Repetitive DNA's Role in Brain Evolution, Disease

DNA carries the complete set of instructions an organism needs to develop and survive, but only about 1.5% of it consists of protein-coding genes that determine traits such as eye colour, height and hair type. The other 98.5%, once written off as 'junk DNA', is now increasingly recognised as an important part of our genome that controls when and where genes are switched on, influencing development, cellular processes and even human evolution.

At Lund University, researchers have been exploring this overlooked portion of the genome. Their latest study published in Cell Genomics shows how specific sequences within the non-coding genome help shape the developing human brain.

"An underlying question in my lab is: how did the human brain become human?" says Johan Jakobsson, professor at the Department of Experimental Medical Science and head of the Laboratory of Molecular Neurogenetics. "We want to know which parts of the genome contribute to uniquely human functions, and how this connects to brain disorders."

Repetitive DNA has an active role in the human brain

In the new study, Johan Jakobsson and his team, together with collaborators at the University of Copenhagen, the University of Cambridge and New York University, investigated segments of repetitive DNA sequences called transposable elements. Sometimes described as "jumping genes", these sequences can move around within the genome, making them challenging to study.

Using induced pluripotent stem cells and brain organoids - miniature, simplified versions of the human brain grown in the lab - the researchers studied one particular family of transposable elements, known as LINE-1 (L1) transposons. By combining CRISPR gene-editing technology with advanced sequencing methods, they were able to switch these sequences off and observe the effects.

"Previously we assumed this part of the genome was switched off and just sitting quietly in the background," Johan Jakobsson says. "It turns out that's a misconception. These elements are not silent; they are active in human stem cells and seem to play an important role in early brain development. And we found that when you block them, there are real consequences."

Jumping genes affect brain development

When the L1 transposons were silenced, the team observed disruptions in gene activity and abnormal brain organoid growth.

"From an evolutionary perspective, this could help explain how the human brain developed differently from that of other primates," Johan Jakobsson notes. "But from a disease perspective, it also tells us that these elements are part of the cell's machinery and probably linked to disorders. If we want to fully understand neurodevelopmental disorders or neuropsychiatric conditions, we have to study this part of the genome."

As many of the genes affected by L1 transposons are linked to brain disorders, the team's work opens up new avenues for future research.

How does the non-coding genome contribute to brain disease?

The Lund team is continuing this work through the ASAP (Aligning Science Across Parkinson's) Collaborative Research Network, working with international partners to investigate how transposable elements contribute to brain diseases using both patient-derived cells and donated brain tissue samples.

"This study points to the fact that these elements are not just evolutionary leftovers, they are important for regulating genes that are active in the brain," Johan Jakobsson concludes. "Our next step is to investigate patient samples, from children with neurodevelopmental disorders and adults with age-related conditions such as Parkinson's disease. The goal is to understand how these hidden parts of our genome contribute to disease and, eventually, how we might use that knowledge to improve treatments."