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  3. DIMPLE: deep insertion, deletion, and missense mutation libraries for exploring protein variation in evolution, disease, and biology

DIMPLE: deep insertion, deletion, and missense mutation libraries for exploring protein variation in evolution, disease, and biology

  • Genome Biol. 2023 Feb 24;24(1):36. doi: 10.1186/s13059-023-02880-6.
Christian B Macdonald 1,  David Nedrud 2,  Patrick Rockefeller Grimes 1,  Donovan Trinidad 3,  James S Fraser 1 4,  Willow Coyote-Maestas 5 6
Affiliations

Affiliations

  • 1 Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, USA.
  • 2 Bio-Techne, Minneapolis, Minnesota, USA.
  • 3 Department of Medicine, Division of Infectious Disease, University of California, San Francisco, USA.
  • 4 Quantitative Biosciences Institute, University of California, San Francisco, USA.
  • 5 Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, USA. willow.coyote-maestas@ucsf.edu.
  • 6 Quantitative Biosciences Institute, University of California, San Francisco, USA. willow.coyote-maestas@ucsf.edu.
PMID: 36829241 DOI: 10.1186/s13059-023-02880-6
Abstract

Insertions and deletions (indels) enable evolution and cause disease. Due to technical challenges, indels are left out of most mutational scans, limiting our understanding of them in disease, biology, and evolution. We develop a low cost and bias method, DIMPLE, for systematically generating deletions, insertions, and missense mutations in genes, which we test on a range of targets, including Kir2.1. We use DIMPLE to study how indels impact Potassium Channel structure, disease, and evolution. We find deletions are most disruptive overall, beta sheets are most sensitive to indels, and flexible loops are sensitive to deletions yet tolerate insertions.

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