Transposable elements and xenobiotic resistance

Abstract

Transposable elements or TEs are well known drivers of adaptive change in plants and animals but their role in insecticide resistance remains poorly documented. This review examines the potential role of transposons in resistance and identifies key areas where our understanding remains unclear. Despite well-known model systems such as upregulation of Drosophila Cyp6g1, many putative examples lack functional validation. The potential types of transposon-associated changes that could lead to resistance are reviewed, including changes in up-regulation, message stability, loss of function and alternative splicing. Where potential mechanisms appear absent from the resistance literature examples are drawn from other areas of biology. Finally, ways are suggested in which transgenic expression could be used to validate the biological significance of TE insertion. In the absence of such functional expression studies many examples of the association of TEs and resistance genes therefore remain as correlations.

Keywords: insect; insecticide; resistance; transposable element; transposon.

Figure 1

Known and potential mechanisms whereby TEs might cause insecticide resistance. (A) Transcriptional up-regulation. A TE insertion in the 5’ end of a potential resistance gene may induce transcriptional upregulation and/or a new pattern of expression of a metabolic gene. An example would be the insertion of the Accord LTR into the 5’ end of the Drosophila Cyp6g1 gene. (B) Increased message stability. Insertion of a TE into the 3’ end of the gene increases message stability and leads to the over-expression of a resistance associated gene product. Examples of this type of resistance mechanism have been suggested but not proven (see text for discussion). (C) Removal of repressor. TEs might cause the excision and movement of a gene away from a local repressor element therefore leading to upregulation. No documented examples of this potential resistance mechanism exist to date (this panel is therefore not referenced in the text). (D) Truncated gene product with novel function. TE insertion disrupts the open reading frame of a gene truncating the associated protein which then adopts a novel function, as speculated for the CHKov1 gene (see text).

Figure 2

Allelic series shown by TE insertions into the 5’ end of the cytochrome P450 encoding Drosophila gene Cyp6g1. The six known alleles of Cyp6g1 are diagramed with the wild type allele at top (panel 1). Allele 2 corresponds to the original insertion of the Accord LTR. Allele 3 represents the duplication of the Cyp6g1 locus. Alleles 4-6 represent further TE insertions into the 5’ ends of both copies of Cyp6g1. Note that the TE insertions tend to target the same ‘hot-spot’ and that some are internal to each other (e.g. Beagle insertion into the Accord LTR in allele 4). The levels of insecticide resistance are thought to increase through the allelic series (from top to bottom) whereas fitness costs associated with each new allele would be expected to decrease. Note that these only represent the extant alleles that have been sequenced and that he presence of further undocumented alleles, new alleles, or now extinct alleles, is likely (see text for discussion).

Figure 3

Loss or maintenance of receptor subunits associated with resistance. (A) The insect Voltage Gated Sodium Channel (VGSC) encoded by the knockdown resistance (kdr) gene. An insect heterozygous for kdr resistance, kdrR/kdrS (left hand panel) suffers a TE insertion into the susceptible allele which stops expression of the corresponding susceptible receptor VGSC subunit (right hand panel). The corresponding receptor is therefore changed from one carrying both R and S subunits (left) to one containing only resistant subunits. In this manner an allele that is recessive (kdrR) is uncovered and becomes fully dominant in its newfound hemizygous condition (kdrR/-). (B) Duplication and maintenance of a susceptible insect gamma-amino butyric acid receptor (GABA-R) encoded by the Resistance to dieldrin (Rdl) gene. In an insect heterozygous for resistance (RdlR/RdlS) transposons flank the susceptible copy of the Rdl gene (left panel). The flanking transposons cause duplication of the RdlS gene and subsequent mutation of one copy to RdlR (right panel). The resulting compound genotype (RdlRS/RdlR) therefore always encodes susceptible copies of the RDL GABA receptor, potentially offsetting any biophysical deficits associated with native receptors carrying only drug insensitive subunits (see text for discussion).