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Combinatorial CRISPR screen identifies fitness effects of gene paralogues

Author

Listed:
  • 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
    Human Technopole)

  • 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)

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.

Suggested Citation

  • Nicola A. Thompson & Marco Ranzani & Louise Weyden & Vivek Iyer & Victoria Offord & Alastair Droop & Fiona Behan & Emanuel Gonçalves & Anneliese Speak & Francesco Iorio & James Hewinson & Victoria Har, 2021. "Combinatorial CRISPR screen identifies fitness effects of gene paralogues," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21478-9
    DOI: 10.1038/s41467-021-21478-9
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    Cited by:

    1. Sumana Srivatsa & Hesam Montazeri & Gaia Bianco & Mairene Coto-Llerena & Mattia Marinucci & Charlotte K. Y. Ng & Salvatore Piscuoglio & Niko Beerenwinkel, 2022. "Discovery of synthetic lethal interactions from large-scale pan-cancer perturbation screens," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Ruitong Li & Olaf Klingbeil & Davide Monducci & Michael J. Young & Diego J. Rodriguez & Zaid Bayyat & Joshua M. Dempster & Devishi Kesar & Xiaoping Yang & Mahdi Zamanighomi & Christopher R. Vakoc & Ta, 2022. "Comparative optimization of combinatorial CRISPR screens," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Luis V. Valcárcel & Edurne San José-Enériz & Raquel Ordoñez & Iñigo Apaolaza & Danel Olaverri-Mendizabal & Naroa Barrena & Ana Valcárcel & Leire Garate & Jesús San Miguel & Antonio Pineda-Lucena & Xab, 2024. "An automated network-based tool to search for metabolic vulnerabilities in cancer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Nazanin Esmaeili Anvar & Chenchu Lin & Xingdi Ma & Lori L. Wilson & Ryan Steger & Annabel K. Sangree & Medina Colic & Sidney H. Wang & John G. Doench & Traver Hart, 2024. "Efficient gene knockout and genetic interaction screening using the in4mer CRISPR/Cas12a multiplex knockout platform," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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