The genetic material circulating in our blood can adopt a form quite different from the famous double helix.
When cells die, tiny fragments of their genetic material pass into the plasma, the liquid part of blood. These circulating fragments are already being studied to look for signs of cancer or other diseases. This time, a team focused not only on their sequence, but also on their shape.
Illustration of classic DNA in a double helix.
Nicola Narracci · Pexels
Some very short fragments, about 50 genetic letters long, easily evade classic methods designed for double-stranded DNA. Computer analyses had identified many sequences rich in guanine among them, one of the four letters of DNA. These sequences can fold in a particular way.
In this structure, four guanines associate to form a kind of small square. Several of these units can then stack on top of one another. This organization is known as a G-quadruplex, or G4. It is already known to exist inside cells, but its direct presence in plasma had remained difficult to establish.
The main problem involved sample preparation. Heating, extracting or heavily manipulating the molecules can disrupt their original shape, or conversely allow them to fold after collection. The researchers therefore captured nucleic acids directly from the plasma without heating or refolding them.
Two different methods then searched for G4s. The first used an antibody that recognizes this shape. The second relied on a small molecule that becomes fluorescent when it binds to it. Both approaches produced a signal, and competition experiments strengthened the idea that they were indeed detecting structures that had already folded.
Their exact nature should nevertheless be treated with caution. The work, released as a preprint, establishes the presence of G4s in nucleic acids captured from plasma. But the detectors used recognize the shape, not the molecule carrying it. The experiment therefore cannot yet determine what proportion corresponds to DNA and what proportion might be RNA.
The next step will be to distinguish between these possibilities. The researchers plan in particular to use enzymes capable of selectively destroying DNA or RNA before detection. They will then be able to sequence the molecules involved, determine their origin in the genome and check whether their shape provides information that could be used in future liquid biopsies.