A male-biased sex-distorter gene drive for the human malaria vector Anopheles gambiae

Abstract Background Population suppression gene drive has been proposed as a strategy for malaria vector control. A CRISPR-Cas9-based transgene homing at the doublesex locus (dsxFCRISPRh) has recently been shown to increase rapidly in frequency in, and suppress, caged laboratory populations of the malaria mosquito vector Anopheles gambiae. Here, problem formulation, an initial step in environmental risk assessment (ERA), was performed for simulated field releases of the dsxFCRISPRh transgene in West Africa. Methods Building on consultative workshops in Africa that previously identified relevant environmental and health protection goals for ERA of gene drive in malaria vector control, 8 potentially harmful effects from these simulated releases were identified. These were stratified into 46 plausible pathways describing the causal chain of events that would be required for potential harms to occur. Risk hypotheses to interrogate critical steps in each pathway, and an analysis plan involving experiments, modelling and literature review to test each of those risk hypotheses, were developed. Results Most potential harms involved increased human (n = 13) or animal (n = 13) disease transmission, emphasizing the importance to subsequent stages of ERA of data on vectorial capacity comparing transgenics to non-transgenics. Although some of the pathways (n = 14) were based on known anatomical alterations in dsxFCRISPRh homozygotes, many could also be applicable to field releases of a range of other transgenic strains of mosquito (n = 18). In addition to population suppression of target organisms being an accepted outcome for existing vector control programmes, these investigations also revealed that the efficacy of population suppression caused by the dsxFCRISPRh transgene should itself directly affect most pathways (n = 35). Conclusions Modelling will play an essential role in subsequent stages of ERA by clarifying the dynamics of this relationship between population suppression and reduction in exposure to specific potential harms. This analysis represents a comprehensive identification of plausible pathways to potential harm using problem formulation for a specific gene drive transgene and organism, and a transparent communication tool that could inform future regulatory studies, guide subsequent stages of ERA, and stimulate further, broader engagement on the use of population suppression gene drive to control malaria vectors in West Africa.

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Next-generation gene drive for population modification of the malaria vector mosquito, Anopheles gambiae

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2010214117 ◽

2020 ◽

Vol 117 (37) ◽

pp. 22805-22814 ◽

Cited By ~ 8

Author(s):

Rebeca Carballar-Lejarazú ◽

Christian Ogaugwu ◽

Taylor Tushar ◽

Adam Kelsey ◽

Thai Binh Pham ◽

...

Keyword(s):

Anopheles Gambiae ◽

Malaria Vector ◽

Genetic Load ◽

Target Site ◽

Performance Criteria ◽

Gene Drive ◽

Guide Rna ◽

Vector Mosquito

A Cas9/guide RNA-based gene drive strain, AgNosCd-1, was developed to deliver antiparasite effector molecules to the malaria vector mosquito, Anopheles gambiae. The drive system targets the cardinal gene ortholog producing a red-eye phenotype. Drive can achieve 98 to 100% in both sexes and full introduction was observed in small cage trials within 6 to 10 generations following a single release of gene-drive males. No genetic load resulting from the integrated transgenes impaired drive performance in the trials. Potential drive-resistant target-site alleles arise at a frequency <0.1, and five of the most prevalent polymorphisms in the guide RNA target site in collections of colonized and wild-derived African mosquitoes do not prevent cleavage in vitro by the Cas9/guide RNA complex. Only one predicted off-target site is cleavable in vitro, with negligible deletions observed in vivo. AgNosCd-1 meets key performance criteria of a target product profile and can be a valuable component of a field-ready strain for mosquito population modification to control malaria transmission.

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Cloning and characterization of a serine protease from the human malaria vector, Anopheles gambiae

Insect Molecular Biology ◽

10.1046/j.1365-2583.1997.00193.x ◽

1997 ◽

Vol 6 (4) ◽

pp. 385-395 ◽

Cited By ~ 15

Author(s):

Y. S. Han ◽

C. E. Salazar ◽

S. R. Reese-Stardy ◽

A. Cornel ◽

M. J. Gorman ◽

...

Keyword(s):

Anopheles Gambiae ◽

Serine Protease ◽

Malaria Vector ◽

Human Malaria

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Immune factor Gambif1, a new rel family member from the human malaria vector, Anopheles gambiae.

The EMBO Journal ◽

10.1002/j.1460-2075.1996.tb00846.x ◽

1996 ◽

Vol 15 (17) ◽

pp. 4691-4701 ◽

Cited By ~ 80

Author(s):

C. Barillas-Mury ◽

A. Charlesworth ◽

I. Gross ◽

A. Richman ◽

J. A. Hoffmann ◽

...

Keyword(s):

Anopheles Gambiae ◽

Family Member ◽

Malaria Vector ◽

Human Malaria ◽

Immune Factor

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Insights into the epigenomic landscape of the human malaria vector Anopheles gambiae

Frontiers in Genetics ◽

10.3389/fgene.2014.00277 ◽

2014 ◽

Vol 5 ◽

Cited By ~ 2

Author(s):

Elena GÃ³mez-DÃaz ◽

Ana Rivero ◽

Fabrice Chandre ◽

Victor G. Corces

Keyword(s):

Anopheles Gambiae ◽

Malaria Vector ◽

Human Malaria

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An Integrated Genetic Map of the African Human Malaria Vector Mosquito, Anopheles gambiae

Genetics ◽

10.1093/genetics/143.2.941 ◽

1996 ◽

Vol 143 (2) ◽

pp. 941-952 ◽

Cited By ~ 5

Author(s):

Liangbiao Zheng ◽

Mark Q Benedict ◽

Anton J Cornel ◽

Frank H Collins ◽

Fotis C Kafatos

Keyword(s):

Microsatellite Markers ◽

Anopheles Gambiae ◽

Genetic Map ◽

Malaria Vector ◽

Average Distance ◽

Polytene Chromosomes ◽

Human Malaria ◽

The Third ◽

Vector Mosquito ◽

Mosquito Anopheles Gambiae

Abstract We present a genetic map based on microsatellite polymorphisms for the African human malaria vector, Anopheles gambiae. Polymorphisms in laboratory strains were detected for 89% of the tested microsatellite markers. Genotyping was performed for individual mosquitoes from 13 backcross families that included 679 progeny. Three linkage groups were identified, corresponding to the three chromosomes. We added 22 new markers to the existing X chromosome map, for a total of 46 microsatellite markers spanning a distance of 48.9 cM. The second chromosome has 57 and the third 28 microsatellite markers spanning a distance of 72.4 and 93.7 cM, respectively. The overall average distance between markers is 1.6 cM (or 1.1, 1.2, and 3.2 cM for the X, second, and third chromosomes, respectively). In addition to the 131 microsatellite markers, the current map also includes a biochemical selectable marker, Dieldrin resistance (Dl), on the second chromosome and five visible markers, pink-eye (p) and white (w) on the X, collarless (c) and lunate (lu) on the second, and red-eye (r) on the third. The cytogenetic locations on the nurse cell polytene chromosomes have been determined for 47 markers, making this map an integrated tool for cytogenetic, genetic, and molecular analysis.

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