The team has pioneered an innovative screening tool, scSNV-seq, that delves into the intricate relationship between genetic alterations and gene activity, potentially shedding light on the origins of various diseases, from cancer to cardiovascular conditions. This state-of-the-art tool revolutionises the field by enabling the simultaneous investigation of numerous DNA mutations previously identified in genetic studies within a single experiment. Its versatility and effectiveness pave the way for developing sophisticated diagnostic methods and treatments.
The scSNV-seq method is not just a theoretical concept but a practical tool that empowers scientists to quickly evaluate the effects of numerous genetic alterations in cells that have not been previously screened. This approach provides a holistic perspective by linking these changes directly to cellular functions, enabling researchers to identify specific mutations that contribute to diseases. This practical application is crucial for developing targeted therapies.
A recent study published in Genome Biology highlights the application of scSNV-seq by researchers at the Wellcome Sanger Institute and their collaborators at Open Targets and EMBL’s European Bioinformatics Institute (EMBL-EBI). In this study, scSNV-seq was applied to the blood cancer gene JAK1, where it precisely determined the impacts of mutations, unveiling a previously unknown “halfway house” phenotype that fluctuates between different states, a discovery not achievable with earlier methodologies.
scSNV-seq is designed for versatility across various cell types, including challenging primary cells like T cells and stem-cell-derived neurons. It accommodates different editing techniques, such as base and prime editing. When applied on a large scale, this technique has the potential to revolutionise our understanding of the genetic alterations that drive cancer and aid in decoding genetic risks for complex diseases like Alzheimer’s, arthritis, and diabetes.
Despite the exponential growth in the identification of genetic variants linked to diseases, thanks to advancements in human genetics and the increased affordability of DNA sequencing technologies, the tools available for interpreting these variants often need to be improved, sometimes relying on laborious manual processes. Additionally, when introducing specific mutations using advanced gene-editing tools, current screening methods struggle to differentiate between cells where the editing was unsuccessful and those where it introduced benign changes without affecting cellular behaviour.
To tackle these challenges, researchers developed scSNV-seq, a technique that directly correlates the genetic makeup of a cell with its gene activity. The effectiveness of scSNV-seq was demonstrated through experiments on the JAK1 gene, associated with inflammation and cancer, to observe the effects of specific DNA modifications on cell behaviour. This technique categorised genetic alterations into three groups: benign, loss of function, and altered function, and revealed mutations that resulted in an intermediate phenotype cycling between states—insights unattainable with previous methods.
Dr Sarah Cooper, the first author of the study from the Wellcome Sanger Institute, emphasised the significance of scSNV-seq in the current genetic landscape, where the rate of variant discovery surpasses our capacity to interpret their impacts. She noted that scSNV-seq is already being used to explore how genetic variants associated with Alzheimer’s and Parkinson’s diseases affect brain cells.
Dr Andrew Bassett, the senior author of the study, also from the Wellcome Sanger Institute, highlighted that their technique uniquely connects mutation effects to cellular behaviours, uncovering downstream impacts previously invisible with older technologies. He remarked that this method accelerates the identification of causal genetic mutations, enhancing diagnostics and deepening our understanding of molecular disease mechanisms, ultimately paving the way for more targeted and effective treatments.
More information: Sarah E. Cooper et al, scSNV-seq: high-throughput phenotyping of single nucleotide variants by coupled single-cell genotyping and transcriptomics, Genome Biology. DOI: 10.1186/s13059-024-03169-y
Journal information: Genome Biology Provided by Wellcome Sanger Institute
