Improving CRISPR guide design with consensus approaches

Background: CRISPR-based systems are playing an important role in modern genome engineering. A large number of computational methods have been developed to assist in the identification of suitable guides. However, there is only limited overlap between the guides that each tool identifies. This can motivate further development, but also raises the question of whether it is possible to combine existing tools to improve guide design. Results: We considered nine leading guide design tools, and their output when tested using two sets of guides for which experimental validation data is available. We found that consensus approaches were able to outperform individual tools. The best performance (with a precision of up to 0.912) was obtained when combining four of the tools and accepting all guides selected by at least three of them. Conclusions: These results can be used to improve CRISPR-based studies, but also to guide further tool development. However, they only provide a short-term solution as the time and computational resources required to run four tools may be impractical in certain applications.