SDR-seq: Unlocking the Hidden DNA Code That Shapes Disease
EMBL researchers have developed SDR-seq, a revolutionary single-cell DNA-RNA sequencing tool that simultaneously analyzes both DNA and RNA from the same cell. This breakthrough technology finally provides access to non-coding regions where over 95% of disease-associated genetic variants occur. By revealing how these variants affect gene activity, scientists can better understand complex diseases like congenital heart disease, autism, and schizophrenia, potentially leading to improved diagnostic tools and treatments.
For centuries, scientists have observed that certain illnesses pass from one generation to the next, a pattern first noted by Hippocrates who observed that some diseases "ran in families." Now, researchers from the European Molecular Biology Laboratory (EMBL) have developed a groundbreaking tool called SDR-seq that takes single-cell analysis to unprecedented levels, finally unlocking access to the non-coding regions of DNA where most disease-associated genetic variants reside.
The Challenge of Non-Coding DNA Regions
DNA contains both coding and non-coding regions that serve fundamentally different functions. The coding parts act as instruction manuals, with genes expressed into RNA that direct cells in building essential proteins. However, non-coding regions contain regulatory elements that guide how cells grow and function. Remarkably, over 95% of disease-linked DNA variants occur in these non-coding regions, yet existing single-cell methods lacked the sensitivity and scale to study them effectively.
According to Dominik Lindenhofer, lead author of the Nature Methods paper and postdoctoral fellow in EMBL's Steinmetz Group, "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. On a single-cell level, you could read out variants in thousands of cells, but only if they had been expressed—so only from coded regions."
How SDR-seq Works
The SDR-seq technology represents a significant advancement in genomic research methodology. Researchers use tiny oil-water droplets, each containing a single cell, allowing them to analyze DNA and RNA simultaneously. This innovative approach enables examination of thousands of cells in a single experiment and directly links genetic changes to patterns of gene activity.
Developing this technology required overcoming major challenges and brought together teams from EMBL's Genome Biology and Structural and Computational Biology units, the Stanford University School of Medicine, and Heidelberg University Hospital. Computational biologists in Oliver Stegle's group designed specialized software to decode the complex DNA barcoding system needed for data analysis, while collaborators from EMBL's Judith Zaugg and Kyung-Min Noh groups developed methods to preserve delicate RNA by "fixing" the cells.
Practical Applications and Future Implications
The SDR-seq tool offers genomic biologists unprecedented scale, precision, and speed to better understand genetic variants. While it could eventually play a role in treating a broad range of complex diseases, it may first help in developing better screening tools for diagnosis. The technology has already shown promise in B-cell lymphoma research, where researchers observed how variations in DNA were linked to disease processes.
Lars Steinmetz, senior author on the paper and EMBL group leader, emphasizes that "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."
This breakthrough represents a significant step forward in our ability to understand the complex relationship between genetic variations and disease development, potentially transforming how we approach diagnosis and treatment of numerous conditions in the coming years.
