Pooled prime editing enhances genetic variant screening efficiency

Scientists at the Francis Crick Institute have developed a new method called "pooled prime editing." This technique can screen many genetic variants in one go and find out how they affect gene function. This method could change genomic research by making it easier to understand the risks of different genetic variants related to diseases like cancer. Genetic variation occurs when parts of DNA are changed, added, or removed. Many of these changes are still not understood, leaving a gap in knowledge about how they impact disease risk. The research team improved on an earlier technique that mapped variants in a cancer risk gene. They've now used pooled prime editing to test large numbers of genetic variants in human cells. They focused on two important tumor suppressor genes, SMARCB1 and MLH1. Mutations in these genes can lead to cancer. When testing SMARCB1, the team discovered specific mutations that led to loss of gene function and cell death. They also looked at MLH1, which has over 2,000 recorded variants of unknown significance. They successfully categorized more than 700 variants, including some linked to loss of function. Overall, the results show that pooled prime editing can effectively screen thousands of variants at once. This could be beneficial for both basic research and future clinical applications. Researchers believe it will help them better understand the impact of genetic changes. One of the researchers, Michael Herger, highlighted the importance of understanding rare variants for assessing disease risk. Another researcher, Christina Kajba, noted that they aim to further scale the method to evaluate even more variants efficiently. Senior author Greg Findlay emphasized that prime editing allows for precise genetic editing. By scaling it up, their team combines accuracy with the ability to test a large number of variants. Understanding these variants will provide clarity for many individuals who have them but do not know their associated risks.