Evolutionary classification of CRISPR–Cas systems: a burst of class 2 and derived variants

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. 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.