There’s plenty of scientific evidence that genes play a key role in defining personality. But how exactly? I mean, how is gene activity in cells ultimately linked to a person’s schmoozing talents at a cocktail party? CIRM-funded research published today in Nature, by collaborative teams at UC San Diego and the Salk Institute identified intriguing connections between brain cells and behavior in Williams Syndrome, a rare genetic disease that has specific effects on personality.

Williams Syndrome 101

Williams Syndrome affects about 1 in 10,000 births. It results from a small deletion on chromosome 7 that removes 25 genes. Common symptoms include heart disease, distinct facial features, visual‑spatial challenges, developmental delays, and hypersensitive hearing.

People with Williams Syndrome also share notable social behaviors. They are unusually outgoing, caring, and skilled at reading emotions.

The research team studied how this deletion produces predictable behaviors. Their goal was to understand the molecular basis of Williams Syndrome and human social interaction. UCSD professor Alysson Muotri described how the project first captured his interest in a university press release interview:

“I was fascinated on how a genetic defect, a tiny deletion in one of our chromosomes, could make us friendlier, more empathetic and more able to embrace our differences.”

Making Williams Syndrome in a Dish with Induced Pluripotent Stem Cells

The research team used stem cell technology to model Williams Syndrome in the lab. With proper permissions, they collected dental pulp from baby teeth of five children with WS and four typically developing children.

They reprogrammed dental pulp cells into induced pluripotent stem (iPS) cells. These stem cells can become nearly any cell type. The team then directed the iPS cells to form neural progenitor cells. NPCs resemble immature brain cells that have not yet matured into neurons.

A defect in WS cells

Initial observations showed a defect in WS neural progenitor cells. WS cells grew more slowly because more of them died.

These findings led the team to study the FZD9 gene. FZD9 is active in NPCs and regulates cell death and division. People with the main form of WS lack this gene. When researchers suppressed FZD9 in typical NPCs, cell death increased, matching WS cells. When they added FZD9 to WS cells, cell death dropped to normal levels.

As NPCs matured into neurons, more differences appeared. Neurons receive signals through dendrites, which branch out like fingers. Small spine structures grow on each dendrite to support signaling.

Compared to typical neurons, WS neurons had more dendrites, more spines, and longer dendrites.

Making Connections Between Brain Cells and Behavior

Are these iPS cell-derived results carried out in a lab dish relevant? Yes. Brain imaging of living study participants with WS shows a reduced surface area in the cortical layer. That is the same area of the brain implicated in other social function disorders. As Muotri explains, increased cell death appears to cause the development of abnormally smaller structures in WS brains.

“We discovered that WS neural progenitor cells failed to proliferate due to high levels of cell death. As a consequence of the lower replication of progenitor cells, WS brains have reduced cortex surface area.”

And a study of brain samples showed increased dendrite length and dendritic spines in neurons, a result also predicted by the iPS experiments.

Putting it all together

Again, these differences were seen particularly in a layer of the brain cortex thought to be involved in other social function disorders like autism. Putting the results together, Muotri speculates that these structural changes may explain the out-going personalities in people with WS.

“At the functional level, they make more synapses or connections to other neurons,
said Murtori. “That might underlie the WS super-social aspect and their gregarious human brain, giving insights into autism and other disorders that affect the social brain.”

By drawing a direct line from genes to cells to brain structure to human behavior, these scientists are in a great position to chip away at a holistic understanding of how personality is generated and how it can go awry.

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