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A theory of resistance to multiplexed gene drive demonstrates the significant role of weakly deleterious natural genetic variation

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 ant...

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Autores principales: Khatri, Bhavin S., Burt, Austin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9371675/
https://www.ncbi.nlm.nih.gov/pubmed/35914131
http://dx.doi.org/10.1073/pnas.2200567119
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author Khatri, Bhavin S.
Burt, Austin
author_facet Khatri, Bhavin S.
Burt, Austin
author_sort Khatri, Bhavin S.
collection PubMed
description 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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spelling pubmed-93716752022-08-12 A theory of resistance to multiplexed gene drive demonstrates the significant role of weakly deleterious natural genetic variation Khatri, Bhavin S. Burt, Austin Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2022-08-01 2022-08-09 /pmc/articles/PMC9371675/ /pubmed/35914131 http://dx.doi.org/10.1073/pnas.2200567119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Khatri, Bhavin S.
Burt, Austin
A theory of resistance to multiplexed gene drive demonstrates the significant role of weakly deleterious natural genetic variation
title A theory of resistance to multiplexed gene drive demonstrates the significant role of weakly deleterious natural genetic variation
title_full A theory of resistance to multiplexed gene drive demonstrates the significant role of weakly deleterious natural genetic variation
title_fullStr A theory of resistance to multiplexed gene drive demonstrates the significant role of weakly deleterious natural genetic variation
title_full_unstemmed A theory of resistance to multiplexed gene drive demonstrates the significant role of weakly deleterious natural genetic variation
title_short A theory of resistance to multiplexed gene drive demonstrates the significant role of weakly deleterious natural genetic variation
title_sort theory of resistance to multiplexed gene drive demonstrates the significant role of weakly deleterious natural genetic variation
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9371675/
https://www.ncbi.nlm.nih.gov/pubmed/35914131
http://dx.doi.org/10.1073/pnas.2200567119
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