10.6084/m9.figshare.7610918.v2 Emanuel Goncalves Emanuel Goncalves Fiona M Behan Fiona M Behan Sandra Louzada Sandra Louzada Damien Arnol Damien Arnol Euan Stronach Euan Stronach Fengtang Yang Fengtang Yang Kosuke Yusa Kosuke Yusa Oliver Stegle Oliver Stegle Francesco Iorio Francesco Iorio Mathew J Garnett Mathew J Garnett Structural rearrangements generate cell-specific, gene-independent CRISPR-Cas9 loss of fitness effects figshare 2019 Crispy CRISPR Ploidy Copy-number Structural rearrangements Computational Biology 2019-01-21 11:34:31 Dataset https://figshare.com/articles/dataset/Structural_rearrangements_generate_cell-specific_gene-independent_CRISPR-Cas9_loss_of_fitness_effects/7610918 <p><i>CRISPR-Cas9 genome editing is widely used to study gene function, from basic biology to biomedical research. Structural rearrangements are a ubiquitous feature of cancer cells and their impact on the functional consequences of CRISPR-Cas9 gene-editing has not yet been assessed. Utilizing CRISPR-Cas9 knockout screens for 250 cancer cell lines, we demonstrate that targeting structurally rearranged regions, in particular tandem or interspersed amplifications, is highly detrimental to cellular fitness in a gene-independent manner. In contrast, amplifications caused by whole chromosomal duplication have little to no impact on fitness. This effect is cell line specific and dependent on the ploidy status. We devise a copy-number ratio metric that substantially improves the detection of gene-independent cell fitness effects in CRISPR-Cas9 screens. Furthermore, we develop a computational tool, called Crispy, to account for these effects on a single sample basis and provide corrected gene fitness effects. Our analysis demonstrates the importance of structural rearrangements in mediating the effect of CRISPR-Cas9-induced DNA damage, with implications for the use of CRISPR-Cas9 gene-editing in cancer cells.</i><br></p>