Development of a confinable gene drive system in the human disease vector  Aedes aegypti

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Abstract

Aedes aegypti is the principal mosquito vector for many arboviruses that increasingly infect millions of people every year. With an escalating burden of infections and the relative failure of traditional control methods, the development of innovative control measures has become of paramount importance. The use of gene drives has sparked significant enthusiasm for genetic control of mosquitoes; however, no such system has been developed in Ae. aegypti. To fill this void, here we develop several CRISPR-based split gene drives for use in this vector. With cleavage rates up to 100% and transmission rates as high as 94%, mathematical models predict that these systems could spread anti-pathogen effector genes into wild populations in a safe, confinable and reversible manner appropriate for field trials and effective for controlling disease. These findings could expedite the development of effector-linked gene drives that could safely control wild populations of Ae. aegypti to combat local pathogen transmission.

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The global distribution and burden of dengue

Samir Bhatt, Peter W. Gething, Oliver J Brady … (2013)

Dengue is a systemic viral infection transmitted between humans by Aedes mosquitoes 1 . For some patients dengue is a life-threatening illness 2 . There are currently no licensed vaccines or specific therapeutics, and substantial vector control efforts have not stopped its rapid emergence and global spread 3 . The contemporary worldwide distribution of the risk of dengue virus infection 4 and its public health burden are poorly known 2,5 . Here we undertake an exhaustive assembly of known records of dengue occurrence worldwide, and use a formal modelling framework to map the global distribution of dengue risk. We then pair the resulting risk map with detailed longitudinal information from dengue cohort studies and population surfaces to infer the public health burden of dengue in 2010. We predict dengue to be ubiquitous throughout the tropics, with local spatial variations in risk influenced strongly by rainfall, temperature and the degree of urbanisation. Using cartographic approaches, we estimate there to be 390 million (95 percent credible interval 284-528) dengue infections per year, of which 96 million (67-136) manifest apparently (any level of clinical or sub-clinical severity). This infection total is more than three times the dengue burden estimate of the World Health Organization 2 . Stratification of our estimates by country allows comparison with national dengue reporting, after taking into account the probability of an apparent infection being formally reported. The most notable differences are discussed. These new risk maps and infection estimates provide novel insights into the global, regional and national public health burden imposed by dengue. We anticipate that they will provide a starting point for a wider discussion about the global impact of this disease and will help guide improvements in disease control strategies using vaccine, drug and vector control methods and in their economic evaluation. [285]

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De novo assembly of the Aedes aegypti genome using Hi-C yields chromosome-length scaffolds.

Olga Dudchenko, Sanjit Batra, Arina Omer … (2017)

The Zika outbreak, spread by the Aedes aegypti mosquito, highlights the need to create high-quality assemblies of large genomes in a rapid and cost-effective way. Here we combine Hi-C data with existing draft assemblies to generate chromosome-length scaffolds. We validate this method by assembling a human genome, de novo, from short reads alone (67× coverage). We then combine our method with draft sequences to create genome assemblies of the mosquito disease vectors Aeaegypti and Culex quinquefasciatus, each consisting of three scaffolds corresponding to the three chromosomes in each species. These assemblies indicate that almost all genomic rearrangements among these species occur within, rather than between, chromosome arms. The genome assembly procedure we describe is fast, inexpensive, and accurate, and can be applied to many species.

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Highly improved gene targeting by germline-specific Cas9 expression in Drosophila.

Shu Kondo, Ryu Ueda (2013)

We report a simple yet extremely efficient platform for systematic gene targeting by the RNA-guided endonuclease Cas9 in Drosophila. The system comprises two transgenic strains: one expressing Cas9 protein from the germline-specific nanos promoter and the other ubiquitously expressing a custom guide RNA (gRNA) that targets a unique site in the genome. The two strains are crossed to form an active Cas9-gRNA complex specifically in germ cells, which cleaves and mutates the target site. We demonstrate rapid generation of mutants in seven neuropeptide and two microRNA genes in which no mutants have been described. Founder animals stably expressing Cas9-gRNA transmitted germline mutations to an average of 60% of their progeny, a dramatic improvement in efficiency over the previous methods based on transient Cas9 expression. Simultaneous cleavage of two sites by co-expression of two gRNAs efficiently induced internal deletion with frequencies of 4.3-23%. Our method is readily scalable to high-throughput gene targeting, thereby accelerating comprehensive functional annotation of the Drosophila genome.

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Author and article information

Contributors

Omar S Akbari:

ORCID: https://orcid.org/0000-0002-6853-9884

Aleksandra M Walczak: Role: Senior Editor

Hugo J Bellen: Role: Reviewing Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 21 January 2020

Publication date Collection: 2020

Volume: 9

Electronic Location Identifier: e51701

Affiliations

[1 ]deptSection of Cell and Developmental Biology University of California, San Diego San DiegoUnited States

[2 ]deptDepartment of Biophysics University of California, Berkeley BerkeleyUnited States

[3 ]deptDivision of Epidemiology and Biostatistics, School of Public Health University of California, Berkeley BerkeleyUnited States

[4 ]deptVector Genetics Laboratory, Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine University of California, Davis DavisUnited States

[5 ]Innovative Genomics Institute BerkeleyUnited States

[6 ]deptTata Institute for Genetics and Society University of California, San Diego La JollaUnited States

École Normale Supérieure France

Baylor College of Medicine United States

Author information

Ming Li https://orcid.org/0000-0002-7578-4968

Ting Yang https://orcid.org/0000-0001-7201-4231

Robyn Raban https://orcid.org/0000-0002-5648-6770

Hanno Schmidt http://orcid.org/0000-0001-8915-891X

John M Marshall https://orcid.org/0000-0003-0603-7341

Omar S Akbari https://orcid.org/0000-0002-6853-9884

Article

Publisher ID: 51701

DOI: 10.7554/eLife.51701

PMC ID: 6974361

PubMed ID: 31960794

SO-VID: abd2299e-d1e4-4b10-b497-08ca3f14e57f

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 06 September 2019

Date accepted : 03 January 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000185, Defense Advanced Research Projects Agency;

Award ID: HR0011-17-2- 0047

Award Recipient : Omar S Akbari

Funded by: FundRef http://dx.doi.org/10.13039/100000030, Centers for Disease Control and Prevention;

Award ID: 1U01CK000516

Award Recipient : Gregory C Lanzaro

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Custom metadata

Author impact statement Highly efficient and confinable split gene drives are a new tool for the control of the dengue mosquito vector.

ScienceOpen disciplines: Life sciences

Keywords: aedes aegypti,crispr,split gene drives,cas9,dengue,other

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: aedes aegypti, crispr, split gene drives, cas9, dengue, other

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Development of a confinable gene drive system in the human disease vector Aedes aegypti

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Abstract

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CRISPR/Cas9 editing in human blood

Most cited references 99

The global distribution and burden of dengue

De novo assembly of the Aedes aegypti genome using Hi-C yields chromosome-length scaffolds.

Highly improved gene targeting by germline-specific Cas9 expression in Drosophila.

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Cited by 83

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