Combinatorial CRISPR screen identifies fitness effects of gene paralogues

Nicola A. Thompson, Marco Ranzani, Louise Weyden, Vivek Iyer, Victoria Offord, Alastair Droop, Fiona Behan, Emanuel Gonçalves, Anneliese Speak, Francesco Iorio, James Hewinson, Victoria Harle, Holly Robertson, Elizabeth Anderson, Beiyuan Fu, Fengtang Yang, Guido Zagnoli-Vieira, Phil Chapman, Martin Castillo Velasco-Herrera, Mathew J. Garnett, Stephen P. Jackson and David J. Adams ()
Additional contact information
Nicola A. Thompson: Wellcome Trust Genome Campus
Marco Ranzani: Wellcome Trust Genome Campus
Louise Weyden: Wellcome Trust Genome Campus
Vivek Iyer: Wellcome Trust Genome Campus
Victoria Offord: Wellcome Trust Genome Campus
Alastair Droop: Wellcome Trust Genome Campus
Fiona Behan: Wellcome Trust Genome Campus
Emanuel Gonçalves: Wellcome Trust Genome Campus
Anneliese Speak: Wellcome Trust Genome Campus
Francesco Iorio: Wellcome Trust Genome Campus
James Hewinson: Wellcome Trust Genome Campus
Victoria Harle: Wellcome Trust Genome Campus
Holly Robertson: Wellcome Trust Genome Campus
Elizabeth Anderson: Wellcome Trust Genome Campus
Beiyuan Fu: Wellcome Trust Genome Campus
Fengtang Yang: Wellcome Trust Genome Campus
Guido Zagnoli-Vieira: Wellcome Trust/Cancer Research UK Gurdon Institute
Phil Chapman: Cancer Research UK, Manchester Institute
Martin Castillo Velasco-Herrera: Wellcome Trust Genome Campus
Mathew J. Garnett: Wellcome Trust Genome Campus
Stephen P. Jackson: Wellcome Trust/Cancer Research UK Gurdon Institute
David J. Adams: Wellcome Trust Genome Campus

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Genetic redundancy has evolved as a way for human cells to survive the loss of genes that are single copy and essential in other organisms, but also allows tumours to survive despite having highly rearranged genomes. In this study we CRISPR screen 1191 gene pairs, including paralogues and known and predicted synthetic lethal interactions to identify 105 gene combinations whose co-disruption results in a loss of cellular fitness. 27 pairs influence fitness across multiple cell lines including the paralogues FAM50A/FAM50B, two genes of unknown function. Silencing of FAM50B occurs across a range of tumour types and in this context disruption of FAM50A reduces cellular fitness whilst promoting micronucleus formation and extensive perturbation of transcriptional programmes. Our studies reveal the fitness effects of FAM50A/FAM50B in cancer cells.

Date: 2021
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DOI: 10.1038/s41467-021-21478-9

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