Three genes found only in humans help us grow large brains

The genes also play a role in neurological disorders, and may provide a path to their treatment

A set of three genes found only in humans appears to play an important role in our large brain size, according to a newly released study. The genes, called NOTCH2NLA, NOTCH2NLB, and NOTCH2NLC, are a type associated with “notch signaling,” a cell signaling system so named because it was first discovered in fruit flies with notched wings. The study is the culmination of five years of research to characterize the genes and understand how they influence not only brain size, but also development. Because of where they are located in the genome, the genes may also be directly implicated in neurological disorders like ADHD, autism spectrum disorder, and schizophrenia. The researchers hope their work could one day lead to new diagnostic tools and treatments. We spoke with study authors David Haussler and Sofie Salama of UC Santa Cruz to learn more.

ResearchGate: What motivated this study?

David Haussler: Researchers specializing in this area are interested understanding which evolutionary changes in our genome underlie human-specific brain features, including our large brain, which is three times larger than that of a chimpanzee. It has been my personal dream to peer into human evolution at the level of individual genes and gene functions.

RG: What are these genes, and what do they do?

Sofie Salama: NOTCH2NL genes are a set of three, nearly identical genes found only in humans that appear to play a critical role in the development of our large brains.

RG: How were they discovered?

Haussler: Our team and that of co-senior author Frank Jacobs of the University of Amsterdam were comparing genes expressed during brain development using small patches of stem-cell derived brain tissue, called cortical organoids, from humans and macaque monkeys.

We discovered that a notch-related gene, NOTCH2NL, is expressed in human cortical tissues but not in those of the macaques. Looking at the DNA, we also realized that this gene is missing in orangutans, and we found only truncated, inactive versions in our closest relatives, gorillas and chimpanzees. We also analyzed the genomes of three archaic humans, two Neanderthals, and one Denisovan, finding in all of them the same three active NOTCH2NL genes that are present in modern humans.

RG: When did these genes first appear?

Salama: The genes appeared in ancient hominins between three and four million years ago, just before the period when fossils show a dramatic increase in the brain sizes of human ancestors.


“By delaying their maturation, the genes allow a larger pool of these stem cells to build up in the developing brain.”


RG: Is it known how they influence brain size?

Salama: Notch proteins are involved in signaling between and within cells. NOTCH2NL seems to amplify notch signaling, which leads to an increased number of neural stem cells and delayed neural maturation. By causing this delay, the genes allow a larger pool of these stem cells to build up in the developing brain, ultimately leading to a larger number of mature neurons in the neocortex. In humans, this part of the brain hosts higher cognitive functions such as language and reasoning.

RG: What is the significance of these genes to present-day humans?

Haussler: While these genes appear to contribute to the increased number of neurons unique to the human neocortex, this capacity also seems to have come with greater potential for a range of neural developmental disorders and disease—like ADHD, autism spectrum disorder, intellectual disability, to macrocephaly (abnormally large head size), and schizophrenia. The DNA copying errors that created the NOTCH2NL genes in the first place are the same type of errors that cause these disorders.


“Our work could lead to new diagnostic tools and eventually to strategies to overcome the defects associated with these mutational events.”


RG: Could this knowledge have medical applications?

Salama: NOTCH2NL is located in 1q21.1, a genome region where duplications and deletions are associated with neurodevelopmental disorders like those David mentioned. This suggests it may have a direct role. Furthermore, the genes’ role in promoting neural stem cell proliferation suggests they may also contribute to the observable traits associated with these genomic rearrangements. Our work could lead to new diagnostic tools, and eventually to strategies to overcome the defects associated with these mutational events.

Haussler: Interestingly, the 1q21.1 genetic changes do not always result in neurological disorders. In about 20 to 50 percent of affected children, 1q21.1 syndrome is the result of a new genetic mistake. However, in many cases, one of the parents is found to also carry the genetic defect, without showing any apparent symptoms. So other factors elsewhere in the genome must contribute to these phenotypes.

RG: What are the challenges to studying these genes?

Haussler: Long stretches of repetitive DNA present challenges for DNA sequencing technologies. In fact, the location of NOTCH2NL in the human reference genome was not accurate when we first started investigating it. After checking other genomic data and contacting the team working on the next iteration of the reference genome, however, we found that NOTCH2NL is in fact located in the interval where the defects occur. Our team developed new methods to sequence and assemble this difficult genomic region which could be used to study other repetitive regions of the genome, many of which have been implicated in human evolution and disease.