Discovering CRISPR-Cas system with self-processing pre-crRNA capability by foundation models

Nature Communications, 2024 · DOI: 10.1038/s41467-024-54365-0 · Published: November 7, 2024

Simple Explanation

The study introduces CHOOSER, an AI framework that uses protein foundation models to discover CRISPR-Cas systems capable of self-processing pre-crRNA. CHOOSER identified 11 Casλ homologs, almost doubling the known catalog, and one homolog, EphcCasλ, was experimentally validated for its functions. This research offers an innovative method for discovering CRISPR-Cas systems with specific functions, highlighting their potential in gene editing.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Not specified

Key Findings

1
CHOOSER identifies 3477 potential CRISPR-Cas systems, enhancing the number of known type II, type V, and type VI systems.
2
CHOOSER detects 39 Cas12 candidates that have previously been overlooked by existing alignment-based CRISPR-Cas mining tools, such as CRISPR-CasTyper.
3
One homolog, EphcCasλ, is experimentally validated for self-processing pre-crRNA, DNA cleavage, and trans-cleavage, showing promise for CRISPR-based pathogen detection.

Research Summary

This study introduces CHOOSER, an AI framework for alignment-free discovery of CRISPR-Cas systems with self-processing pre-crRNA capability using protein foundation models. By using CHOOSER, the study identifies 11 Casλ homologs and experimentally validates one homolog, EphcCasλ, for self-processing pre-crRNA, DNA cleavage, and trans-cleavage. The study emphasizes an innovative approach for discovering CRISPR-Cas systems with specific functions, highlighting their potential in gene editing and CRISPR-based pathogen detection.

Practical Implications

Enhanced CRISPR-Cas Discovery

CHOOSER provides a new AI-driven method to identify novel CRISPR-Cas systems and homologs that traditional methods may miss.

Improved Gene Editing Tools

The discovery and functional validation of new Cas homologs, like EphcCasλ, can lead to the development of more efficient and versatile gene editing tools.

CRISPR-based Pathogen Detection

The temperature-dependent trans-cleavage activity of EphcCasλ makes it a promising candidate for developing CRISPR-based pathogen detection systems.

Study Limitations

1
The CHOOSER framework is specific for identifying Cas single effectors, such as Cas9, Cas12, and Cas13.
2
The study only experimentally validated a single clade of the discovered Cas12 candidates.
3
The underlying biological mechanisms involved in the self-processing pre-crRNA trait of Cas12 enzymes have not been fully elucidated.

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