Over the last million years of evolution, our brain underwent a considerable increase in size and complexity, resulting in the exceptional cognitive abilities of the human species. This brain enlargement is largely due to an increase in the number of neurons in the cerebral cortex, the outer part of the brain.

Since we share about 99% of our genome with that of our closest living relative, the chimpanzee, it has remained a daunting task for scientists to identify which human-specific gene changes may underlie the unique aspects of human brain evolution.

Genetic duplicates
One of the drivers of evolution is the emergence of novel genes through duplication: an ancestral gene is duplicated and the copy evolves into a related, so-called "paralog" gene. Prof. Pierre Vanderhaeghen and his team were particularly interested in duplicated genes that arose specifically in the lineage common to humans and great apes.

Vanderhaeghen: "Developmental biologists usually look at changes in the regulation of genes to explain evolutionary differences, and not so much at genes themselves, since we share so many of our genes even with simple organisms such as worms. But gene duplication can lead to novel genes in a species, which could contribute to the rapid emergence of human-specific traits, like the increased size of the brain's cortex."

Several dozens of 'human-specific' genes have been found in the human genome, but their role has often remained unknown. Many of these genes are thought to be non-functional or redundant, and are not even appropriately annotated in genome databases.

Digging in the dark matter of the human genome
Searching for human-specific genes involved in brain development proved challenging. Ikuo Suzuki, postdoctoral researcher in the lab of Vanderhaeghen, explains why: "One of the main difficulties is distinguishing the expression of ancestral genes (present in all species) and human-specific paralogs (present only in human DNA), as obviously they are extremely similar.

That is why we had to use a tailored RNAseq analysis for specific and sensitive detection of the human-specific genes of interest. In that way, we could identify a whole repertoire of duplicated genes that are involved in the development of the cerebral cortex in humans."

Among these, the researchers focused on one particular family, NOTCH2NL, a cluster of human-specific paralogs of the NOTCH2 receptor. The Notch pathway is well known as a key player in organ development, including that of the brain. Using a stem-cell-based model for cortical development, the scientists found that NOTCH2NL genes stood out for their ability to promote expansion of cortical stem cells, which in turn generated more neurons (see figure).

Vanderhaeghen: "Given the paramount importance of the Notch pathway during neurogenesis, we hypothesized that NOTCH2NL genes could act as species-specific regulators of brain size. It is fascinating to see that genes that arose very recently during evolution interact with probably the oldest signaling pathway among all animals: the Notch pathway."

Brain developmental disorders
The genomic location of the NOTCH2NL genes made them particularly interesting. Ikuo Suzuki: "Three human-specific NOTCH2NL genes are located on the first chromosome, in a region that had previously been linked to disease-related changes in brain size: genetic microdeletions in this region are associated with microcephaly and schizophrenia, while microduplications are associated with macrocephaly and autism spectrum disorders. So naturally, we wondered whether these effects could be linked to NOTCH2NL genes."

The answer came from a group of American scientists led by David Haussler (UC Santa Cruz and Howard Hughes Medical Institute). They analyzed DNA from such patients with microcephaly or macrocephaly and found that the precise regions of origin of deletions and duplications remarkably matched the regions of two of the NOTCH2NL genes. Their findings are reported in the same issue of Cell.

Vanderhaeghen: "Taken together, our study and that of our colleagues in the US point to a selective repertoire of human-specific gene duplications that may act as key controllers of human brain size and function: fewer copies of NOTCH2NL would lead to reduced brain size, while more copies would lead to an increase in brain size."

But there remains more to be discovered, continues Vanderhaeghen: "Intriguingly, the same region in the genome holds several other human-specific genes with unknown function. It will be interesting to see if they control other aspects of human brain development." Human-specific NOTCH2NL genes expand cortical neurogenesis through Delta/Notch regulation, Suzuki et al., 2018 Cell

Related Links
the Flanders Institute for Biotechnology
All About Human Beings and How We Got To Be Here

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