Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 32, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2200567119
Keywords
gene drive; resistance; multisite resistance; standing variation; population rescue
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Funding
- Bill & Melinda Gates Foundation
- Open Philanthropy Project
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Evolution of resistance is a major barrier to the successful deployment of gene-drive systems. Multiplexed guide RNAs (gRNAs) that require resistance mutations at all target cut sites are a promising strategy to combat resistance. Research findings suggest that weakly deleterious naturally occurring variants greatly increase the probability of multisite resistance. This study provides design criteria for developing antiresistance multiplexed systems.
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 (gRNAs) that require resistance mutations in all target cut sites are a promising antiresistance strategy since, in principle, resistance would only arise in unrealistically large populations. Using stochastic simulations that accurately model evolution at very large population sizes, we explore the probability of resistance due to three important mechanisms: 1) nonhomologous end-joining mutations, 2) single-nucleotide mutants arising de novo, or 3) single-nucleotide polymorphisms preexisting 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 that this leads to a phenomenon where weakly deleterious naturally occurring variants greatly amplify the probability of multisite resistance compared to de novo mutation. This key result provides design criterion for antiresistance multiplexed systems, which, in general, will need a larger number of gRNAs compared to de novo expectations. This theory may have wider application to the evolution of resistance or evolutionary rescue when multiple changes are required before selection can act.
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