The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito

Gene drives have enormous potential for the control of insect populations of medical and agricultural relevance. By preferentially biasing their own inheritance, gene drives can rapidly introduce genetic traits even if these confer a negative fitness effect on the population. We have recently develo...

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Veröffentlicht in:	PLoS genetics Jg. 13; H. 10; S. e1007039
Hauptverfasser:	Hammond, Andrew M., Kyrou, Kyros, Bruttini, Marco, North, Ace, Galizi, Roberto, Karlsson, Xenia, Kranjc, Nace, Carpi, Francesco M., D’Aurizio, Romina, Crisanti, Andrea, Nolan, Tony
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Public Library of Science 04.10.2017 Public Library of Science (PLoS)
Schlagworte:	Alleles Amino Acid Sequence Animals Anopheles - genetics Anopheles gambiae Bioinformatics Biology and life sciences Clustered Regularly Interspaced Short Palindromic Repeats - genetics Control Culicidae Female Fertility Fertility - genetics Fitness Gene Frequency Gene Library Gene mutation Genes Genes, Essential Genetic aspects Genetic Engineering Genetic research Genetics Genetics, Population Genomics Haplotypes Heredity High-Throughput Nucleotide Sequencing Homing Homology Insect Vectors - genetics Life sciences Malaria Malaria - prevention & control Male Medicine and Health Sciences Methods Models, Genetic Mosquito Control - methods Mosquitoes Mutation Nuclease Population Positive selection Reproductive fitness Research and Analysis Methods Selection, Genetic Sequence Analysis, RNA Technology assessment
ISSN:	1553-7404, 1553-7390, 1553-7404
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Abstract	Gene drives have enormous potential for the control of insect populations of medical and agricultural relevance. By preferentially biasing their own inheritance, gene drives can rapidly introduce genetic traits even if these confer a negative fitness effect on the population. We have recently developed gene drives based on CRISPR nuclease constructs that are designed to disrupt key genes essential for female fertility in the malaria mosquito. The construct copies itself and the associated genetic disruption from one homologous chromosome to another during gamete formation, a process called homing that ensures the majority of offspring inherit the drive. Such drives have the potential to cause long-lasting, sustainable population suppression, though they are also expected to impose a large selection pressure for resistance in the mosquito. One of these population suppression gene drives showed rapid invasion of a caged population over 4 generations, establishing proof of principle for this technology. In order to assess the potential for the emergence of resistance to the gene drive in this population we allowed it to run for 25 generations and monitored the frequency of the gene drive over time. Following the initial increase of the gene drive we observed a gradual decrease in its frequency that was accompanied by the spread of small, nuclease-induced mutations at the target gene that are resistant to further cleavage and restore its functionality. Such mutations showed rates of increase consistent with positive selection in the face of the gene drive. Our findings represent the first documented example of selection for resistance to a synthetic gene drive and lead to important design recommendations and considerations in order to mitigate for resistance in future gene drive applications.
AbstractList	Gene drives have enormous potential for the control of insect populations of medical and agricultural relevance. By preferentially biasing their own inheritance, gene drives can rapidly introduce genetic traits even if these confer a negative fitness effect on the population. We have recently developed gene drives based on CRISPR nuclease constructs that are designed to disrupt key genes essential for female fertility in the malaria mosquito. The construct copies itself and the associated genetic disruption from one homologous chromosome to another during gamete formation, a process called homing that ensures the majority of offspring inherit the drive. Such drives have the potential to cause long-lasting, sustainable population suppression, though they are also expected to impose a large selection pressure for resistance in the mosquito. One of these population suppression gene drives showed rapid invasion of a caged population over 4 generations, establishing proof of principle for this technology. In order to assess the potential for the emergence of resistance to the gene drive in this population we allowed it to run for 25 generations and monitored the frequency of the gene drive over time. Following the initial increase of the gene drive we observed a gradual decrease in its frequency that was accompanied by the spread of small, nuclease-induced mutations at the target gene that are resistant to further cleavage and restore its functionality. Such mutations showed rates of increase consistent with positive selection in the face of the gene drive. Our findings represent the first documented example of selection for resistance to a synthetic gene drive and lead to important design recommendations and considerations in order to mitigate for resistance in future gene drive applications. Gene drives have enormous potential for the control of insect populations of medical and agricultural relevance. By preferentially biasing their own inheritance, gene drives can rapidly introduce genetic traits even if these confer a negative fitness effect on the population. We have recently developed gene drives based on CRISPR nuclease constructs that are designed to disrupt key genes essential for female fertility in the malaria mosquito. The construct copies itself and the associated genetic disruption from one homologous chromosome to another during gamete formation, a process called homing that ensures the majority of offspring inherit the drive. Such drives have the potential to cause long-lasting, sustainable population suppression, though they are also expected to