Hidden within our DNA are repetitive sequences known as transposable elements. These elements are suspected to have played a key role in shaping the development of the human brain. Transposable elements have the unique ability to move within our DNA, causing or reversing mutations, altering genes, and even affecting the size of our genome. These elements, once considered "Junk DNA", are now providing important clues as to how our brain has evolved to differ from that of our closest living relative, the chimpanzee.
In Lund, researchers are investigating these repetitive regions of our DNA to understand the role transposable elements play in human brain development and evolution.
Their latest investigations have led them to a specific family of transposable elements known as LINE-1 retrotransposons, which currently make up roughly 17% of our DNA. The challenge has been to determine what these elements do and how they affect human tissues, given their abundant and repetitive presence in the human genome.
Johan Jakobsson, a professor at Lund University and research group leader at Lund Stem Cell Center, explains, “LINE-1 retrotransposons are a rich source of genetic sequences that we suspect have shaped the evolution of the human brain, and we now have the tools to explore their role in brain development.”
Using advanced sequencing technologies and a set of specialized bioinformatics tools, created by PhD student Raquel Garza, the researchers successfully detected the activity of LINE-1 elements and were able to dig into their functions and epigenetic profiles.
“This approach helped us to address these highly repetitive sequences, usually masked in standard bioinformatics pipelines, allowing us to accurately measure LINE-1 expression in each cell type found in our samples,” explains Raquel Garza, co-first author of the study.
The Influence of LINE-1 Elements on Brain Development
To better understand how these repetitive genetic sequences influence brain development, researchers analyzed both fetal and adult brain tissue samples. “Our goal was to identify any distinct characteristics that could help to explain unique traits specific to humans,” says Johan Jakobsson.
They discovered that LINE-1 elements play an important role in shaping the structural and functional complexity of our brains as we age. “We observed that LINE-1s are highly expressed in the developing human brain and particularly in neurons in the adult human brain. These elements appear to influence the expression of both protein-coding genes and non-coding transcripts in the human brain through various mechanisms,” says Raquel Garza.
Unique LINE-1 derived Long Non-Coding RNA Found in Human Neural Cells
Comparing human brain cells with those of primates, the researchers also identified a distinct long non-coding RNA that comes from a LINE-1 element. They found that the expression of this LINE-1 long non-coding RNA is unique to humans and only present as the human brain develops.
To determine its impact on the developing brain, the researchers silenced this RNA in cerebral organoids, or mini-brain models, grown from stem cells in the laboratory. "As a result, our organoids were smaller in size and cells in the model seemed to differentiate earlier, suggesting that LINE-1s play a role in developmental processes specific to humans,” describes Raquel Garza.
The Next Stage: Investigating LINE-1 Elements and Their Connection to Human Diseases
The lab's next step is to explore the impact of LINE-1 elements on the development of brain conditions and diseases. To achieve this, they will once again utilize their tailored bioinformatics pipeline, while also refining it for future applications. "We have already started to identify potential candidates that could lead to better understanding the role of LINE-1 elements in cancers and neurodegenerative diseases," concludes Johan Jakobsson.
