A group of genes that is found only in humans and arose in our ancestors 3–4 million years ago may have driven the evolution of our bigger brains.

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Why are human brains so comparatively large?

This revelation — and the work that led up to it — is the subject of two studies now reported in the journal Cell.

One study was led by the University of California (UC) Santa Cruz, and the other was led by the Université Libre de Bruxelles in Belgium.

The findings plug a gap in our knowledge about the changes that drove the evolution of our larger brains and gave us the ability to think and solve problems.

The genes — named NOTCH2NL — belong to a very old family called Notch that was first identified in fruit flies; they got their name because they were linked to genetic faults that caused the flies to have notched wings.

Notch genes go back “hundreds of millions of years” and “play important roles in embryonic development,” says David Haussler, who is a professor of biomolecular engineering at UC Santa Cruz and co-senior author of the first study paper.

“To find,” he continues, “that humans have a new member of this family that is involved in brain development is extremely exciting.”

The researchers found that the human-only NOTCH2NL genes appear to have a key role in the development of the human cortex, the seat of advanced cognitive abilities such as reasoning and language.

The genes are strongly expressed in the neural stem cells of the cortex and delay their maturation into specific cell types.

This delay results in the accumulation of a larger pool of stem cells, which, in turn, leads to more neurons being produced over the course of brain development.

NOTCH2NL genes are located on an area of the human genome — “the long arm of chromosome 1” — that has been linked to several neurodevelopmental disorders such as autism, microcephaly, macrocephaly, and schizophrenia.

Some of the disorders are linked to duplication of large sections of DNA, and some are linked to deletions. They are known by their collective name “1q21.1 deletion/duplication syndromes.”

The proteins coded by the Notch gene family are concerned with signaling inside cells and also between cells.

Many of these signals direct the fate of stem cells — for instance, whether to differentiate into brain cells or heart cells — in many parts of the body.

The researchers found that the NOTCH2NL genes encode proteins that “enhance” Notch signaling.

“Notch signaling,” explains co-senior study author Dr. Sofie R. Salama, who is a research scientist in biomolecular engineering at UC Santa Cruz, “was already known to be important in the developing nervous system.”

“NOTCH2NL seems to amplify Notch signaling, which leads to increased proliferation of neural stem cells and delayed neural maturation,” she adds.

However, Dr. Salama points out that the genes are just part of a much larger process that controls the development of the human cortex: they do not “act in a vacuum.”

They came into play at a “provocative time in human evolution.” She and her colleagues also found it interesting that the genes are associated with developmental disorders.

It appears that the “DNA copying errors” that occurred in our ancestors that gave rise to the NOTCH2NL genes are of a similar type to those that give rise to neurological disorders in 1q21.1 deletion/duplication syndrome.

Typically, the errors happen in locations on chromosomes that have long sequences of DNA that are “almost identical.”

“These long segments of DNA that are almost identical can confuse the replication machinery and cause instability in the genome,” Prof. Haussler explains.

Paradoxically, it would appear that the gene duplication process in the chromosome 1 region that gave us our bigger brains may also be responsible for making us vulnerable to 1q21.1 deletion/duplication syndrome.

Using sequencing tools, the researchers found eight versions of NOTCH2NL in today’s humans, and they suspect that there are more to be discovered.

Each NOTCH2NL version varies slightly in the sequencing of its DNA, but to what effect is still a mystery.

The genes showed subtle differences when tested in laboratory-grown cells. However, there is still a “lot more work to do” to find out what these differences mean, says Dr. Salama.

We’ve found that all of them can promote Notch signaling.”

Dr. Sofie R. Salama