High-resolution genome-wide mapping of chromosome-arm-scale truncations induced by CRISPR-Cas9 editing
Lazar, N. H.; Celik, S.; Chen, L.; Fay, M.; Irish, J. C.; Jensen, J.; Tillinghast, C. A.; Urbanik, J.; Bone, W. P.; Roberts, G. H. L.; Gibson, C. C.; Haque, I. S.
Show abstract
CRISPR-Cas9 editing is a scalable technology for mapping of biological pathways, but it has been reported to cause a variety of undesired large-scale structural changes to the genome. We performed an arrayed CRISPR-Cas9 scan of the genome in primary human cells, targeting 17,065 genes for knockout with 101,029 guides. High-dimensional phenomics reveals a "proximity bias" in which CRISPR knockouts bear unexpected phenotypic similarity to knockouts of biologically-unrelated genes on the same chromosome arm, recapitulating both canonical genome structure and structural variants. Transcriptomics connects proximity bias to chromosome-arm truncations. Analysis of published large-scale knockout and knockdown experiments confirms that this effect is general across cell types, labs, Cas9 delivery mechanisms, and assay modalities, and suggests proximity bias is caused by DNA double-strand-breaks with cell cycle control in a mediating role. Finally, we demonstrate a simple correction for large-scale CRISPR screens to mitigate this pervasive bias while preserving biological relationships.
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