Brain Gene Tops the List for Making Humans, Human

In a study involving marmosets, a primate genetically similar to humans, researchers have come closer to understanding brain evolution

A gene unique to humans increased brain size in common marmosets. (Leszek Leszczynski / CC BY)
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Why do humans have such large brains? This evolutionary mystery has challenged scientists for ages, but some researchers are using genetics, specifically those genes that can only be found in Homo sapiens, for an answer.

ARHGAP11B, a gene found only in humans, is known for its role in expanding neocortex, the part of the brain responsible for higher cognitive functions such as language and planning. In experiments detailed in a new study published today in the journal Science, researchers inserted the gene into the fetuses of marmosets, who, like humans, are primates, but don’t carry the gene. The team found that after 101 days, the neocortices of the monkeys’ developing brains were larger and had more folds in the tissue than normal monkey fetuses without the gene.

Having more folds in this part of the brain is important because those folds increase the surface area available for brain cells, or neurons, without making the brain too big for the skull. Demonstrating that the human gene fulfills a similar purpose in the brain of another primate provides new insight into how humans may have evolved and may point the way to future treatments for brain disease.

Microscopy image of marmoset brain
Microscopy image of a section through one brain hemisphere of a ARHGAP11B -transgenic marmoset fetus (Heide et al. / MPI-CBG)

The brain, amplified

The ARHGAP11B gene appeared about 5 million years ago, not long after the evolutionary split between chimpanzee and human ancestors. It emerged via mutation when another gene, ARHGAP11A, was copied, or duplicated. However, the 5-million-year-old version of ARHGAP11B, known as the “ancestral B” version, isn’t the one that humans have today. Scientists think another mutation of ARHGAP11B occurred in human ancestors between 1.5 million and 500,000 years ago, creating the human-specific gene the researchers used in their latest study.

“That human-specific sequence is absolutely essential for the ability of the gene to amplify the relevant brain stem cells in development,” says Wieland Huttner of the Max Planck Institute of Molecular Cell Biology, one of the study’s authors.

Previous studies showed similar effects in mice and ferrets modified to have the “new B” version of the gene. However, using those animal models meant the gene was not necessarily expressed in the same way it is in humans. Study author Michael Heide, also of the Max Planck Institute, says the team wanted to study a model organism closely related to humans, and the two most practical options were the marmoset and the macaque.

“We thought that the marmoset would be the better model because the macaque neocortex has many features that it shares with our big and folded neocortex. However, the marmoset is smooth and very small in size.” Thus, any changes to the size and shape of the marmoset neocortex would be easy to see.

To introduce the gene into monkey embryos, the researchers used a “lentivirus,” a virus carrier that cannot replicate. The lentivirus contained ARHGAP11B as well as a protein marker that would allow the researchers to see where that gene was expressed. They included a promoter gene, or a DNA sequence that regulates expression of specific genes.

Debra Silver, an investigator at the Duke University Institute for Brain Sciences, says the researchers’ methods in this study, improved from those used with mice and ferrets, lend a lot of weight to the significance of the results. “One of the challenges [for this kind of study] is you can have abnormally high levels [of expression]. It's like taking a Mack truck to drive something versus something subtler like a Toyota. The idea is, with this they're trying to get closer to what would be normally expressed in the human brain.”

In addition, Silver says, the study demonstrated that a predominant effect of the gene, in addition to increasing the size and number of folds in the neocortex, is controlling the production of certain neurons that develop later and are more important for higher-order processing.

Megan Dennis, who studies the genetics of the human brain at the University of California, Davis, MIND Institute but was not involved in the study, said this research achieved a major step by proving the effect of the gene in a primate.

“We have a whole list of genes that we think might be important in what makes us uniquely human, but very rarely have we definitively shown that they actually are contributors,” Dennis says. “And I have to say that a study like this really brings ARHGAP11B up to the top of the list as a gene that could very well be important in human brain development.”

Enlarged marmoset neocortex
Imaging shows comparison of neocortex size and folds between normal marmosets and those with the human brain gene ARHGAP11B inserted. (Heide et al. / MPI-CBG)

What’s to come

Because ARHGAP11B falls into a region of the human genome that is known to be associated with intellectual disability, schizophrenia and epilepsy, learning more about how it functions could also be important for understanding disease. For example, human brains that become too large (macrocephalized) can suffer a suite of neurological and behavioral disorders, including autism.

Understanding uniquely human genes such as ARHGAP11B also could aid in the development of new kinds of therapies. This study’s authors suggest this gene has the potential to be useful in growing stem cells that could help treat diseases like Parkinson’s, where clear mutations have been identified.

But the idea of using the gene or others like it to alter the essential structure and function of the human brain raises a host of ethical concerns around both animal testing models and genetic engineering.

“You have to be very careful,” Huttner says. “If you do genetic manipulation in humans, you can only do it if it is to cure a disease where you have an abnormal mutation and you bring it back to the identified normal sequence. Only then. But to try to ‘improve’ humans, no way.”

About Courtney Sexton
Courtney Sexton

Courtney Sexton, a writer and researcher based in Washington, DC, studies human-animal interactions. She is a 2020 AAAS Mass Media Fellow and the co-founder and director of The Inner Loop, a nonprofit organization for writers.

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