The clustered regularly interspaced short palindromic repeats (CRISPR) nuclease system offers the ability for unprecedented functional genetic experiments and the promise for therapy of a variety of genetic disorders. The understanding of factors contributing to CRISPR targeting efficacy and specificity continue to evolve. As CRISPR systems rely on Watson-Crick base pairing to ultimately mediate genomic cleavage, it logically follows that genetic variation would affect CRISPR targeting by increasing or decreasing sequence homology at on- and off-target sites or by altering protospacer adjacent motifs (PAMs). Numerous efforts have been made to document the extent of human genetic variation, which serve as resources to understand and mitigate the effect of genetic variation on CRISPR targeting. Here, we examine the effect of human genetic variation on CRISPR targeting at on-target and off-target sites with consideration for clinical translation of CRISPR-based therapies
