Sommaire:

Cas nucleases are enzymes that can be programmed with guide RNA to cut DNA with a complementary sequence. This programmability has made Cas nucleases popular genome editing tools, as they can be directed towards any desired genomic sequence by synthetically produced guide RNA. Due to the large number of competing off-targets in a genome, DNA is also cleaved at sequences with only a partial match to the guide. Such off-targeting poses a significant problem for any therapeutic application, and a large number of experiments have been performed to establish a rather peculiar set of empirical targeting rules. These empirical rules are as of yet unexplained, and detail the effect of mismatches at various positions and at various relative distances. We construct a kinetic model that explains the empirical targeting rules, and argue that it can be used to improve on current bioinformatic approaches used to predict off-target locations for genome editing applications.

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