Scientists at the European Molecular Biology Laboratory (EMBL) have developed SDR-seq, a new tool that simultaneously analyzes DNA and RNA in single cells. This innovation targets non-coding DNA regions, where over 95% of disease-associated genetic variants are located. The method promises to enhance understanding of complex diseases like heart disease, autism, and lymphoma.
For centuries, observers like Hippocrates noted diseases running in families, hinting at genetic roots. Now, EMBL researchers have advanced single-cell analysis with SDR-seq, published in Nature Methods on October 16, 2025. This tool captures genomic variations and RNA from the same cell, offering greater accuracy and scalability than prior technologies.
Coding regions of DNA act like instruction manuals, expressing genes into RNA for protein production. Non-coding regions, however, regulate cell growth and function, harboring over 95% of disease-linked variants. Existing methods lacked the sensitivity to study these areas effectively at scale. "This has been a long-standing problem, as current single-cell methods to study DNA and RNA in the same cell have had limited throughput, lacked sensitivity, and are complicated," said lead author Dominik Lindenhofer, a postdoctoral fellow in EMBL's Steinmetz Group.
SDR-seq uses tiny oil-water droplets to isolate single cells, enabling analysis of thousands in one experiment. It links genetic changes directly to gene activity patterns, regardless of variant location. Development involved EMBL's Genome Biology and Structural and Computational Biology units, Stanford University School of Medicine, and Heidelberg University Hospital. Teams preserved RNA through cell fixation and created specialized decoding software for DNA barcoding.
The tool was tested on B-cell lymphoma patient samples, revealing how DNA variants influence tumor growth. Cells with more variants showed stronger activation signals and a more malignant state. "We are using these small reaction chambers to read out DNA and RNA in the same single cell," Lindenhofer explained. "With the B-cell lymphoma cells, we were able to show that depending on the variant makeup of cells, they had different propensities to belong to distinct cellular states."
Senior author Lars Steinmetz, an EMBL group leader and Stanford genetics professor, highlighted its potential: "We have a tool that can link variants to disease. This capability opens up a wide range of biology that we can now discover. If we can discern how variants actually regulate disease and understand that disease process better, it means we have a better opportunity to intervene and treat it."
SDR-seq could improve diagnostics for diseases like congenital heart disease, autism, and schizophrenia, paving the way for personalized medicine.