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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 <jats:italic>FAM50A\/FAM50B<\/jats:italic>, two genes of unknown function. Silencing of <jats:italic>FAM50B<\/jats:italic> occurs across a range of tumour types and in this context disruption of <jats:italic>FAM50A<\/jats:italic> reduces cellular fitness whilst promoting micronucleus formation and extensive perturbation of transcriptional programmes. Our studies reveal the fitness effects of <jats:italic>FAM50A\/FAM50B<\/jats:italic> in cancer cells.<\/jats:p>","DOI":"10.1038\/s41467-021-21478-9","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T11:04:53Z","timestamp":1614337493000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":130,"title":["Combinatorial CRISPR screen identifies fitness effects of gene paralogues"],"prefix":"10.1038","volume":"12","author":[{"given":"Nicola A.","family":"Thompson","sequence":"first","affiliation":[]},{"given":"Marco","family":"Ranzani","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0645-1879","authenticated-orcid":false,"given":"Louise","family":"van der Weyden","sequence":"additional","affiliation":[]},{"given":"Vivek","family":"Iyer","sequence":"additional","affiliation":[]},{"given":"Victoria","family":"Offord","sequence":"additional","affiliation":[]},{"given":"Alastair","family":"Droop","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9070-7688","authenticated-orcid":false,"given":"Fiona","family":"Behan","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9967-5205","authenticated-orcid":false,"given":"Emanuel","family":"Gon\u00e7alves","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4890-4685","authenticated-orcid":false,"given":"Anneliese","family":"Speak","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7063-8913","authenticated-orcid":false,"given":"Francesco","family":"Iorio","sequence":"additional","affiliation":[]},{"given":"James","family":"Hewinson","sequence":"additional","affiliation":[]},{"given":"Victoria","family":"Harle","sequence":"additional","affiliation":[]},{"given":"Holly","family":"Robertson","sequence":"additional","affiliation":[]},{"given":"Elizabeth","family":"Anderson","sequence":"additional","affiliation":[]},{"given":"Beiyuan","family":"Fu","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3573-2354","authenticated-orcid":false,"given":"Fengtang","family":"Yang","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5656-1056","authenticated-orcid":false,"given":"Guido","family":"Zagnoli-Vieira","sequence":"additional","affiliation":[]},{"given":"Phil","family":"Chapman","sequence":"additional","affiliation":[]},{"given":"Martin","family":"Del Castillo Velasco-Herrera","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2618-4237","authenticated-orcid":false,"given":"Mathew J.","family":"Garnett","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9317-7937","authenticated-orcid":false,"given":"Stephen P.","family":"Jackson","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9490-0306","authenticated-orcid":false,"given":"David J.","family":"Adams","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,2,26]]},"reference":[{"key":"21478_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.febslet.2010.11.024","volume":"585","author":"SM Nijman","year":"2011","unstructured":"Nijman, S. 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