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Study Shows Genes Unique to Humans Tied to Bigger Brains

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cortical organoid

Caption: Cortical organoid, showing radial glial stem cells (green) and cortical neurons (red).
Credit: Sofie Salama, University of California, Santa Cruz

In seeking the biological answer to the question of what it means to be human, the brain’s cerebral cortex is a good place to start. This densely folded, outer layer of grey matter, which is vastly larger in Homo sapiens than in other primates, plays an essential role in human consciousness, language, and reasoning.

Now, an NIH-funded team has pinpointed a key set of genes—found only in humans—that may help explain why our species possesses such a large cerebral cortex. Experimental evidence shows these genes prolong the development of stem cells that generate neurons in the cerebral cortex, which in turn enables the human brain to produce more mature cortical neurons and, thus, build a bigger cerebral cortex than our fellow primates.

That sounds like a great advantage for humans! But there’s a downside. Researchers found the same genomic changes that facilitated the expansion of the human cortex may also render our species more susceptible to certain rare neurodevelopmental disorders.

This remarkable story of discovery began back in 2012 when Frank Jacobs, then a postdoctoral researcher working with David Haussler and Sofie Salama at the University of California, Santa Cruz, grew small patches of cerebral cortex in lab dishes. Jacobs coaxed radial glial stem cells from humans and rhesus macaques to differentiate into cortical neurons. Those cortical neurons went on to form multi-layered pieces of cortex, which they call cortical organoids. The goal was to examine gene activity within those developing organoids in search of notable differences between the brains of people and macaques.

An obvious place to look is the so-called Notch signaling genes, long known for their roles in brain development. Jacobs noticed that the Notch signal seemed to come on stronger and longer in human compared to macaque organoids in the first several weeks of development. Even more intriguing was a gene, called NOTCH2NL. While highly active in the developing human organoids, that gene was missing altogether in macaques.

As published recently in the journal Cell, Haussler’s team discovered that NOTCH2NL resides on the long arm of chromosome 1. This region of the chromosome is known as a site for genetic defects associated with disorders collectively known as 1q21.1 microdeletion or duplication syndromes [1].

Studies had shown that extra copies of DNA in this region are associated with macrocephaly (an abnormally large head and brain) and autism spectrum disorder, while deletions lead to microcephaly (an abnormally small head and brain) and schizophrenia. That seemed to fit with what Haussler’s team knew about NOTCH2NL. But there was one problem: the reference sequence of the human genetic blueprint, completed about 15 years ago as part of the Human Genome Project and updated periodically, placed the newly discovered NOTCH2NL gene near, but not within, this vexing portion of the genome.

That left the researchers frustrated and a bit baffled. They caught a break in 2014 when researchers re-sequenced that portion of the human genome. In fact, this particular portion of the human genome includes highly repetitive sequences, making accurate sequencing especially difficult. And, it turned out that this is one of those unusual instances where the human reference sequence had been wrong! NOTCH2NL is indeed within the stretch of DNA that is duplicated or deleted in people with 1q21.1 syndromes.

In fact, as Haussler and colleagues now report, the human genome includes three nearly identical copies of NOTCH2NL. They call them NOTCH2NL A, B, and C. The new evidence shows that those duplicate gene copies arose from an original copy of NOTCH2 (one of four previously known mammalian Notch genes) that appeared about 10 million years ago in the common ancestor of humans, chimpanzees, and gorillas.

At first, that partial duplicate was completely non-functional. But, in the human lineage, that useless extra gene copy got written over or “gene-corrected” using the original NOTCH2 as a template, giving Homo an additional working copy not found in other primates. This new Notch gene was subsequently duplicated twice more sometime within the last few million years, just as fossil evidence shows that the human brain continued to evolve and expand.

In another series of experiments, Haussler’s team used the gene-editing tool CRISPR/Cas9 to remove NOTCH2NL genes from human stem cells. When those edited cells were used to grow cortical organoids, the stem cells differentiated and matured faster to produce smaller organoids. When the genes were inserted into embryonic mouse cells, it boosted the Notch signal to delay neural maturation. A companion paper in the same issue of Cell led by a Belgium team also offers highly complementary evidence for NOTCH2NL’s role in the expansion of the cerebral cortex in people [2].

People with duplications or deletions in the 1q21.1 region are known to have a wide range of neurological symptoms, including ADHD, autism spectrum disorder, intellectual disabilities, and anxiety. Some also have microcephaly and macrocephaly. Despite considerable study, a role for NOTCH2NL in these disorders hadn’t been considered before because of that error in the reference human genome, which placed the gene outside the relevant area.

To explore this possibility further, the researchers reanalyzed data showing variations in gene copy numbers in 11 patients with microcephaly or macrocephaly that had previously been unexplained. They found that the nine patients with microcephaly were missing one or more NOTCH2NL copies. The two patients with macrocephaly both showed just the opposite: extra copies of NOTCH2NL.

Interestingly, the DNA sequencing data also showed that these NOTCH2NL genes vary even in healthy people. Haussler says his team has found eight different versions of the NOTCH2NL gene so far, and surely there are more. It’s also clear that some people, such as parents of children with 1q21.1 syndromes, carry deletions or duplications in NOTCH2NL genes without any apparent neurological symptoms.

In other words, there’s a lot more to learn about variations in these genes and their effects on the structure and function of our brains. There are also plenty more genes to study and explore in a similar manner. When it comes to our understanding of the human brain, this is an absolutely extraordinary time.


[1] Human-specific NOTCH2NL genes affect Notch signaling and cortical neurogenesis. Fiddes IT, Lodewijk GA, Mooring M, Bosworh CM, Ewing AD, Salama SR, Jacobs FMJ, Haussler D, et al. Cell. 2018 May 31;173(6):1356-1369.

[2] Human-specific NOTCH2NL genes expand cortical neurogenesis through Delta/Notch regulation. Suzuki IK, Gacquer D, Van Heurck, Kumar D, Wonjo M, Bilheu A, Herpoel A, Lambert N, Cheron J, Polleux F, Detours V, Vanderhaeghen P. Cell. 2018 May 31;173(6):1370-1384.


Chromosome 1q21.1 duplication syndrome (Genetic and Rare Diseases Information Center, National Center for Advancing Translational Sciences/NIH)

1q21.1 microdeletion syndrome (Genetic and Rare Diseases Information Center, NCATS)

Haussler Lab (University of California, Santa Cruz)

NIH BRAIN Initiative

NIH Support: National Human Genome Research Institute; National Institute of General Medical Sciences; National Cancer Institute



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