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Structural rearrangements generate cell-specific, gene-independent CRISPR-Cas9 loss of fitness effects.

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 duplications 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.

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Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.

Study ID Study Title Study Type
EGAS00001000166 Cancer Genomics

This table displays only public information pertaining to the files in the dataset. If you wish to access this dataset, please submit a request. If you already have access to these data files, please consult the download documentation.

ID File Type Size Located in
EGAF00000073089 bam 22.2 GB
EGAF00000073090 bam 40.6 GB
EGAF00000073093 bam 23.1 GB
EGAF00000073095 bam 24.6 GB
EGAF00000073096 bam 25.4 GB
EGAF00000073097 bam 24.3 GB
EGAF00000073099 bam 22.7 GB
EGAF00000073100 bam 23.4 GB
EGAF00000073101 bam 25.6 GB
EGAF00000073103 bam 32.6 GB
EGAF00000092596 bam 32.6 GB
EGAF00000096358 bam 42.8 GB
EGAF00000096359 bam 39.6 GB
EGAF00000096360 bam 41.7 GB
EGAF00000096561 bam 34.0 GB
EGAF00000096562 bam 31.0 GB
EGAF00000096563 bam 34.4 GB
EGAF00000096564 bam 35.6 GB
EGAF00000096565 bam 35.0 GB
EGAF00000096569 bam 70.1 GB
EGAF00000096570 bam 47.8 GB
EGAF00000096571 bam 58.5 GB
EGAF00000096572 bam 59.4 GB
EGAF00000096573 bam 55.5 GB
EGAF00000096574 bam 59.7 GB
EGAF00000096579 bam 60.2 GB
EGAF00000096580 bam 60.3 GB
EGAF00000096581 bam 60.2 GB
EGAF00000096582 bam 60.8 GB
EGAF00000096720 bam 55.8 GB
EGAF00000098608 bam 45.0 GB
EGAF00000098609 bam 44.6 GB
EGAF00000101734 bam 28.8 GB
EGAF00000101735 bam 29.4 GB
EGAF00000101736 bam 25.7 GB
EGAF00000101737 bam 32.5 GB
EGAF00000104237 bam 16.9 GB
EGAF00000115721 bam 43.2 GB
EGAF00000115727 bam 16.2 GB
EGAF00000115728 bam 17.1 GB
EGAF00000115729 bam 16.9 GB
EGAF00000115731 bam 19.4 GB
EGAF00000115732 bam 16.9 GB
EGAF00000115733 bam 20.1 GB
EGAF00000115734 bam 33.5 GB
EGAF00000115735 bam 33.9 GB
EGAF00000115736 bam 21.7 GB
EGAF00000115737 bam 21.5 GB
EGAF00000115738 bam 32.4 GB
EGAF00000115739 bam 31.8 GB
EGAF00000115740 bam 31.2 GB
EGAF00000115741 bam 31.8 GB
EGAF00000115742 bam 38.2 GB
EGAF00000118570 bam 33.7 GB
EGAF00000118571 bam 34.0 GB
EGAF00000118573 bam 39.1 GB
EGAF00000118574 bam 36.7 GB
EGAF00000118575 bam 37.4 GB
EGAF00000120856 bam 39.9 GB
EGAF00000121457 bam 36.8 GB
EGAF00000127390 bam 43.1 GB
EGAF00000127391 bam 42.3 GB
EGAF00000127392 bam 36.6 GB
63 Files (2.3 TB)