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Figure 2 | Genome Biology

Figure 2

From: Engineering the control of mosquito-borne infectious diseases

Figure 2

Current and future genetic engineering technologies for vector control. (a) First-generation technologies make use of transposable elements to insert genetic cargo randomly into the genome. The transposable element is mobilized by a transposase enzyme produced by another plasmid, which recognizes and cleaves the terminal repeats (TR) of the transposon cassette and mediates insertion of the transposable element into the genome. Insertion is visualized using selectable markers such as the green fluorescent protein (GFP) [19]. (b) Mosquitoes can be engineered to carry anti-pathogenic effector genes that reduce the pathogen load [21]-[31]. In the figure, the effector gene blocks Plasmodium ookinete invasion of the midgut epithelium, preventing oocyst development. (c) Schematic of the RIDL system currently used for suppression of Aedes aegypti populations [16]. In the presence of tetracycline, expression of the tetracycline transactivator (tTA) is repressed. In the absence of tetracycline, tTA binds to the tetracycline-responsive element (tRE) and drives its own expression in a positive feedback loop that leads to the accumulation of toxic levels of tTA. The progeny of released males carrying this transgene are not viable. Other combinations of inducible systems and toxic genes can be used in place of tTA and tRE to achieve population suppression. (d) Second generation technologies include HEGs, ZFNs, TALENs and CRISPR/Cas9 [11]-[13],[32],[33]. These technologies facilitate double-stranded DNA breaks in the genome at desired loci. (e) HEGs, TALENs and ZFNs have been used in Ae. aegypti and Anopheles gambiae to generate null mutants [11]-[13], including eye color mutants [11]. (f) ZFNs have been used to generate site-specific knock-ins of exogenous sequences in Ae. aegypti[34]. The figure illustrates a possible application for knock-in technology, which would enable scientists to fuse protein domains to the end of endogenous genes. These domains include those encoding fluorescent proteins or epitope tags, such as an HA tag (shown). (g) Sex distorter strains make use of an HEG, I-PpoI, to destroy sperm carrying an X chromosome (X-shredder), producing male-only populations. When mated to wild-type females, transgenic males sire only sons, potentially leading to population suppression [35]. (h) Gene drives are genetic elements that are inherited in a non-Mendelian fashion and can spread through populations. Gene drives using HEGs have been successfully developed to drive through laboratory mosquito populations [36], whereas evolutionarily stable drives enabled by CRISPR/Cas9 have been proposed [37].

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