The impact of dissociation on transposon-mediated disease control strategies

Abstract

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.

Figure 1.—

Abortive gap-repair mechanism of internal deletion. (A) An intact TE construct consists, at the very least, of a transposase gene (Tr), a disease-resistance gene (R), and a pair of inverted repeats (IR) marking its boundaries. (B) Following transposition or deletion, a double-stranded gap is introduced into the host chromosome DNA. (C) This gap is sometimes filled by copying information from a homologous chromosome, sister chromatid, or ectopic chromosomal site containing the intact construct. (D) If this process is interrupted, then the central portions of the TE will not be copied. In some cases, this produces a dissociated construct not containing the resistance gene.

Figure 2.—

Schematic for the spread of an element construct incorporating dissociation of the resistance gene. An individual having two copies of the intact construct (TER) and two copies of the dissociated construct (TE) can gain a copy of either through transposition and lose a copy of either through deletion. The proportion of individuals having this genotype can also increase or decrease as a result of transposition or deletion. Dissociation is a one-way process leading to a TER becoming a TE. Analogous schematics can be drawn for every other genotype.

Figure 3.—

Element spread with dissociation. The resistance gene has no impact on host fitness or transposition rate. (A–C) Total element copy number reaches an equilibrium of four within 20 years, while the proportion of intact element copies decreases monotonically over time. Lines correspond to numerical solutions of the differential equation model for three different dissociation rates. (D) The prevalence of the disease-resistant vectors reaches a maximum within 10 years and then decreases gradually. The maximum prevalence and duration of presence depend largely on dissociation rate.

Figure 4.—

Maximum prevalence of disease-resistant vectors. The resistance gene influences both transposition rate and host fitness. (A) The replicative transposition rate of an intact element construct is reduced by a fraction, . Increasing the value of decreases the maximum prevalence of resistant vectors and makes dissociation requirements more demanding. (B) The fitness cost conferred by the resistance gene, , has a large impact on its maximum prevalence. (C) Dissociation requirements are considerably relaxed when the resistance gene confers a fitness benefit, . (D) A highly advantageous resistance gene is able to spread irrespective of a daunting dissociation rate or transpositional handicap.