Researchers from the Wellcome Sanger Institute have developed a new screening tool to explore the mechanisms behind diseases such as cancer, autoimmunity and neurodegeneration.
Published in Genome Biology, scSNV-seq will allow researchers to rapidly assess the impact of thousands of genetic changes in cells that have never been screened before, directly linking them to how those same cells operate.
The current screening methods used can be challenging when distinguishing whether gene-edited cells did or did not work, successfully introducing a harmless change without affecting the cell’s behaviour.
In collaboration with researchers from Open Targets and EMBL’s European Bioinformatics Institute, the new screening technique directly couples the specific genetic information in the genotype of a cell to its gene activity.
The tool works across cell types, including hard-to-culture primary cells such as T cells and stem-cell-derived neurons, as well as various editing methods, including base editing and prime editing.
After applying scSNV-seq to JAK1 – the blood cancer gene – and altering specific DNA bases linked to inflammation and cancer, researchers found that the technique accurately assessed the impact of JAK1 mutations.
Additionally, the team discovered that scSNV-seq accurately categorised different types of genetic changes into three categories: benign, causing loss of function and altering function.
It revealed, for the first time, that certain JAK1 mutations caused an intermediate phenotype cycling between different states.
When applied on a larger scale, the technique could advance understandings of the genetic changes that drive cancer and decode the genetic risk for Alzheimer’s disease, arthritis, diabetes and other complex diseases.
In addition, the process could be used to determine the mutations that contribute to disease and offer crucial insights for developing targeted therapies.
“scSNV-seq fills a major gap for studying challenging cells like T cells and neurons,” said the first author of the study at the Wellcome Sanger Institute, Dr Sarah Cooper.
Dr Andrew Bassett, senior author of the study, Wellcome Sanger Institute, said: “The technique speeds up the identification of causal genetic mutations, which will allow better diagnosis and deepens our molecular understanding of diseases, paving the way for more targeted and effective treatments.”