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Review
. 2016 Mar;32(3):219-229.
doi: 10.1016/j.pt.2015.12.003. Epub 2016 Feb 17.

Control of Mosquito-Borne Infectious Diseases: Sex and Gene Drive

Zach N Adelman  1 , Zhijian Tu  2
Affiliations
Review

Control of Mosquito-Borne Infectious Diseases: Sex and Gene Drive

Zach N Adelman et al. Trends Parasitol. 2016 Mar.

Abstract

Sterile male releases have successfully reduced local populations of the dengue vector, Aedes aegypti, but challenges remain in scale and in separating sexes before release. The recent discovery of the first mosquito male determining factor (M factor) will facilitate our understanding of the genetic programs that initiate sexual development in mosquitoes. Manipulation of the M factor and possible intermediary factors may result in female-to-male conversion or female killing, enabling efficient sex separation and effective reduction of target mosquito populations. Given recent breakthroughs in the development of CRISPR-Cas9 reagents as a source of gene drive, more advanced technologies at driving maleness, the ultimate disease refractory phenotype, become possible and may represent efficient and self-limiting methods to control mosquito populations.

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Figures

Figure 1
Figure 1. Sex determination pathways
(A) Drosophila melanogaster. (B) Aedes aegypti. (C) Consequences of homing of a maleness gene in Ae. aegypti. The cascade of events leading to sex-specific splicing of doublesex (dsx), one of the two key transcription factors that program sexual differentiation, is shown. Sex-specific splicing of fruitless (fru), the other key transcription factor, is not shown. Ovals indicate protein products and green question marks represent possible unknown gene products. Black questions marks indicate possible interactions. Boxes represent dsx exons and the numbers indicate their order. The inhibition and activation arrows pointing to exon-intron junctions indicate the inhibition of a strong or promotion of weak splice site, respectively. SXLE, early sex-lethal protein that is expressed from the early embryonic sxl promoter; SXLL, late sex-lethal protein; TRA and TRA2 form a complex that regulate the splicing of dsx and fru. Transformer (TRA) confers sex-specificity when in complex with Transformer 2 (TRA/TRA2). Homing refers to the general process where a gene is duplicated onto its homologous chromosome, for instance driven by a homing endonuclease or CRISPR/Cas9.
Figure 2
Figure 2. Gene drive systems based on homology-dependent repair
(A) Transposable element (TE) mobilization leaves behind an open double-stranded DNA break. (B) Site-specific integration of a homing endonuclease (HEG) or Cas9/sgRNA into its own target site can be followed by cutting of the homologous chromosome. (C) Fixation of germline-expressed active Cas9 can result in the drive of any subsequent guide RNA if placed at its target site. In all cases, if DNA break induction occurs while the sister chromatid or homologous chromosome is present (mitotic divisions of germline stem cells or during meiosis), homology-dependent repair can regenerate the TE, HEG or Cas9 system resulting in a net increase in copy number.
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