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Gene drives and the introgression of background genes into wild populations – Part II

In the first post of this series, I presented a brief overview of the paper called “Transgenic Aedes aegypti mosquitoes transfer genes into a natural population”, which focuses on Oxitec’s recent field trial with (non-gene-drive) transgenic mosquitoes in Brazil. As I mentioned, the paper speculates on the potential impact of gene flow – not of the transgene, but of the rest of the genetic makeup of the released mosquitoes. In this second of two posts, I will focus on the following question “what is the impact of introgressing background genetic information from a release strain into a local population”?

Almost all genetic control systems will do this, unless the released mosquitoes are truly, absolutely, completely incapable of forming fertile hybrids with the local target population. Note that this has little to do with transgenes, and applies equally to classical radiation-based SIT, Wolbachia-based gene drives, etc.

In general, such gene flow is likely to have very little impact. There are a few obvious potential exceptions, such as introgressing genes (alleles) conferring enhanced insecticide resistance or ability to transmit relevant pathogens. Clearly this would be undesirable, and regulators – and Oxitec and presumably also other developers – are well aware of this.

1. Insecticide resistance: In practice, standard laboratory strains are typically more susceptible to insecticides than local wild strains, since they were collected from the field many years ago and have been maintained without selection for resistance for tens or hundreds of generations. This should be tested for actual release strains. Interestingly, this has been a problem for Aedes aegypti-wMel, the only mosquito gene drive system so far used in the field. In Brazil, the Wolbachia-based gene drive failed to establish; this was attributed to use of a pyrethroid-susceptible gene drive strain. A derivative strain with much higher pyrethroid resistance was developed and released to establish the gene drive. This may be a consideration for future gene drives, though different designs will differ in their sensitivity to this issue.

2. Vector competence (ability to transmit pathogens): Target populations are typically highly competent vectors – that’s why they are target populations – and it is unlikely that lab strains are significantly better vectors, though this should be tested for key pathogens.

3. General fitness: The authors of the paper speculate that any mixing of (non-transgene) genomes would “very likely” result in a more robust population “due to hybrid vigour”. This is highly conjectural and likely untrue. Laboratory strains of mosquitoes – and for that matter mice, fruit flies, and other laboratory organisms – have been reared in captivity for tens or hundreds of generations. They are highly adapted to their laboratory environments – and correspondingly maladapted to the field environment, even from where they were first caught, let alone somewhere else. Indeed, one of the major problems with mass-release methods is that the laboratory-reared insects perform rather poorly in the field. Evans et al themselves note elsewhere in their paper that the frequency of OX513A-derived sequences declined over time after releases ceased and “that introgressed individuals may be at a selective disadvantage causing their apparent decrease after release ceased” – this is the opposite of their later speculation.

In addition to the potential negative impacts above – which need to be considered, though do not seem likely to be problematic in most cases – there is also the potential for positive impacts from introgressing background genes. If the release strain can be arranged to have more desirable genetic traits than the local target population then such desirable alleles will enter the wild population and that population correspondingly become somewhat more benign.

We analysed this some years ago at the Journal of Economic Entomology and Journal of Theoretical Biology in the context of managing insecticide resistance and found it potentially very effective for slowing or even reversing the spread of insecticide resistance. Of course, the magnitude of the effect depends on the amount of introgression and the fertility or otherwise of hybrids. This will vary considerably depending on the genetic control strain. Sterile-male methods need large, repeated releases, but most hybrids will not reproduce, limiting the degree of introgression. Highly invasive (low-threshold) gene drives can potentially establish from even very low release numbers, but larger releases needed for higher-threshold drives – including Wolbachia-based drives as well as various transgene-based systems – appear to have much higher potential for gene introgression.

If necessary, the degree of introgression could be reduced – but not eliminated – by repeatedly backcrossing the release strain to locally-caught mosquitoes before releases start. This may be advantageous for a different reason, which is to improve the degree of mating between the released mosquitoes and the target population. On the other hand, such more wild-like mosquitoes are likely to be harder to rear, being less lab-adapted, and consequently more expensive to produce.

What is clear is that the fears raised regarding the prospect of gene flow from released mosquitoes to local wild mosquitoes are largely unfounded. Some aspects of potential gene flow should be carefully assessed, to avoid any negative impacts, but in most cases, introgression is broadly neutral and potentially positive.

Written by Luke Alphey, who has been interested in genetic control systems for 25 years. He co-founded Oxitec Ltd in 2002 while at the University of Oxford and was Oxitec’s CSO until 2014 when he returned to public-sector research, at The Pirbright Institute. He no longer has any financial interest in Oxitec. This is the second of two posts examining the implications of recent interventions carried out by Oxitec in Brazil and its potential environmental and health implications. The first post is available here.

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