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Integral gene drives for population replacement

A first generation of CRISPR-based gene drives has now been tested in the laboratory in a number of organisms, including malaria vector mosquitoes. Challenges for their use in the area-wide genetic control of vector-borne disease have been identified, including the development of target site resista...

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Autores principales: Nash, Alexander, Urdaneta, Giulia Mignini, Beaghton, Andrea K., Hoermann, Astrid, Papathanos, Philippos Aris, Christophides, George K., Windbichler, Nikolai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361204/
https://www.ncbi.nlm.nih.gov/pubmed/30498016
http://dx.doi.org/10.1242/bio.037762
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author Nash, Alexander
Urdaneta, Giulia Mignini
Beaghton, Andrea K.
Hoermann, Astrid
Papathanos, Philippos Aris
Christophides, George K.
Windbichler, Nikolai
author_facet Nash, Alexander
Urdaneta, Giulia Mignini
Beaghton, Andrea K.
Hoermann, Astrid
Papathanos, Philippos Aris
Christophides, George K.
Windbichler, Nikolai
author_sort Nash, Alexander
collection PubMed
description A first generation of CRISPR-based gene drives has now been tested in the laboratory in a number of organisms, including malaria vector mosquitoes. Challenges for their use in the area-wide genetic control of vector-borne disease have been identified, including the development of target site resistance, their long-term efficacy in the field, their molecular complexity, and practical and legal limitations for field testing of both gene drive and coupled anti-pathogen traits. We have evaluated theoretically the concept of integral gene drive (IGD) as an alternative paradigm for population replacement. IGDs incorporate a minimal set of molecular components, including drive and anti-pathogen effector elements directly embedded within endogenous genes – an arrangement that in theory allows targeting functionally conserved coding sequences without disrupting their function. Autonomous and non-autonomous IGD strains could be generated, optimized, regulated and imported independently. We performed quantitative modeling comparing IGDs with classical replacement drives and show that selection for the function of the hijacked host gene can significantly reduce the establishment of resistant alleles in the population, while drive occurring at multiple genomic loci prolongs the duration of transmission blockage in the face of pre-existing target site variation. IGD thus has potential as a more durable and flexible population replacement strategy.
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spelling pubmed-63612042019-02-05 Integral gene drives for population replacement Nash, Alexander Urdaneta, Giulia Mignini Beaghton, Andrea K. Hoermann, Astrid Papathanos, Philippos Aris Christophides, George K. Windbichler, Nikolai Biol Open Research Article A first generation of CRISPR-based gene drives has now been tested in the laboratory in a number of organisms, including malaria vector mosquitoes. Challenges for their use in the area-wide genetic control of vector-borne disease have been identified, including the development of target site resistance, their long-term efficacy in the field, their molecular complexity, and practical and legal limitations for field testing of both gene drive and coupled anti-pathogen traits. We have evaluated theoretically the concept of integral gene drive (IGD) as an alternative paradigm for population replacement. IGDs incorporate a minimal set of molecular components, including drive and anti-pathogen effector elements directly embedded within endogenous genes – an arrangement that in theory allows targeting functionally conserved coding sequences without disrupting their function. Autonomous and non-autonomous IGD strains could be generated, optimized, regulated and imported independently. We performed quantitative modeling comparing IGDs with classical replacement drives and show that selection for the function of the hijacked host gene can significantly reduce the establishment of resistant alleles in the population, while drive occurring at multiple genomic loci prolongs the duration of transmission blockage in the face of pre-existing target site variation. IGD thus has potential as a more durable and flexible population replacement strategy. The Company of Biologists Ltd 2018-11-29 /pmc/articles/PMC6361204/ /pubmed/30498016 http://dx.doi.org/10.1242/bio.037762 Text en © 2019. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/4.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Nash, Alexander
Urdaneta, Giulia Mignini
Beaghton, Andrea K.
Hoermann, Astrid
Papathanos, Philippos Aris
Christophides, George K.
Windbichler, Nikolai
Integral gene drives for population replacement
title Integral gene drives for population replacement
title_full Integral gene drives for population replacement
title_fullStr Integral gene drives for population replacement
title_full_unstemmed Integral gene drives for population replacement
title_short Integral gene drives for population replacement
title_sort integral gene drives for population replacement
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361204/
https://www.ncbi.nlm.nih.gov/pubmed/30498016
http://dx.doi.org/10.1242/bio.037762
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