Goncalves, Emanuel
Behan, Fiona M
Louzada, Sandra
Arnol, Damien
Stronach, Euan
Yang, Fengtang
Yusa, Kosuke
Stegle, Oliver
Iorio, Francesco
Garnett, Mathew J
2019-01-03
<p>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.</p>
<p>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.</p>
<p>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.</p>
https://doi.org/10.5281/zenodo.2530755
oai:zenodo.org:2530755
eng
Zenodo
https://doi.org/10.5281/zenodo.2530754
info:eu-repo/semantics/openAccess
BSD 3-Clause "New" or "Revised" License
https://opensource.org/licenses/BSD-3-Clause
CRISPR
Copy-number
Ploidy
Structural Rearrangements
Python
Crispy
Structural rearrangements generate cell-specific, gene-independent CRISPR-Cas9 loss of fitness effects
info:eu-repo/semantics/other