Quantum biological insights into CRISPR-Cas9 sgRNA efficiency from explainable-AI driven feature engineering

Abstract

AbstractCRISPR-Cas9 tools have transformed genetic manipulation capabilities in the laboratory. Empirical rules-of-thumb have been established for only a narrow range of model organisms, and mechanistic underpinnings for sgRNA efficiency remain poorly understood. This work establishes a novel feature set and new public resource, produced with quantum chemical tensors, for interpreting and predicting sgRNA efficiency. Feature engineering for sgRNA efficiency is performed using an explainable-artificial intelligence model; iterative Random Forest (iRF). By encoding quantitative attributes of position-specific sequences for E. coli sgRNAs, we identify important traits for sgRNA design in bacterial species. Additionally, we show that expanding positional encoding to quantum descriptors of base-pair, dimer, trimer and tetramer sequences captures intricate interactions in local and neighboring nucleotides of the target DNA. These features highlight variation in CRISPR-Cas9 sgRNA dynamics between E. coli and H. sapien genomes. These novel encodings of sgRNAs greatly enhance our understanding of the elaborate quantum biological processes involved in CRISPR-Cas9 machinery.