The Impact of Dissociation on Transposon-Mediated Disease Control Strategies
Marshall, John M., Genetics
Vector-borne diseases such as malaria and dengue fever continue to be a major health concern through much of the world. The emergence of chloroquine-resistant strains of malaria and insecticide-resistant mosquitoes emphasize the need for novel methods of disease control. Recently, there has been much interest in the use of transposable elements to drive resistance genes into vector populations as a means of disease control. One concern that must be addressed before a release is performed is the potential loss of linkage between a transposable element and a resistance gene. Transposable elements such as P and hobo have been shown to produce internal deletion derivatives at a significant rate, and there is concern that a similar process could lead to loss of the resistance gene from the drive system following a transgenic release. Additionally, transposable elements such as Himar1 have been shown to transpose significantly more frequently when free of exogenous DNA. Here, we show that any transposon-mediated gene drive strategy must have an exceptionally low rate of dissociation if it is to be effective. Additionally, the resistance gene must confer a large selective advantage to the vector to surmount the effects of a moderate dissociation rate and transpositional handicap.
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THE creation of transgenic mosquitoes that have a fitness advantage when feeding on Plasmodiuminfected blood(Marrelli et al. 2007)has greatly renewed interest in the use of genetically modified vectors as a means of disease control. Resistance genes are unlikely to reach fixation in a wild-vector population on their own, partly because disease prevalence tends to be relatively low in vector populations (Beier et al. 1999) and partly because the selective advantage of a resistance gene diminishes as the disease becomes less prevalent (Boe?te and Koella 2003). Consequently, a series of gene drive systems have been proposed to bias the disease-resistance gene in favor of fixation (Craig 1963; Curtis 1968). One such drive system is a transposable element (TE), which is able to spread through a population by virtue of its ability to replicate within a genome (Charlesworth et al. 1994).
Any successful gene drive strategy requires tight linkage between the drive system and effector gene ( James 2005). A general concern of drive systems is that rare recombination events can lead to loss of linkage between the drive system and effector gene (Curtis 2003; Knols and Scott 2003; Riehle et al. 2003). For TEs, there is an additional concern that internal deletion of DNA sequences within elements can occur during transposition. In the class of transposons being considered for genetic modification, this is thought to occur by an abortive gap-repair mechanism (Rubin and Levy 1997). Following excision or transposition, a doublestranded gap is introduced into the host chromosomal DNA. This gap is sometimes filled by copying information from a homologous chromosome, sister chromatid, or ectopic chromosomal site still containing the TE. If this process is interrupted, then the central portions of the element will not be copied, leading to an internal deletion event (Figure 1).
The rate of internal deletion is largely dependent on the TE and host species being considered. In Drosophila melanogaster, P (Engels 1989) and hobo (Gelbart and Blackman 1989) elements produce deletion derivatives at a significant frequency due to abortive gap repair. The same mechanism is primarily responsible for the formation of nonautonomous Ds elements in maize (Rubin and Levy 1997) and the prevalence of nonautonomous mariner elements in many natural populations (Lohe et al. 2000). Despite this, there are other TEs, such as the Herves element in Anopheles gambiae, that remain in an almost exclusively intact form throughout evolutionary history (Subramanian et al. 2007).
Variability in the rate of internal deletion poses the question: What dissociation rate can be tolerated by an effective disease control strategy? …