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Updated: Jan 12, 2026
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Substrate Generation for Endonucleases of CRISPR/Cas Systems
Published on: September 8, 2012
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An updated evolutionary classification of CRISPR-Cas systems including rare variants
Kira S Makarova1, Sergey A Shmakov1,2, Yuri I Wolf1
1Division of Intramural Research, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA.
Nature Microbiology
|November 6, 2025
Summary
The CRISPR-Cas system diversity is expanding, with an updated classification now including 2 classes, 7 types, and 46 subtypes. New variants show rare functionalities, highlighting the need for further experimental characterization.
Area of Science:
- Microbiology
- Molecular Biology
- Bioinformatics
Background:
- CRISPR-Cas systems are crucial adaptive immune mechanisms in prokaryotes.
- The known diversity and complexity of CRISPR-Cas systems are continuously increasing.
- Previous classifications require updates to incorporate novel discoveries.
Purpose of the Study:
- To present an updated evolutionary classification of CRISPR-Cas systems.
- To classify the cyclic oligoadenylate-dependent signaling pathway in type III systems.
- To discuss novel CRISPR-Cas functionalities and their abundance.
Main Methods:
- Comparative genomic and metagenomic analysis.
- Phylogenetic analysis of CRISPR-Cas loci.
- Bioinformatic identification and classification of system variants.
Main Results:
- An updated classification with 2 classes, 7 types, and 46 subtypes.
- A classification of the cyclic oligoadenylate-dependent signaling pathway in type III systems.
- Identification of rare type IV (DNA cleavage) and type V (replication inhibition) variants.
Conclusions:
- The CRISPR-Cas landscape is more diverse than previously recognized.
- Newly identified variants are rare but possess distinct functionalities.
- Further experimental characterization of low-abundance variants is essential.
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