Science – a new perspective on the ancient human genome

Science – a new perspective on the ancient human genome
03/10/2021 Neanderthal Jaw Research and Technology University of OXFORD

Madrid, 27 years old (European press)

Differences in gene activation, not just the genetic code, could be the basis for the development of the brain and vocal system in humans.

It’s a discovery that examined 14,000 genetic variants between modern humans and our more recent ancestors with a new level of detail.

The genome itself is like a recipe without a chef: full of important information, but it needs an explanation. So although we have sequenced the genomes of our closest extinct relatives, Neanderthals and Denisovans, many unknowns remain about how differences in our genomes lead to differences in physical traits.

“When we look at the ancient genome, we don’t have all the layers and markers that we normally have in samples from current individuals that help us explain the organization in the genome, such as RNA or cell structure,” said David Gokhman, a postdoctoral fellow. In biology at Stanford University.

“We only have the naked DNA sequence, all we can really do is look at it and hope that one day we can understand what it means,” he said in a statement.

Motivated by these hopes, a team of researchers from Stanford University and the University of California, San Francisco (UCSF) devised a new method for gathering more information from the ancient human genome to reveal the physical consequences of the genetic differences between us and them. .

Their work, published in eLife, focused on sequences related to gene expression, the process by which genes are turned on or silenced, and that determines when, how, and where DNA instructions are followed. Gene expression tends to be the genetic details that define the physical differences between closely related groups.

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Starting with 14,042 genetic variants unique to modern humans, researchers have found 407 gene variants that specifically contribute to differences in gene expression between modern humans and humans. In a more detailed analysis, they determined that the differences were most likely related to the vocal tract and the cerebellum, which is the part of our brain that receives sensory input and controls voluntary movement, including walking, coordination, and balance. Speaking.

“It seems unreasonable to say something like, ‘I think the larynx has evolved’ from the information we have, ‘said Dmitry Petrov, Professor Michael and Kevin Douglas at the School of Humanities and Sciences, who is co-chair. Author on the paper with Gokhman and Nadav Ahituv, Professor of Bioengineering at UCSF. “Predictions are almost science fiction. If someone told me five years ago that this would be possible, I wouldn’t have invested so much money in it.”

With such a large number of variants to be examined, researchers have relied on a technique called “massively parallel reporter assay” to test the sequences that actually affect gene regulation. His version of this technology, developed by Ahituv, involves assembling the altered DNA sequences into a “reporter gene” inside the virus. Then this virus enters the cell. If this variant affects gene expression, the reporter gene produces an encoding molecule that determines which DNA sequence it came from. The barcode allows researchers to scan the products of a large number of variants at the same time.

Essentially, the entire process simulates a condensed version of how each variable in a cell evolves in real life and report results.

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Lana Harshman, a UCSF graduate student and co-author of the paper, infected three cell types with the altered bundles of the group. These cells were linked to the brain, skeleton and early development, subjects that are likely to reveal the evolutionary differences between us and our more recent ancestors. Carly Weiss, a postdoctoral researcher in Petrov’s lab and co-lead author of the paper, analyzed the results of these experiments.

In total, the researchers found 407 sequences that represented a change in expression in modern humans compared to our ancestors. Among that list, genes that affect the cerebellum and genes affecting the larynx, pharynx, larynx and vocal cords appear to be overrepresented.

“This would indicate some kind of rapid development of those organs or some kind of pathway of modern man,” said Jockman. He added that the next step would be to try to understand more about these sequences and the roles they played in the evolution of modern humans.

Petrov said that even with this unknown, the technology itself is an important advance for evolutionary research. “This goes beyond DNA sequencing of Neanderthal and Denisovan bones. It starts with understanding these differences,” Petrov said. “It is an important conceptual step from mere sequencing, neither tissue, nor cells, to biological information, and will allow for many future studies.”

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