New technology reveals genes underlying human evolution

One of the best ways to study human evolution is by comparing us to non-human species that, evolutionarily speaking, are closely related to us. That closeness can help scientists limit exactly what makes us human, but the scope is so narrow that it can also be very difficult to define. To address this complication, Stanford University researchers have developed a new technique for comparing genetic differences.

Through two separate experiments with this technique, the researchers discovered new genetic differences between humans and chimpanzees. They found a significant difference in the expression of the gene SSTR2 – which modulates the activity of neurons in the cerebral cortex and has been linked in humans to certain neuropsychiatric diseases such as Alzheimer’s dementia and schizophrenia – and the gene EVC2, which is linked to face shape. The results were published on March 17 Nature and Natural genetics, respectively.

“It’s important to study human evolution, not only to understand where we come from, but also why humans contract so many diseases that are not seen in other species,” said Rachel Agoglia, a recent student at Stanford. genetics, who is the lead author of the Nature paper.

The Nature The new technique involves the fusion of skin and chimpanzee skin cells that have been modified to act as stem cells – many malleable cells that can be encouraged to transform into different types of cells (though not a complete organism).

“These cells serve a very important specific purpose in this type of study by enabling us to accurately compare human and chimpanzee genes and their activities,” said Hunter Fraser, associate professor of biology at Stanford’s School of Humanities and. Sciences said. Fraser is a senior author of the Natural genetics paper and co-senior author of the Nature Sergiu Pauca, associate professor of psychiatry and behavioral sciences at the Stanford School of Medicine.

Close comparisons

The Fraser Laboratory is particularly interested in how the genetics of humans and other primates compare at the level of cis-regulatory elements, which affect the expression of nearby genes (located on the same DNA molecule or chromosome). The alternative – called transregulatory factors – could regulate the expression of distant genes on other chromosomes elsewhere in the genome. Due to its broad effects, transregulatory factors (such as proteins) are less likely to differ between closely related species than regulatory elements.

But even when scientists have access to similar cells from humans and chimpanzees, there is a risk of confusing factors. For example, differences in the timing of development between species are a major obstacle in the study of brain development, explains Pa, ca. This is because human brains and chimpanzee brains develop at very different rates and there is no exact way to compare them directly. By harboring human DNA and chimpanzee DNA in the same cellular nucleus, scientists can rule out the most confusing factors.

For the initial experiments using these cells, Agoglia enticed the cells to form so-called cortical spheroids or organoids – a bundle of brain cells that mimics a developing cerebral cortex of mammals. The Pașca Laboratory is at the forefront of the development of brain organs and compounds to investigate how the human brain is composed and how this process goes wrong in diseases.

“For the most part, the human brain is essentially inaccessible at the molecular and cellular level, which is why we have introduced cortical spheroids to help us access these important processes,” says Pașca, who is also the Bonnie Uytengsu and is family director of Stanford Brain. Organogenesis.

As the 3-D clusters develop brain cells in a dish and mature, they mimic genetic activity that occurs in early neurodevelopment in each species. Because the human and chimpanzee DNA are bound together in the same cellular environment, they are exposed to the same conditions and mature in parallel. Therefore, any observed differences in the genetic activity of the two can reasonably be attributed to actual genetic differences between our two species.

By studying brain organoids derived from the fused cells cultured for 200 days, the researchers found thousands of genes showing the difference between species between cysts. They decided to further investigate one of these genes – SSTR2 – which is more strongly expressed in human neurons and as a receptor for a neurotransmitter called somatostatin. In subsequent comparisons between human and chimpanzee cells, the researchers confirmed this increased protein expression of SSTR2 in human cortical cells. When the researchers exposed the chimpanzee cells and human cells to a small-molecule drug that binds to SSTR2, they found that human neurons respond much more to the drug than the chimpanzee cells.

This indicates a way in which the activity of human neurons in cortical circuits can be adjusted by neurotransmitters. Interestingly, this neuromodulatory activity is also associated with diseases, as SSTR2 appears to be involved in brain diseases.

“The evolution of the primate brain has possibly added sophisticated neuromodulatory properties to neural pathways, which can be disrupted under certain conditions and increase susceptibility to neuropsychiatric diseases,” Pașca said.

Fraser said these results are essentially evidence that the activity we see in these fused cells is actually relevant to cellular physiology. ‘

Investigate extreme differences

For the experiments performed in Natural genetics, the team brought their fused cells to the neural crest cells of the skull, giving rise to bones and cartilage in the skull and face, and determining the appearance of the face.

“We were interested in these types of cells because facial differences are considered to be the most extreme anatomical differences between humans and chimpanzees – and these differences actually affect other aspects of our behavior and evolution, such as nutrition, our senses, brain expansion and speech,” said David Gokhman. , a postdoctoral fellow in the Fraser Laboratory and lead author of the Natural genetics paper. “The most common congenital diseases in humans are also related to facial structure.”

In the fused cells, the researchers identified a gene expression pathway that is much more active in the chimpanzee genes of the cells than in the human genes – with one specific gene called EVC2, which is apparently six times more active in chimpanzees. Existing research has shown that humans with inactive EVC2 genes have flatter faces than others, suggesting that this gene may explain why humans have flatter faces than other primates.

What’s more, the researchers found that 25 observable facial features associated with inactive EVC2 differ markedly between humans and chimpanzees – and 23 of them differ in the direction the researchers would predict, given lower EVC2 activity in humans. In follow-up experiments, where the researchers reduced the activity of EVC2 in mice, the rodents also developed flatter faces.

Another tool in the toolbox

This new experimental platform is not intended to replace the existing cell comparison studies, but the researchers hope it will support many new findings on human evolution and evolution in general.

“Human development and the human genome have been studied very well,” Fraser said. “My lab is very interested in human evolution, but because we can build on such a wealth of knowledge, this work can also reveal broader insights into the process of evolution.”

The Fraser Laboratory is working to differentiate the fused cells into other cell types, such as muscle cells, other types of neurons, skin cells and cartilage, to expand their studies on unique human characteristics. The Pașca laboratory, meanwhile, wants to investigate genetic differences associated with astrocytes – large, multifunctional cells in the central nervous system that are often overlooked by scientists in favor of flashing neurons.

“While humans often reflect on how neurons evolved, we should not underestimate how astrocytes have changed during evolution. The size difference alone, between human astrocytes and astrocytes in other primates, is large,” Pașca said. “My mentor, the late Ben Barres, called astrocytes ‘the basis of humanity’ and we absolutely think he wanted to do something.”