Over the past six million years, the human brain size tripled. Most of that super-growing happened during the last two million years, and scientists are still speculating about what caused that great burst. On Thursday, an international team of scientists announced a new explanation: Brain expansion is controlled by genes that, to date, have only been found in humans.

In Cell, they theorize that these brain-enlarging genes emerged around two to three million years ago, which fits the previously established brain expansion timeline. Eight different variants of the genes, known as NOTCHN2NL, have been identified, and the scientists write that they’re all derived from an even more ancient DNA family: the NOTCH genes.

“This is a family of genes that go back hundreds of millions of years in evolutionary history and is known to play important roles in embryonic development,” senior author and scientific director of the University of California, Santa Cruz Genomics Institute David Haussler, Ph.D. explained in a statement released Thursday, referring to the NOTCH genes. “To find that humans have a new member of this family that is involved in brain development is extremely exciting.”

NOTCH2NL genes
Researchers studied the effects of NOTCH2NL genes in cortical organoids grown from human embryonic stem cells.

Study author and University of Amsterdam professor Frank Jacobs, Ph.D. started investigating NOTCH2NL genes in 2012 while trying to manipulate human and rhesus monkey embryonic stem cells into neurons. During this process, he noticed that certain genes turned on as the human cells self-organized into a miniature version of the brain’s cortex, a sci-fi-ready structure known as a “cortical organoid.” In these organizing cells, it became abundantly clear that something weird was going on with the NOTCH2NL genes, which were found only in the human cells.

“It was screaming hot in human cells and zero in rhesus,” senior author and UC Santa Cruz research scientist Sofie Salama, Ph.D. said in the statement, referring to the activity of the genes. “Rhesus cells just don’t have this gene. Finding a new Notch gene in humans set us off on a long journey.”

When the scientists started sharing their findings in 2013, other scientists were skeptical that these genes were truly unique to humans. So the team grew, buckled down, and spent five more years studying them. At UC Santa Cruz, the scientists used the CRISPR/Cas9 system to find out what would happen if the NOTCH2NL genes were deleted from human embryonic stem cells. The little brains that grew showed accelerated neural maturation and were smaller in size. And when the genes were put into mouse embryonic stem cells, the reverse happened: The neural maturation process was delayed.

That was an important clue that the NOTCH2NL genes played a huge role in the brain development of humans — and only humans. It’s well established that our brains are big and that the maturation process of our brains is slow, which is why the little human brains lacking the genes matured quickly and stayed small. Meanwhile, the mouse cells manipulated to carry the genes took on human-like traits.

NOTCH2NL genes
Evolution of the NOTCH2NL gene.

NOTCH genes are found in all mammals, telling stem cells what to turn into. The human-specific NOTCH2NL genes, which are an offshoot of NOTCH family, seem to amplify the stem cell signaling process, which is what the scientists think is responsible for the proliferation of neural stem cells and delayed neural maturation in the human brain. As a result, humans have a larger number of mature neurons in the neocortex, which boosts cognitive functions like language and reasoning — and accounts for bigger brain size.

To ensure NOTCH2NL genes are a strictly human family, the researchers analyzed the genomes of three ancient hominins: Two Neanderthals and one Denisovan. The proof was in the pudding: Each of these ancient humans had NOTCH2NL genes in their genome, just like modern humans. They too, had relatively big brains, though not nearly as big as ours.

The uniquely large human brain came about because of a genetic duplication event that occurred in the common ancestor of humans and other hominids millions of years ago, the scientists speculate. This event created an extra partial copy of the NOTCH2 gene, which got added to the genome. Over evolutionary time, however, its role became very different in humans, chimps, and gorillas. Today, ape genomes have a partial duplicate nonfunctional “pseudogene” version of the gene. Humans, meanwhile, kept a functional version of that gene — and gained several copies of it over the years.

This was great for our brain evolution — except for the fact that those genes are now also implicated in some neurological disorders. The DNA copying error that created the NOTCH2NL genes is believed to cause something called 1q21.1 deletion/duplication syndrome, which can cause developmental delays and intellectual disabilities. NOTCH2NL defects don’t always lead to this disorder, however, which is an idiosyncrasy that the scientists plan on pursuing further.

“These long segments of DNA that are almost identical can confuse the replication machinery and cause instability in the genome,” says Hassler. “We may have gained our larger brains in part through the duplication of these genes, but at the expense of greater instability in that region of chromosome 1, which makes us susceptible to the deletion/duplication syndrome.”