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Weakly deleterious natural genetic variation greatly amplifies probability of resistance in multiplexed gene drive systems

View ORCID ProfileBhavin S. Khatri, Austin Burt
doi: https://doi.org/10.1101/2021.12.23.473701
Bhavin S. Khatri
1Department of Life Sciences, Imperial College London, Silwood Park, Ascot, SL5 7PY, United Kingdom
2The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, United Kingdom
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  • For correspondence: bkhatri@imperial.ac.uk
Austin Burt
1Department of Life Sciences, Imperial College London, Silwood Park, Ascot, SL5 7PY, United Kingdom
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Abstract

Evolution of resistance is a major barrier to successful deployment of gene drive systems to suppress natural populations, which could greatly reduce the burden of many vector borne diseases. Multiplexed guide RNAs that require resistance mutations in all target cut sites is a promising anti-resistance strategy, since in principle resistance would only arise in unrealistically large populations. Using novel stochastic simulations that accurately model evolution at very large population sizes, we explore the probability of resistance due to three important mechanisms: 1) non-homologous end-joining mutations, 2) single nucleotide mutants arising de novo or, 3) single nucleotide polymorphisms pre-existing as standing variation. Our results explore the relative importance of these mechanisms and highlight a complexity of the mutation-selection-drift balance between haplotypes with complete resistance and those with an incomplete number of resistant alleles. We find this leads to a qualitatively new phenomenon where weakly deleterious naturally occurring variants greatly amplify the probability of multi-site resistance. This challenges the intuition that many target sites would guarantee prevention of resistance, where in the face of standing genetic variation, it can be probable even in not very large populations. This result has broad application to resistance arising in many multi-site evolutionary scenarios including multi-drug resistance to antibiotics, antivirals and cancer treatments, as well as the evolution of vaccine escape mutations in large populations.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Edited down for submission. Otherwise small changes.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 11, 2022.
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Weakly deleterious natural genetic variation greatly amplifies probability of resistance in multiplexed gene drive systems
Bhavin S. Khatri, Austin Burt
bioRxiv 2021.12.23.473701; doi: https://doi.org/10.1101/2021.12.23.473701
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Weakly deleterious natural genetic variation greatly amplifies probability of resistance in multiplexed gene drive systems
Bhavin S. Khatri, Austin Burt
bioRxiv 2021.12.23.473701; doi: https://doi.org/10.1101/2021.12.23.473701

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