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Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing

There is a need for new interventions against the ongoing burden of vector-borne diseases such as malaria and dengue. One suggestion has been to develop genes encoding effector molecules that block parasite development within the vector, and then use the nuclease-based homing reaction as a form of g...

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Autores principales: Beaghton, Andrea, Hammond, Andrew, Nolan, Tony, Crisanti, Andrea, Godfray, H. Charles J., Burt, Austin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Genetics Society of America 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378115/
https://www.ncbi.nlm.nih.gov/pubmed/28159753
http://dx.doi.org/10.1534/genetics.116.197632
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author Beaghton, Andrea
Hammond, Andrew
Nolan, Tony
Crisanti, Andrea
Godfray, H. Charles J.
Burt, Austin
author_facet Beaghton, Andrea
Hammond, Andrew
Nolan, Tony
Crisanti, Andrea
Godfray, H. Charles J.
Burt, Austin
author_sort Beaghton, Andrea
collection PubMed
description There is a need for new interventions against the ongoing burden of vector-borne diseases such as malaria and dengue. One suggestion has been to develop genes encoding effector molecules that block parasite development within the vector, and then use the nuclease-based homing reaction as a form of gene drive to spread those genes through target populations. If the effector gene reduces the fitness of the mosquito and does not contribute to the drive, then loss-of-function mutations in the effector will eventually replace functional copies, but protection may nonetheless persist sufficiently long to provide a public health benefit. Here, we present a quantitative model allowing one to predict the duration of protection as a function of the probabilities of different molecular processes during the homing reaction, various fitness effects, and the efficacy of the effector in blocking transmission. Factors that increase the duration of protection include reducing the frequency of pre-existing resistant alleles, the probability of nonrecombinational DNA repair, the probability of homing-associated loss of the effector, the fitness costs of the nuclease and effector, and the completeness of parasite blocking. For target species that extend over an area much larger than the typical dispersal distance, the duration of protection is expected to be highest at the release site, and decrease away from there, eventually falling to zero, as effector-less drive constructs replace effector-containing ones. We also model an alternative strategy of using the nuclease to target an essential gene, and then linking the effector to a sequence that restores the essential function and is resistant to the nuclease. Depending upon parameter values, this approach can prolong the duration of protection. Our models highlight the key design criteria needed to achieve a desired level of public health benefit.
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spelling pubmed-53781152017-04-05 Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing Beaghton, Andrea Hammond, Andrew Nolan, Tony Crisanti, Andrea Godfray, H. Charles J. Burt, Austin Genetics Investigations There is a need for new interventions against the ongoing burden of vector-borne diseases such as malaria and dengue. One suggestion has been to develop genes encoding effector molecules that block parasite development within the vector, and then use the nuclease-based homing reaction as a form of gene drive to spread those genes through target populations. If the effector gene reduces the fitness of the mosquito and does not contribute to the drive, then loss-of-function mutations in the effector will eventually replace functional copies, but protection may nonetheless persist sufficiently long to provide a public health benefit. Here, we present a quantitative model allowing one to predict the duration of protection as a function of the probabilities of different molecular processes during the homing reaction, various fitness effects, and the efficacy of the effector in blocking transmission. Factors that increase the duration of protection include reducing the frequency of pre-existing resistant alleles, the probability of nonrecombinational DNA repair, the probability of homing-associated loss of the effector, the fitness costs of the nuclease and effector, and the completeness of parasite blocking. For target species that extend over an area much larger than the typical dispersal distance, the duration of protection is expected to be highest at the release site, and decrease away from there, eventually falling to zero, as effector-less drive constructs replace effector-containing ones. We also model an alternative strategy of using the nuclease to target an essential gene, and then linking the effector to a sequence that restores the essential function and is resistant to the nuclease. Depending upon parameter values, this approach can prolong the duration of protection. Our models highlight the key design criteria needed to achieve a desired level of public health benefit. Genetics Society of America 2017-04 2017-02-02 /pmc/articles/PMC5378115/ /pubmed/28159753 http://dx.doi.org/10.1534/genetics.116.197632 Text en Copyright © 2017 Beaghton et al. Available freely online through the author-supported open access option. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Investigations
Beaghton, Andrea
Hammond, Andrew
Nolan, Tony
Crisanti, Andrea
Godfray, H. Charles J.
Burt, Austin
Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing
title Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing
title_full Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing
title_fullStr Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing
title_full_unstemmed Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing
title_short Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing
title_sort requirements for driving antipathogen effector genes into populations of disease vectors by homing
topic Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378115/
https://www.ncbi.nlm.nih.gov/pubmed/28159753
http://dx.doi.org/10.1534/genetics.116.197632
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