impose a large selection pressure for resistance in the mosquito. One of these population suppression gene drives showed rapid invasion of a caged population over 4 generations, establishing proof of principle for this technology. In order to assess the potential for the emergence of resistance to the gene drive in this population we allowed it to run for 25 generations and monitored the frequency of the gene drive over time. Following the initial increase of the gene drive we observed a gradual decrease in its frequency that was accompanied by the spread of small, nuclease-induced mutations at the target gene that are resistant to further cleavage and restore its functionality. Such mutations showed rates of increase consistent with positive selection in the face of the gene drive. Our findings represent the first documented example of selection for resistance to a synthetic gene drive and lead to important design recommendations and considerations in order to mitigate for resistance in future gene drive applications.Gene drives have enormous potential for the control of insect populations of medical and agricultural relevance. By preferentially biasing their own inheritance, gene drives can rapidly introduce genetic traits even if these confer a negative fitness effect on the population. We have recently developed gene drives based on CRISPR nuclease constructs that are designed to disrupt key genes essential for female fertility in the malaria mosquito. The construct copies itself and the associated genetic disruption from one homologous chromosome to another during gamete formation, a process called homing that ensures the majority of offspring inherit the drive. Such drives have the potential to cause long-lasting, sustainable population suppression, though they are also expected to impose a large selection pressure for resistance in the mosquito. One of these population suppression gene drives showed rapid invasion of a caged population over 4 generations, establishing proof of principle for this technology. In order to assess the potential for the emergence of resistance to the gene drive in this population we allowed it to run for 25 generations and monitored the frequency of the gene drive over time. Following the initial increase of the gene drive we observed a gradual decrease in its frequency that was accompanied by the spread of small, nuclease-induced mutations at the target gene that are resistant to further cleavage and restore its functionality. Such mutations showed rates of increase consistent with positive selection in the face of the gene drive. Our findings represent the first documented example of selection for resistance to a synthetic gene drive and lead to important design recommendations and considerations in order to mitigate for resistance in future gene drive applications. Gene drives have enormous potential for the control of insect populations of medical and agricultural relevance. By preferentially biasing their own inheritance, gene drives can rapidly introduce genetic traits even if these confer a negative fitness effect on the population. We have recently developed gene drives based on CRISPR nuclease constructs that are designed to disrupt key genes essential for female fertility in the malaria mosquito. The construct copies itself and the associated genetic disruption from one homologous chromosome to another during gamete formation, a process called homing that ensures the majority of offspring inherit the drive. Such drives have the potential to cause long-lasting, sustainable population suppression, though they are also expected to impose a large selection pressure for resistance in the mosquito. One of these population suppression gene drives showed rapid invasion of a caged population over 4 generations, establishing proof of principle for this technology. In order to assess the potential for the emergence of resistance to the gene drive in this population we allowed it to run for 25 generations and monitored the frequency of the gene drive over time. Following the initial increase of the gene drive we observed a gradual decrease in its frequency that was accompanied by the spread of small, nuclease-induced mutations at the target gene that are resistant to further cleavage and restore its functionality. Such mutations showed rates of increase consistent with positive selection in the face of the gene drive. Our findings represent the first documented example of selection for resistance to a synthetic gene drive and lead to important design recommendations and considerations in order to mitigate for resistance in future gene drive applications. Gene drives are selfish genetic elements that are able to bias their own inheritance among offspring. Starting from very low frequencies they can rapidly invade a population in just a few generations, even when imposing a fitness cost. Gene drives based on the precise DNA cutting enzyme CRISPR have been shown recently to be highly efficient at copying themselves from one chromosome to the other during the process of gamete formation in mosquitoes, resulting in transmission to 99% of offspring instead of the 50% expected for a single gene copy. One proposed use for CRISPR-based gene drives is in the control of mosquitoes by designing the gene drive to target mosquito genes involved in fertility, thereby reducing their overall reproductive output and leading to population suppression. Like any intervention designed to suppress a population these gene drives are expected to select for mutations in the mosquito that are resistant to the drive and restore fertility to mosquitoes. We have analyzed the origin and selection of resistant alleles in caged populations of mosquitoes initiated with a gene drive construct targeting a female fertility gene. We find the selected alleles are in-frame insertions and deletions that are resistant to cleavage and restore female fertility. Our findings allow us to improve predictions on gene drive behaviour and to make concrete recommendations on how to improve future gene drive designs by decreasing the likelihood that they generate resistance.
