sequences, for example, which have remained intact for millions of years.
Humans are a rare exception to this club. For whatever reason, the recipes long held by our ancient ancestors were suddenly “spiced up” in a short period of evolution. Because we are the only species in which these regions have been rewritten so quickly, they are called ‘human accelerated regions’ (or HARs). Furthermore, scientists believe that at least some of the HAR may be the source of many qualities that distinguish humans from their close relatives, such as chimpanzees and bonobos.
Led by computational biologist Katie Pollard, director of the Gladstone Institute of Data Science and Biotechnology in the United States, a team of researchers identified HAR nearly two decades ago by comparing human and chimpanzee genomes. In a new study, Pollard’s team found that 3D folding of human DNA in the nucleus is a key driver of this pivotal moment for our species. Imagine a piece of DNA from our last common ancestor with chimpanzees in the form of a long scarf wrapped around your neck, with stripes of different colors running the length of its fabric.
Now imagine that someone tried to make the exact same scarf, but it didn’t follow the original pattern. Some stripes are narrower, some are wider, and some have colors in a different order than the original. When you wrap this new scarf around your neck in the same way as the original, the side-by-side stripes on the loop are no longer the same. Like this scarf, a big difference between human and chimpanzee DNA is structural: large chunks of the building blocks of DNA have been inserted, deleted, or rearranged in the human genome. Therefore, human DNA folds differently in the nucleus compared to DNA from other primates.
Pollard’s team investigated whether these structural changes to human DNA and its altered 3D folding might have resulted in the ‘hijacking’ of particular genes within HAR, linking them to different protein-coding genes to which they were initially applied. Many genes within HAR are linked to other genes, acting as enhancers (meaning they increase the transcription of their linked genes).
“Enhancers can affect the activity of any nearby gene, which can vary depending on how the DNA folds.” Pollard said. In a study published earlier this year, Pollard’s team created a model that suggested that the rapid variations that appeared in HAR in early humans often opposed each other, causing the activity of a trigger to rise and fall in a sort of genetic fit, a model supported by his new research. For their most recent study, the team compared the genomes of 241 mammalian species using machine learning to handle large amounts of data.
They identified 312 HARs and examined where they fit into the 3D “quarters” of the folded DNA. Nearly 30% of the HARs were found in regions of DNA where structural variations had caused the genome to fold differently in humans than in other primates. The team also discovered that neighborhoods containing HARs were rich in genes that differentiate humans from our closest relatives, chimpanzees.
In an experiment comparing DNA in growing human and chimpanzee stem cells, one-third of the HARs identified were specifically transcribed during the development of the human neocortex. Many HARs play a role in embryonic development, particularly in the formation of neural pathways associated with intelligence, reading, social skills, memory, attention, and concentration, based on traits that we know are markedly different in humans. humans than in other animals. In HAR, these activating genes, unchanged for millions of years, may have had to adapt to their different target genes and regulatory domains.
“Imagine you’re an activator controlling hormone levels in the blood, then DNA folds in a new way, and suddenly you’re sitting next to a neurotransmitter gene and you need to regulate chemical levels in the brain instead of the blood.” ». Pollard said. “Something big is happening, like this massive genome folding change, and our cells need to quickly correct it to avoid an evolutionary disadvantage.” We still don’t understand exactly how these changes affected specific aspects of our brain development and how they became part of our species’ DNA. Although Pollard and his team are already planning to investigate these questions.