The number and diversity of known CRISPR–Cas systems have substantially increased in recent years. Here, we provide an updated evolutionary classification of CRISPR–Cas systems and cas genes, with an emphasis on the major developments that have occurred since the publication of the latest classification, in 2015. The new classification includes 2 classes, 6 types and 33 subtypes, compared with 5 types and 16 subtypes in 2015. A key development is the ongoing discovery of multiple, novel class 2 CRISPR–Cas systems, which now include 3 types and 17 subtypes. A second major novelty is the discovery of numerous derived CRISPR–Cas variants, often associated with mobile genetic elements that lack the nucleases required for interference. Some of these variants are involved in RNA-guided transposition, whereas others are predicted to perform functions distinct from adaptive immunity that remain to be characterized experimentally. The third highlight is the discovery of numerous families of ancillary CRISPR-linked genes, often implicated in signal transduction. Together, these findings substantially clarify the functional diversity and evolutionary history of CRISPR–Cas.
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K.S.M., Y.I.W., J.I., S.A.S. and E.V.K. are supported through the Intramural Research Program of the US National Institutes of Health; F.J.M.M. was supported by grants BIO2014-53029-P (Ministerio de Ciencia, Innovación y Universidades, Spain), and 291815 Era-Net ANIHWA (7th Framework Programme, European Commission) and PROMETEO/2017/129 (Conselleria d'Educació, Investigació, Cultura i Esport, Generalitat Valenciana, Spain); S.A.S. was supported by RFBR (research project 18-34-00012) and a Systems Biology Fellowship from Philip Morris Sales and Marketing; S.M. was funded by funding from the Natural Sciences and Engineering Research Council of Canada (Discovery program) and holds a Tier 1 Canada Research Chair in Bacteriophages.
The authors declare no competing interests.
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Clustered regularly interspaced short palindromic repeats, present in most archaeal and many bacterial genomes.
First stage of the CRISPR–Cas response that involves spacer acquisition.
Final stage of the CRISPR–Cas response, which involves recognition and cleavage of the target DNA or RNA.
- Protospacer-adjacent motif
(PAM). A short nucleotide sequence next to the protospacer that is required for target recognition by the crRNA effector.
Segment of DNA (typically, from a virus or plasmid) that is acquired by CRISPR–Cas systems via the activity of the adaptation complex.
- CRISPR array
Genomic locus containing multiple, tandem CRISPR.
Unique segment of DNA inserted between CRISPR units.
Archaeal and bacterial system of adaptive immunity that consists of a CRISPR array and cas genes.
Long transcript of a CRISPR locus that is processed to yield the crRNA CRISPR–Cas system, where it is incorporated as a spacer.
Short RNA molecules containing the spacer sequence and parts of the CRISPR, used as the guide to target and cleave cognate foreign DNA or RNA.
A mobile genetic element, typically flanked by inverted terminal repeats, that changes its location in the host genome by inserting into new sites with the help of a transposon-encoded enzyme known as transposase, integrase or recombinase.
A member of a distinct class of transposons that employ a Cas1 homologue as the transposases and are thought to be the ancestors of CRISPR–Cas adaptation modules.
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Makarova, K.S., Wolf, Y.I., Iranzo, J. et al. Evolutionary classification of CRISPR–Cas systems: a burst of class 2 and derived variants. Nat Rev Microbiol 18, 67–83 (2020). https://doi.org/10.1038/s41579-019-0299-x