Role of Transposable Elements in Brain Development Uncovered

For much of modern genetics, nearly all of the human genome not coding for proteins was dismissed as useless “junk.” Yet new research shows that repetitive DNA sequences, once overlooked, are active during early brain formation and may hold importance for understanding brain-related disorders. These findings, published in Cell Genomics, indicate that sections of the genome long thought to be silent actually influence development and disease.

Only about 1.5% of human DNA provides the code for making proteins, such as those determining physical traits. The remaining 98.5% was traditionally disregarded as having little function. Growing evidence suggests, however, that these non-coding regions control when and where genes are turned on, impacting cellular regulation and development. At Lund University, Professor Johan Jakobsson and his team are working to better define how this hidden fraction of the genome shapes the human brain. “An underlying question in my lab is: how did the human brain become human?” Jakobsson explains. “We want to know which parts of the genome contribute to uniquely human functions, and how this connects to brain disorders.”

The researchers focused on transposable elements, or “jumping genes,” repetitive DNA sequences that can move within the genome. In collaboration with teams from the University of Copenhagen, the University of Cambridge, and New York University, they studied one prominent family of these sequences, LINE-1 (L1) transposons. By employing induced pluripotent stem cells and brain organoids alongside CRISPR gene-editing and advanced sequencing, the researchers were able to switch off the L1 elements and observe changes.

The silencing experiments showed that L1 transposons are not passive. Instead, they were active in stem cells and essential during early neural development. When blocked, gene activity was disrupted and brain organoids grew abnormally. “Previously we assumed this part of the genome was switched off and just sitting quietly in the background,” says Jakobsson. “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.”

The team notes that many of the genes impacted by L1 elements are associated with brain disorders, suggesting relevance not only to evolution but also to conditions such as neurodevelopmental and neuropsychiatric diseases. As Jakobsson concludes, “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. 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.”