Scientists have obtained a powerful new tool for the first time, enabling them to decode the hidden genetic codes shaping human diseases with unprecedented precision. A team led by the European Molecular Biology Laboratory (EMBL) has developed SDR-seq, a next-generation sequencing technology that reveals how non-coding genomic regions influence health by simultaneously analyzing DNA and RNA in the same cell—an area long regarded as the "dark matter" of the genome.
The core breakthrough of SDR-seq lies in its ability to link genetic variations (DNA) to their functional outcomes (RNA) on a large scale. Researchers use tiny oil-water droplets to capture single cells, allowing them to analyze the genetic material of thousands of cells simultaneously.
"This has been a long-standing challenge because current single-cell methods for studying DNA and RNA in the same cell have limited throughput, lack sensitivity, and are highly complex," explained Dominik Lindenhofer, first author of the new paper published in Nature Methods and a postdoctoral fellow in EMBL's Steinmetz Group. "At the single-cell level, you can only read variations from expressed genes—that is, coding regions. Our tool, however, is not restricted by the location of variations and enables high-throughput analysis of complex samples."
Only a small fraction (less than 5%) of the human genome consists of "coding regions" that encode proteins. The remaining over 95% are "non-coding regions," which contain key instructions regulating when and how genes are turned on or off. The vast majority of disease-related genetic variations are located in these non-coding regions, but previous technologies have struggled to study them effectively.
"In this non-coding space, we know there are variations associated with diseases such as congenital heart disease, autism, and schizophrenia, but most of these areas remain unexplored," said Lindenhofer. "We needed a tool to investigate which variations are functional in their genomic context and understand how they contribute to disease progression."
To test the technology, the research team collaborated with partners at Heidelberg University Hospital to analyze samples from patients with B-cell lymphoma, a type of blood cancer. Using SDR-seq, they were able to directly demonstrate how DNA variations accumulated in cancer cells affect gene activity and drive tumors toward a more aggressive state.
"We use these tiny reaction chambers to read both DNA and RNA in the same single cell," Lindenhofer said. "This allows us to accurately determine whether a variation is located on one or both copies of a gene and measure its impact on gene expression within the same cell. In B-cell lymphoma, we found that cells with more variations tend to exhibit a more malignant phenotype."
This tool provides scale, precision, and speed to genomic biology, opening new avenues for understanding a wide range of complex diseases, from cancer to neurodevelopmental disorders. While it may ultimately aid in treatment, its initial impact is likely to be seen in the development of better diagnostic and screening tools.
"We now have an instrument that can link variations to diseases," said Lars Steinmetz, senior author of the paper, EMBL Group Leader, and Professor of Genetics at Stanford University. "This capability opens up a vast, unexplored new world of biology. If we can decipher how variations regulate diseases and better understand this process, it means we have a better chance to intervene and treat them."
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