How did our brains get so big?

C73 brain 1
The folding on the right side of this mouse embryo’s cortex reflects the increased growth stimulated by the insertion of a human gene into that side of the brain.
Credit: Marta Florio / Wieland B. Huttner / Max Planck Institute of Molecular Cell Biology and Genetics

About six million years ago our human ancestors branched off the primate family tree, leaving their cousins – the ancestors of chimpanzees – in the African dust.

They made simple tools and, thus equipped, eventually travelled out of Africa.

The evolutionary leap that started the journey was the mushrooming of the human brain. A modern human brain is three times larger than a chimp’s; the most enlarged region is the six-layered neocortex, a part of the cerebral cortex that is the seat of reasoning and language.

How did this circuit upgrade take place?

For the past decade, scientists have been comparing the DNA of chimpanzees and humans to look for clues. The most recent discovery comes from Wieland Huttner’s lab at the Max Planck Institute in Germany. Remarkably, they showed that just a single letter change in the DNA of one gene triggered an increase in a population of stem cells called basal radial glia. These cells are thought to have powered the expansion of the human cerebral cortex. The finding was published in Science Advances last December.

The dramatic finding is the latest in a series of revelations about the DNA upgrades that delivered the human brain. Human and chimpanzee genomes are 98.8% the same.

Intriguingly, within many of the regions that differ, it looks as if chunks of DNA in the human had been Xeroxed – meaning humans acquired “back-up copies” of particular genes, That made them ripe for some evolutionary tinkering; if the copy happens to acquire a few coding errors, there’s no drama – there’s still the functioning original. Once in a while however, a copying error might lead to a new function that is useful.

Six million years ago, around the time our ancestors were branching off from non-human primates, there was a burst of these gene duplications. Smoking guns! Problem is, there were thousands of them.

To get a clue as to which ones might be involved in the human brain upgrade, researchers tested to see whether related genes in mice were involved in the development of their brain.

One success came in 2012, when Cécile Charrier at the Scripps Research Institute in California and her colleagues took a closer look at a duplicated human gene named SRGAP2C. It was a slightly altered copy of the original found in chimps and mice, and it was active in their developing brains. The scientists came up with an irresistible experiment: they genetically engineered the human copy into embryonic mice.

As neurons develop, they acquire spines that act like antennae for receiving messages from other neurons. But the spines stop sprouting once the neurons mature. Charrier and her team found that introducing the human backup gene, SRGAP2C, delayed the maturation so spines kept sprouting, which enabled them to make more connections. The experiment showed how, through the copying and then tweaking of a single gene, evolution increased the circuit complexity of the human brain.

C73 brain graphic
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Credit: Cosmos Magazine

The latest work follows a similar plot line. Marta Florio, a PhD student in the Huttner lab studied another backup copy of a gene that is present in humans but absent from chimps and mice. It is called ARHGAP11B. When the human version was introduced into developing mice, it caused a particular population of brain stem cells – basal radial glia – to increase their rounds of multiplication. Not only did mice double the number of these stem cells in some cases their ballooning brains started folding to fit into the skull – just as the brains of primates do.

That finding was reported in Science in 2015. The latest finding is that just a single letter change in the ARHGAP11B DNA is able to increase the multiplication of basal radial glia.

So are these mice any smarter? The German team has yet to test them. But at least one strain of mice are smarter today for having acquired a human gene.

The FOXP2 gene is needed to turn thoughts into speech; human families who lack the functional gene show defects in language and vocalisation. According to a paper published in 2014 by Christiane Schreiweis at the Max Planck Institute and colleagues at MIT, when the human form of this gene was introduced into mice, they got better at learning mazes and squeaked more often.

As stunning as these results are, researchers are still far from providing a manifest of the upgrades that delivered the human brain. “Evolution went through a process of trial and error over millions of years,” says neuroscientist Seong Sen Tan of the Florey Institute in Melbourne. “There will be numerous switches.”

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