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Germline Cas9 promoters with improved performance for homing gene drive

Author

Listed:
  • Jie Du

    (Peking University)

  • Weizhe Chen

    (Peking University
    Tsinghua University)

  • Xihua Jia

    (Peking University)

  • Xuejiao Xu

    (Peking University)

  • Emily Yang

    (Cornell University)

  • Ruizhi Zhou

    (Peking University)

  • Yuqi Zhang

    (Peking University)

  • Matt Metzloff

    (Cornell University)

  • Philipp W. Messer

    (Cornell University)

  • Jackson Champer

    (Peking University)

Abstract

Gene drive systems could be a viable strategy to prevent pathogen transmission or suppress vector populations by propagating drive alleles with super-Mendelian inheritance. CRISPR-based homing gene drives convert wild type alleles into drive alleles in heterozygotes with Cas9 and gRNA. It is thus desirable to identify Cas9 promoters that yield high drive conversion rates, minimize the formation rate of resistance alleles in both the germline and the early embryo, and limit somatic Cas9 expression. In Drosophila, the nanos promoter avoids leaky somatic expression, but at the cost of high embryo resistance from maternally deposited Cas9. To improve drive efficiency, we test eleven Drosophila melanogaster germline promoters. Some achieve higher drive conversion efficiency with minimal embryo resistance, but none completely avoid somatic expression. However, such somatic expression often does not carry detectable fitness costs for a rescue homing drive targeting a haplolethal gene, suggesting somatic drive conversion. Supporting a 4-gRNA suppression drive, one promoter leads to a low drive equilibrium frequency due to fitness costs from somatic expression, but the other outperforms nanos, resulting in successful suppression of the cage population. Overall, these Cas9 promoters hold advantages for homing drives in Drosophila species and may possess valuable homologs in other organisms.

Suggested Citation

  • Jie Du & Weizhe Chen & Xihua Jia & Xuejiao Xu & Emily Yang & Ruizhi Zhou & Yuqi Zhang & Matt Metzloff & Philipp W. Messer & Jackson Champer, 2024. "Germline Cas9 promoters with improved performance for homing gene drive," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48874-1
    DOI: 10.1038/s41467-024-48874-1
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    1. Weizhe Chen & Jialiang Guo & Yiran Liu & Jackson Champer, 2024. "Population suppression by release of insects carrying a dominant sterile homing gene drive targeting doublesex in Drosophila," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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