Overcoming evolved resistance to population-suppressing homing-based gene drives

Abstract The recent development of a CRISPR-Cas9-based homing system for the suppression of Anopheles gambiae is encouraging; however, with current designs, the slow emergence of homing-resistant alleles is expected to result in suppressed populations rapidly rebounding, as homing-resistant alleles...

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Autores principales:	John M. Marshall, Anna Buchman, Héctor M. Sánchez C., Omar S. Akbari
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e2e393ef8d1346af8d9d36efd77d8122
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spelling	oai:doaj.org-article:e2e393ef8d1346af8d9d36efd77d81222021-12-02T15:05:47ZOvercoming evolved resistance to population-suppressing homing-based gene drives10.1038/s41598-017-02744-72045-2322https://doaj.org/article/e2e393ef8d1346af8d9d36efd77d81222017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02744-7https://doaj.org/toc/2045-2322Abstract The recent development of a CRISPR-Cas9-based homing system for the suppression of Anopheles gambiae is encouraging; however, with current designs, the slow emergence of homing-resistant alleles is expected to result in suppressed populations rapidly rebounding, as homing-resistant alleles have a significant fitness advantage over functional, population-suppressing homing alleles. To explore this concern, we develop a mathematical model to estimate tolerable rates of homing-resistant allele generation to suppress a wild population of a given size. Our results suggest that, to achieve meaningful population suppression, tolerable rates of resistance allele generation are orders of magnitude smaller than those observed for current designs for CRISPR-Cas9-based homing systems. To remedy this, we theoretically explore a homing system architecture in which guide RNAs (gRNAs) are multiplexed, increasing the effective homing rate and decreasing the effective resistant allele generation rate. Modeling results suggest that the size of the population that can be suppressed increases exponentially with the number of multiplexed gRNAs and that, with four multiplexed gRNAs, a mosquito species could potentially be suppressed on a continental scale. We also demonstrate successful proof-of-principle use of multiplexed ribozyme flanked gRNAs to induce mutations in vivo in Drosophila melanogaster – a strategy that could readily be adapted to engineer stable, homing-based drives in relevant organisms.John M. MarshallAnna BuchmanHéctor M. Sánchez C.Omar S. AkbariNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q John M. Marshall Anna Buchman Héctor M. Sánchez C. Omar S. Akbari Overcoming evolved resistance to population-suppressing homing-based gene drives
description	Abstract The recent development of a CRISPR-Cas9-based homing system for the suppression of Anopheles gambiae is encouraging; however, with current designs, the slow emergence of homing-resistant alleles is expected to result in suppressed populations rapidly rebounding, as homing-resistant alleles have a significant fitness advantage over functional, population-suppressing homing alleles. To explore this concern, we develop a mathematical model to estimate tolerable rates of homing-resistant allele generation to suppress a wild population of a given size. Our results suggest that, to achieve meaningful population suppression, tolerable rates of resistance allele generation are orders of magnitude smaller than those observed for current designs for CRISPR-Cas9-based homing systems. To remedy this, we theoretically explore a homing system architecture in which guide RNAs (gRNAs) are multiplexed, increasing the effective homing rate and decreasing the effective resistant allele generation rate. Modeling results suggest that the size of the population that can be suppressed increases exponentially with the number of multiplexed gRNAs and that, with four multiplexed gRNAs, a mosquito species could potentially be suppressed on a continental scale. We also demonstrate successful proof-of-principle use of multiplexed ribozyme flanked gRNAs to induce mutations in vivo in Drosophila melanogaster – a strategy that could readily be adapted to engineer stable, homing-based drives in relevant organisms.
format	article
author	John M. Marshall Anna Buchman Héctor M. Sánchez C. Omar S. Akbari
author_facet	John M. Marshall Anna Buchman Héctor M. Sánchez C. Omar S. Akbari
author_sort	John M. Marshall
title	Overcoming evolved resistance to population-suppressing homing-based gene drives
title_short	Overcoming evolved resistance to population-suppressing homing-based gene drives
title_full	Overcoming evolved resistance to population-suppressing homing-based gene drives
title_fullStr	Overcoming evolved resistance to population-suppressing homing-based gene drives
title_full_unstemmed	Overcoming evolved resistance to population-suppressing homing-based gene drives
title_sort	overcoming evolved resistance to population-suppressing homing-based gene drives
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e2e393ef8d1346af8d9d36efd77d8122
work_keys_str_mv	AT johnmmarshall overcomingevolvedresistancetopopulationsuppressinghomingbasedgenedrives AT annabuchman overcomingevolvedresistancetopopulationsuppressinghomingbasedgenedrives AT hectormsanchezc overcomingevolvedresistancetopopulationsuppressinghomingbasedgenedrives AT omarsakbari overcomingevolvedresistancetopopulationsuppressinghomingbasedgenedrives
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Overcoming evolved resistance to population-suppressing homing-based gene drives

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