Scientists find DNA in human blood can fold into strange four-stranded shapes — a hidden layer of genetic information that ordinary sequencing may miss

Scientists have detected unusual four-stranded genetic structures in human blood plasma, suggesting that DNA fragments circulating through the body may contain information that standard sequencing cannot reveal.

The structures are known as G-quadruplexes, or G4s. Unlike the familiar DNA double helix, they form when the genetic letter guanine bonds with other guanine molecules, creating compact, four-stranded shapes.

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G4s have previously been observed inside cells. The new research provides evidence that similar structures can also exist in genetic material collected directly from human blood plasma. The study is currently available as a preprint and has not yet undergone peer review.

DNA in blood may carry hidden information

Blood plasma contains fragments of DNA and RNA released when cells die or shed genetic material. Scientists already study these fragments to investigate conditions such as cancer, pregnancy-related changes and organ damage.

Most research focuses on the genetic sequence, including the order of letters, fragment length and the region of the genome involved.

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The new study examines whether the shape of genetic material may also provide useful information.

Robert Hänsel-Hertsch, a molecular biologist at the University of Cologne, said the research provides, to the team’s knowledge, the first direct biochemical evidence of folded G-quadruplex structures in nucleic acids captured from human plasma.

How four-stranded DNA structures form

A G-quadruplex develops when four guanine bases come together to form a square-shaped unit called a G-quartet. Several of these units can stack together, creating a structure unlike the traditional DNA helix.

Scientists became interested in blood-based G4s after examining extremely short fragments of cell-free DNA. Some are only about 50 genetic letters long. Certain fragments contain enough guanine to potentially form G-quadruplexes.

However, a sequence that can fold into a G4 does not prove that it was folded inside the body. The researchers needed to detect the structures before laboratory processing could change their shape.

Two tests detected the unusual structures

The team used gentle methods to capture genetic material directly from plasma. They avoided heating and extraction steps that could break apart folded structures or cause them to refold later.

Researchers then used two independent detection methods. One involved an antibody designed to recognize G4s. The other used a small molecule that produces a signal when it binds to the structures.

Both methods produced signals.

A control sequence that could not fold into a G-quadruplex did not produce the same response. Further competition tests also suggested that the detection tools were identifying folded G4 structures rather than attaching randomly to the captured material.

Could G4s help explain disease?

The discovery may eventually support blood-based medical research, but it is not a new cancer test.

G-quadruplexes often appear in parts of the genome involved in gene regulation. Changes in G4 activity have also been reported in several cancer types, raising the possibility that folded genetic structures could provide information missed by sequence analysis alone.

Several questions remain unanswered. The study could not establish whether the detected structures were made from DNA or RNA, since both can form G4s. Scientists also do not know which tissues released them or whether they folded inside cells or after entering the bloodstream.

Future studies may use enzymes that selectively destroy DNA or RNA, followed by sequencing to identify the molecules and their genomic origins.

For now, the findings suggest that genetic information may exist not only in the order of DNA letters but also in the way those letters fold.

Frequently asked questions

1. What are G-quadruplexes?

They are four-stranded structures formed when guanine bases join and stack together.

2. Where were they found?

In genetic material collected directly from human blood plasma.

3. Can they diagnose cancer?

Not yet. More research is needed to establish any medical application.

4. What happens next?

Scientists must identify the molecules, trace their tissue origins and study whether the structures change during disease.