by A groundbreaking screening tool has been developed by scientists to delve into the mechanisms through which genetic alterations impact gene activity and give rise to conditions such as cancer, autoimmunity, neurodegeneration, and cardiovascular disease. This innovative tool, known as scSNV-seq, allows for the simultaneous exploration of numerous DNA mutations identified through genetic studies, facilitating the advancement of cutting-edge diagnostics and therapies.
The scSNV-seq technique empowers researchers to swiftly evaluate the effects of thousands of genetic changes in previously untested cells, establishing a direct link between these alterations and the cellular functions they govern. This framework offers a comprehensive perspective that aids researchers in identifying mutations that contribute to disease etiology, thereby providing invaluable insights for the development of targeted therapeutic interventions.
In a recent study published in Genome Biology, scientists from the Wellcome Sanger Institute, in collaboration with Open Targets and EMBL’s European Bioinformatics Institute (EMBL-EBI), applied scSNV-seq to investigate the blood cancer-associated gene JAK1.
By effectively assessing the impact of JAK1 mutations, the technique unveiled a novel finding: certain mutations induced an intermediate phenotype characterized by cyclical transitions between distinct cellular states—an observation previously unattainable via conventional methodologies.
Designed to exhibit versatility across various cell types, including challenging-to-culture primary cells like T cells and stem-cell-derived neurons, as well as diverse gene editing modalities such as base editing and prime editing, the utility of scSNV-seq on a broad scale has the potential to revolutionize our comprehension of the genetic alterations underlying cancer pathogenesis and shed light on the genetic predispositions for complex diseases like Alzheimer’s, arthritis, and diabetes.
Despite the rapid expansion in disease-associated genetic variants revealed by advancements in human genetics and the increasing accessibility of DNA sequencing technologies, the tools required for interpreting these variants have lagged behind, often relying on laborious manual processes.
To address this gap, researchers from the Wellcome Sanger Institute and their collaborators devised the scSNV-seq screening technique, which directly correlates the genetic information encoded in a cell’s genotype with its gene activity. Through experimental perturbations of specific DNA bases within the JAK1 gene, linked to inflammatory responses and oncogenesis, the team demonstrated the efficacy of scSNV-seq in elucidating the effects of genetic alterations on cellular behavior.
Dr. Sarah Cooper, the lead author of the study at the Wellcome Sanger Institute, emphasized the significance of scSNV-seq in bridging the gap between the rapid discovery of genetic variants and the understanding of their functional consequences, particularly in complex cell types like T cells and neurons. The technique is already being leveraged to elucidate the impact of genetic variants associated with Alzheimer’s and Parkinson’s on neuronal cells.
Dr. Andrew Bassett, the senior author of the study at the Wellcome Sanger Institute, highlighted how scSNV-seq enables the direct correlation of mutation effects with cellular behaviors, unveiling downstream consequences that elude traditional technologies. This innovative tool expedites the identification of causal genetic mutations, thereby enhancing diagnostic capabilities and deepening our molecular insights into diseases, ultimately paving the way for more precise and efficacious therapeutic strategies.
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1. Source: Coherent Market Insights, Public sources, Desk research
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