Audience	Academic
Author	Hammond, Andrew M. Crisanti, Andrea D’Aurizio, Romina North, Ace Bruttini, Marco Nolan, Tony Kranjc, Nace Galizi, Roberto Carpi, Francesco M. Kyrou, Kyros Karlsson, Xenia
AuthorAffiliation	Institute of Science and Technology Austria (IST Austria), AUSTRIA 4 Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics and Telematics (IIT), CNR, Pisa, Italy 3 Department of Zoology, University of Oxford, Oxford, England 1 Dept. of Life Sciences, Imperial College London, London, United Kingdom 2 Polo d’Innovazione Genomica, Genetica e Biologia, Siena, Italy
AuthorAffiliation_xml	– name: 2 Polo d’Innovazione Genomica, Genetica e Biologia, Siena, Italy – name: Institute of Science and Technology Austria (IST Austria), AUSTRIA – name: 3 Department of Zoology, University of Oxford, Oxford, England – name: 4 Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics and Telematics (IIT), CNR, Pisa, Italy – name: 1 Dept. of Life Sciences, Imperial College London, London, United Kingdom
Author_xml	– sequence: 1 givenname: Andrew M. surname: Hammond fullname: Hammond, Andrew M. – sequence: 2 givenname: Kyros surname: Kyrou fullname: Kyrou, Kyros – sequence: 3 givenname: Marco orcidid: 0000-0003-1063-2522 surname: Bruttini fullname: Bruttini, Marco – sequence: 4 givenname: Ace orcidid: 0000-0002-4253-396X surname: North fullname: North, Ace – sequence: 5 givenname: Roberto orcidid: 0000-0003-3134-7480 surname: Galizi fullname: Galizi, Roberto – sequence: 6 givenname: Xenia surname: Karlsson fullname: Karlsson, Xenia – sequence: 7 givenname: Nace surname: Kranjc fullname: Kranjc, Nace – sequence: 8 givenname: Francesco M. surname: Carpi fullname: Carpi, Francesco M. – sequence: 9 givenname: Romina orcidid: 0000-0002-1728-6397 surname: D’Aurizio fullname: D’Aurizio, Romina – sequence: 10 givenname: Andrea surname: Crisanti fullname: Crisanti, Andrea – sequence: 11 givenname: Tony orcidid: 0000-0002-2982-8333 surname: Nolan fullname: Nolan, Tony
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/28976972$$D View this record in MEDLINE/PubMed
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ContentType	Journal Article
Copyright	COPYRIGHT 2017 Public Library of Science 2017 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Hammond AM, Kyrou K, Bruttini M, North A, Galizi R, Karlsson X, et al. (2017) The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito. PLoS Genet13(10): e1007039. https://doi.org/10.1371/journal.pgen.1007039 2017 Hammond et al 2017 Hammond et al 2017 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Hammond AM, Kyrou K, Bruttini M, North A, Galizi R, Karlsson X, et al. (2017) The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito. PLoS Genet13(10): e1007039. https://doi.org/10.1371/journal.pgen.1007039
Copyright_xml	– notice: COPYRIGHT 2017 Public Library of Science – notice: 2017 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Hammond AM, Kyrou K, Bruttini M, North A, Galizi R, Karlsson X, et al. (2017) The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito. PLoS Genet13(10): e1007039. https://doi.org/10.1371/journal.pgen.1007039 – notice: 2017 Hammond et al 2017 Hammond et al – notice: 2017 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Hammond AM, Kyrou K, Bruttini M, North A, Galizi R, Karlsson X, et al. (2017) The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito. PLoS Genet13(10): e1007039. https://doi.org/10.1371/journal.pgen.1007039
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DOI	10.1371/journal.pgen.1007039
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SubjectTerms	Alleles Amino Acid Sequence Animals Anopheles - genetics Anopheles gambiae Bioinformatics Biology and life sciences Clustered Regularly Interspaced Short Palindromic Repeats - genetics Control Culicidae Female Fertility Fertility - genetics Fitness Gene Frequency Gene Library Gene mutation Genes Genes, Essential Genetic aspects Genetic Engineering Genetic research Genetics Genetics, Population Genomics Haplotypes Heredity High-Throughput Nucleotide Sequencing Homing Homology Insect Vectors - genetics Life sciences Malaria Malaria - prevention & control Male Medicine and Health Sciences Methods Models, Genetic Mosquito Control - methods Mosquitoes Mutation Nuclease Population Positive selection Reproductive fitness Research and Analysis Methods Selection, Genetic Sequence Analysis, RNA Technology assessment
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Title	The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito
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