A synthetic homing endonuclease-based gene drive system in the human malaria mosquito

• Published in: Nature (London) 2011-05, Vol.473 (7346), p.212-215
• Main Authors: Windbichler, Nikolai, Menichelli, Miriam, Papathanos, Philippos Aris, Thyme, Summer B., Li, Hui, Ulge, Umut Y., Hovde, Blake T., Baker, David, Monnat, Raymond J., Burt, Austin, Crisanti, Andrea
• Format: Article
• Language: English
• Subjects: 631/1647/1511; 631/61/338/552; 692/699/255/1629; Animals; Animals, Genetically Modified; Anopheles; Anopheles - genetics; Anopheles gambiae; Aquatic insects; Biological and medical sciences; Biotechnology; Chromosomes; Control; Deoxyribonucleases, Type II Site-Specific - genetics; Disease transmission; Environment and pollution; Female; Fundamental and applied biological sciences. Psychology; Genes; Genes, Reporter - genetics; Genetic aspects; Genetic Engineering; Genetically engineered organisms behavior (microorganisms, plants, animals); Genomes; Genotype; Genotype & phenotype; Health aspects; Humanities and Social Sciences; Industrial applications and implications. Economical aspects; Insect Vectors - genetics; letter; Malaria; Male; Males; Mathematical models; Medically important nuisances and vectors, pests of stored products and materials: population survey and control; Molecular Sequence Data; Mosquito Control - methods; Mosquitoes; multidisciplinary; Pest control; Reading; Saccharomyces cerevisiae Proteins - genetics; Science; Science (multidisciplinary); Vector control; Vector-borne diseases; Vectors. Intermediate hosts
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature09937

Manipulating an insect vector Genetic approaches to manipulating or eradicating disease vectors have been proposed as alternatives to malaria eradication. The success of this approach depends on efficient spread of a genetic modification in field populations. Windbichler et al . show that a synthetic genetic element consisting of mosquito regulatory elements and the homing endonuclease gene I-SceI can spread from a small number of individual Anopheles gambiae mosquitoes into large receptive populations in just a few generations. This is the first demonstration of a synthetic gene drive system in the main human malaria vector — and a similar approach should be applicable to many other pest species. Genetic methods of manipulating or eradicating disease vector populations have long been discussed as an attractive alternative to existing control measures because of their potential advantages in terms of effectiveness and species specificity 1 , 2 , 3 . The development of genetically engineered malaria-resistant mosquitoes has shown, as a proof of principle, the possibility of targeting the mosquito’s ability to serve as a disease vector 4 , 5 , 6 , 7 . The translation of these achievements into control measures requires an effective technology to spread a genetic modification from laboratory mosquitoes to field populations 8 . We have suggested previously that homing endonuclease genes (HEGs), a class of simple selfish genetic elements, could be exploited for this purpose 9 . Here we demonstrate that a synthetic genetic element, consisting of mosquito regulatory regions 10 and the homing endonuclease gene I-SceI 11 , 12 , 13 , can substantially increase its transmission to the progeny in transgenic mosquitoes of the human malaria vector Anopheles gambiae . We show that the I-SceI element is able to invade receptive mosquito cage populations rapidly, validating mathematical models for the transmission dynamics of HEGs. Molecular analyses confirm that expression of I-SceI in the male germline induces high rates of site-specific chromosomal cleavage and gene conversion, which results in the gain of the I-SceI gene, and underlies the observed genetic drive. These findings demonstrate a new mechanism by which genetic control measures can be implemented. Our results also show in principle how sequence-specific genetic drive elements like HEGs could be used to take the step from the genetic engineering of individuals to the genetic engineering of populations.