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Gene drive that results in addiction to a temperature-sensitive version of an essential gene triggers population collapse in Drosophila - pnas.org

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  1. Edited by Dana Carroll, The University of Utah, Salt Lake City, UT, and approved October 14, 2021 (received for review April 21, 2021)

Abstract

One strategy for population suppression seeks to use gene drive to spread genes that confer conditional lethality or sterility, providing a way of combining population modification with suppression. Stimuli of potential interest could be introduced by humans, such as an otherwise benign virus or chemical, or occur naturally on a seasonal basis, such as a change in temperature. Cleave and Rescue (ClvR) selfish genetic elements use Cas9 and guide RNAs (gRNAs) to disrupt endogenous versions of an essential gene while also including a Rescue version of the essential gene resistant to disruption. ClvR spreads by creating loss-of-function alleles of the essential gene that select against those lacking it, resulting in populations in which the Rescue provides the only source of essential gene function. As a consequence, if function of the Rescue, a kind of Trojan horse now omnipresent in a population, is condition dependent, so too will be the survival of that population. To test this idea, we created a ClvR in Drosophila in which Rescue activity of an essential gene, dribble, requires splicing of a temperature-sensitive intein (TS-ClvRdbe ). This element spreads to transgene fixation at 23 °C, but when populations now dependent on Ts-ClvRdb e are shifted to 29 °C, death and sterility result in a rapid population crash. These results show that conditional population elimination can be achieved. A similar logic, in which Rescue activity is conditional, could also be used in homing-based drive and to bring about suppression and/or killing of specific individuals in response to other stimuli.

  • gene drive
  • population suppression
  • selfish genetic element
  • Drosophila

Footnotes

    • Accepted October 4, 2021.
  • Author contributions: G.O. and B.A.H. designed research; G.O., T.I., and B.A.H. performed research; G.O., T.I., and B.A.H. analyzed data; and G.O. and B.A.H. wrote the paper.

  • This paper results from the NAS Colloquium of the National Academy of Sciences, “Life 2.0: The Promise and Challenge of a CRISPR Path to a Sustainable Planet,” held December 10–11, 2019, at the Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering in Irvine, CA. NAS colloquia began in 1991 and have been published in PNAS since 1995. The complete program and video recordings of presentations are available on the NAS website at http://www.nasonline.org/CRISPR. The collection of colloquium papers in PNAS can be found at https://www.pnas.org/cc/the-promise-and-challenge-of-a-crispr-path.

  • Competing interest statement: The authors have filed patent applications on ClvR and related technologies (US Application No. 15/970,728 and No. 16/673,823; provisional patent No. CIT-8511-P).

  • This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2107413118/-/DCSupplemental.

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