Recent studies show why brain is genetically diverse, and neurons in the same brain can carry slightly different DNA blueprints. These differences may give neurons distinct functions.

We can see this in genetically identical twins who sometimes grow less identical over time. Some develop different appearances. Others diverge in health, with one twin developing a serious disease while the other stays healthy. Environment explains part of this, but genetics within the brain may also play a role.

The brain contains about 100 billion neurons, each carrying DNA that guides its function. Scientists once believed all cells, including neurons, shared identical DNA.

Jumping genes and genetic diversity

Why and how neurons have differences in their DNA are questions that Salk Institute professor Fred Gage has pursued for more than a decade. In 2005, his lab discovered a mechanism during neural development that causes differences in the DNA of neurons. As a brain stem cell develops into a neuron, long interspersed nuclear elements (L1s), which are small pieces of DNA, copy and paste themselves, seemingly at random, throughout a neuron’s genome.

These elements were originally dubbed “jumping genes” because of their ability to hop around and insert themselves into DNA. It turns out that L1s do more than copy and paste themselves to create changes in DNA, they also can delete chunks of DNA. In a CIRM-funded study published this week in the journal Nature Neuroscience, Gage and colleagues at the Salk Institute reported new insights into L1 activity and how it creates genetic diversity in the brain.

Copy, paste, delete

Gage and his team first saw clues in 2013 that L1s could delete DNA in neurons. Using single‑cell sequencing, they examined individual neuronal genomes and saw large sections of DNA added or missing.

They suspected L1s caused these insertions and deletions but lacked proof. Their new study used an improved method to identify genome regions modified by L1s. Combined with a computer algorithm that distinguished different L1 changes, the method showed that L1‑rich regions were prone to DNA cutting by enzymes that target L1 sequences. These breaks produced the observed deletions.

Gage explained the findings:

“In 2013, we discovered that different neurons within the same brain have various complements of DNA, suggesting that they function slightly differently from each other even within the same person. This recent study reveals a new and surprising form of variation that will help us understand the role of L1s, not only in healthy brains but in those affected by schizophrenia and autism.”

Jennifer Erwin, the study’s first author, added:

“The surprising part was that we thought all L1s could do was insert into new places. But the fact that they’re causing deletions means that they’re affecting the genome in a more significant way.”

Insights into brain disorders

Scientists now know that L1s help create genetic diversity in the brain. Gage also believes L1s may drive disorders like schizophrenia and autism, which show higher L1 activity in patient neurons. His team will next study how L1‑driven changes affect genes linked to these disorders, and how those changes alter brain function and lead to disease.