Historical story

Brain doubler found

One mutation in our ancestors' genes may be responsible for the large brains that humans have. That one change resulted in a cerebral cortex twice as large and with it what transformed the great ape into a human being. In this variant, the gene only occurs in modern humans, in Neanderthals and other primordial humans.

About five million years ago, a genetic split arose between the chimpanzee and the ancestor of modern humans. That has been known for a long time. But German research published this week in Science Advances appears, claims that it was not until a million years later that the decisive mutation occurred in the ARHGAP11B gene, which greatly increased the size of the cerebral cortex. One C was replaced by a G in one gene for brain development.

A kind of bonobo

Would humans still be some kind of chimpanzee or bonobo without this mutation? “That is too strong a statement,” said Wieland Huttner, one of the researchers. “We don't know how human evolution would have gone without this mutation. Keep in mind that so far we have only experimented with mice.”

Thousands of genes are involved in the development of the brain during the growth of a fetus, but this applies to mice just as much as it does to humans. And in many ways, development in humans and other mammals is parallel. Brain researchers have long – and with little success – tried to get a finger on the genetic difference between humans and animals.

Growth of the cortex

The specific human gene ARHGAP11B seems to play a crucial role in this. In all mammalian embryos, during the growth of the cortex - the highly folded outer layer of the cerebrum - brain cells arise from precursor cells, the basal progenitor cells (BP cells). But ARHGAP11B creates many more BP cells, which double an entire layer of the cortex, the subventricular zone. The cortex thus becomes double-thick and richer in brain cells.

Marta Florio and her colleagues from various Max Planck Institutes in Germany had already discovered this last year, but now they have also explored how this works down to DNA level. The human gene is derived from an ancient gene, ARHGAP11A, which is found in many animal species, even the single-celled organism yeast.

Doubling

The human variant is largely a duplication of the old gene. Duplication of genes can occur in rare cases if a gene is read and copied twice during cell division; there are more known examples. This may have already happened when the ancestor of man split evolutionarily from the chimpanzee.

But that's not enough to also double the subventricular layer in the cortex. The researchers found that in one place in ARHGAP11B, compared to the primal gene, a 'letter' C (the molecule cysteine) has been replaced by a 'letter' G (the molecule guanine). As a result, a whole part of the gene is no longer read and a certain protein is no longer produced. Because this protein inhibits the division of the BP cells, the C-G replacement stimulates this.

This may be the mutation that started the frenetic growth of our brains about four million years ago. If it really is that simple to give your brain such a turbo boost, why did it only happen in the ancestor of humans? Huttner:"No other animal species has that 'duplicated' gene, so that mutation cannot occur."

Fossil DNA

If this gene variant is millions of years old, it must have originated in an early human ancestor from which all known hominids descend. Fortunately, fossil DNA of several of Homo Sapien's cousins ​​has been preserved and read, and those letter orders are in online databases. This made it easy for the researchers to check that Neanderthals and Denisovans are also carriers of the human gene variant ARHGAP11B. Also in all modern humans whose DNA is read and available, the gene ARHGAP11B, not ARHGAP11A, is present.

With new techniques for genetic modification, such as Crispr/Cas9 , it is possible to very effectively incorporate foreign genes into an organism. Huttner:“This is what we are doing in our lab right now. We are analyzing mice with a functioning human ARHGAP11B gene.” He does not want to say anything about whether these mice also have other brains and are more intelligent:“I will publish those results in a scientific publication.”