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Genome-scale analysis of interactions between genetic perturbations and natural variation

Author

Listed:
  • Joseph J. Hale

    (University of Southern California)

  • Takeshi Matsui

    (SLAC National Accelerator Laboratory)

  • Ilan Goldstein

    (University of Southern California)

  • Martin N. Mullis

    (University of Southern California)

  • Kevin R. Roy

    (Stanford University
    Stanford University School of Medicine)

  • Christopher Ne Ville

    (University of Southern California)

  • Darach Miller

    (SLAC National Accelerator Laboratory)

  • Charley Wang

    (University of Southern California)

  • Trevor Reynolds

    (University of Southern California)

  • Lars M. Steinmetz

    (Stanford University
    Stanford University School of Medicine
    Genome Biology Unit)

  • Sasha F. Levy

    (SLAC National Accelerator Laboratory
    BacStitch DNA)

  • Ian M. Ehrenreich

    (University of Southern California)

Abstract

Interactions between genetic perturbations and segregating loci can cause perturbations to show different phenotypic effects across genetically distinct individuals. To study these interactions on a genome scale in many individuals, we used combinatorial DNA barcode sequencing to measure the fitness effects of 8046 CRISPRi perturbations targeting 1721 distinct genes in 169 yeast cross progeny (or segregants). We identified 460 genes whose perturbation has different effects across segregants. Several factors caused perturbations to show variable effects, including baseline segregant fitness, the mean effect of a perturbation across segregants, and interacting loci. We mapped 234 interacting loci and found four hub loci that interact with many different perturbations. Perturbations that interact with a given hub exhibit similar epistatic relationships with the hub and show enrichment for cellular processes that may mediate these interactions. These results suggest that an individual’s response to perturbations is shaped by a network of perturbation-locus interactions that cannot be measured by approaches that examine perturbations or natural variation alone.

Suggested Citation

  • Joseph J. Hale & Takeshi Matsui & Ilan Goldstein & Martin N. Mullis & Kevin R. Roy & Christopher Ne Ville & Darach Miller & Charley Wang & Trevor Reynolds & Lars M. Steinmetz & Sasha F. Levy & Ian M. , 2024. "Genome-scale analysis of interactions between genetic perturbations and natural variation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48626-1
    DOI: 10.1038/s41467-024-48626-1
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    References listed on IDEAS

    as
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