A portion of our genome that was once dismissed as being “junk” may actually play an important role in regulating gene expression, new research suggests. According to the work of an international team of scientists, the “junk” has actually evolved to influence how genes are turned on and off, especially during early human development.
The story of how this DNA became relegated to being considered pointless occurred at the start of the century, but before we discuss that, we need to know what we’re dealing with. During the 1940s, the cytogeneticist Barbara McClintock identified what are called transposable elements (TEs), or “jumping genes”, in corn. Essentially, these are DNA sequences that can move to different locations within the genome. At first, scientists were skeptical about this discovery, but decades later, they agreed that these genes don’t just “jump”; they also appear in almost every organism.
Later, TEs were identified as making up around 45 percent of the human genome. It seemed they had managed to proliferate using a simple repetitive process over millions of years.
This repetitive process meant that the sequences appear to be nearly identical, and so, they were dismissed as a genetic leftover from ancient and now extinct viruses. Today, we know some TEs act like “genetic switches”, controlling the activity of nearby genes in certain cell types.
But the repetitive and near identical nature of these sequences has made them tricky to study, especially younger TE families, such as MER11. These TEs have been poorly categorized in current genomic databases, which has contributed to our not knowing what they do.
To address this, researchers developed a new way to classify TEs that does not rely on standard annotation tools, instead grouping MER11 sequences based on their evolutionary relationships and how well they’ve been conserved in primate genomes. With this, the scientists were able to divide MER11A/B/C into four distinct families – MER11_G1 through to MER11_G4. This categorization also ranged from oldest to youngest in terms of when they first popped up in the primate genome evolutionary history.
What did this categorization reveal? Previously unknown patterns of gene regulation potential that are hidden within the sequences. The researchers then compared the new MER11 subfamilies to various epigenetic markers – chemical tags on DNA and associated proteins that impact gene activity. This demonstrated that this new classification is more aligned with actual regulatory function than other methods have shown.
Next, the researchers tested the MER11 sequences with a technique known as lentiMPRA (lentiviral massively parallel reporter assay). This method can test thousands of DNA sequences at the same time to assess how much each one boosts gene activity. After analyzing nearly 7,000 MER11 sequences from primates, including humans, and measuring their effects in human stem cells and early-stage neural cells, the team found that MER11_G4 was particularly good at activating gene expression.
The team also found that this sequence had a distinct set of regulatory “motifs”, which are short stretches of DNA that act as docking ports for transcription factors – the proteins that control when genes are expressed or “turned on”. These motifs have a significant influence on how genes respond to developmental signals or environmental cues.
Interestingly, it seems the MER11_G4 sequences have accumulated slightly different changes across time in humans, chimpanzees, and macaques. In the former two, some sequences had mutations that could increase their regulatory potential in human stem cells. The research also found that MER11_G4 binds to a distinct set of transcription factors, suggesting that this group gained alternative regulatory functions through sequence changes and may contribute to speciation – the evolutionary process that leads to distinct species.
The study is published in Science Advances.
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