Scientists Finally Read the Hidden DNA Code That Shapes Complex Diseases
HEIDELBERG – In a significant leap forward for genomics, researchers from the European Molecular Biology Laboratory (EMBL) have developed a powerful new tool that finally allows scientists to effectively read the hidden instructions within the human genome that shape complex diseases. The technology, called SDR-seq, promises to accelerate the discovery of how genetic variations lead to illness.
The study, published on October 18, 2025, in Nature Methods, addresses a long-standing problem in genetics. While scientists have known that over 95% of disease-linked DNA variants reside in non-coding regions—the parts of the genome that control gene activity rather than code for proteins—existing tools lacked the sensitivity and scale to study them in detail.
"This has been a long-standing problem," said Dr. Dominik Lindenhofer, the paper's lead author. "Our tool works, irrespective of where variants are located, yielding single-cell numbers that enable analysis of complex samples."
Unlocking the Genome's "Control Center"
SDR-seq (Single-cell DNA-RNA Sequencing) is a breakthrough because it can capture both the DNA sequence and the RNA output from the very same cell. This means researchers can now directly see how a specific genetic variation (the DNA change) affects how a gene is used (the RNA output), even if that variation is in a remote, non-coding "control switch."
The technology uses a sophisticated droplet-based system to isolate thousands of individual cells, creating miniature reaction chambers to analyze their genetic material simultaneously.
Proven in Cancer Research
The power of SDR-seq was demonstrated in collaboration with clinicians at Heidelberg University Hospital. Using samples from patients with B-cell lymphoma, the team found that cancer cells with a greater number of genetic variants were more likely to be in a aggressive, malignant state.
"We could see that increasing variants in a cell actually were associated with a more malignant B-cell lymphoma state," Lindenhofer noted, showcasing the tool's ability to connect genetic makeup with disease severity.
A Collaborative Effort for a Complex Challenge
Developing SDR-seq was a multidisciplinary effort. It involved experts in RNA biology, who developed methods to preserve delicate RNA, and computational biologists, who created new software to decode the complex data. This collaborative spirit was key to solving a problem that had hindered the field for years.
A Wide-Open Future for Discovery
The implications extend far beyond cancer. "In this non-coding space, we know there are variants related to things like congenital heart disease, autism, and schizophrenia that are vastly unexplored," Lindenhofer said.
Senior author Professor Lars Steinmetz emphasized the tool's potential: "This capability opens up a wide range of biology that we can now discover. If we can discern how variants actually regulate disease... it means we have a better opportunity to intervene and treat it."
With its unparalleled precision and scalability, SDR-seq marks the beginning of a new, more detailed chapter in our understanding of the genetic roots of disease.