Medusa: Harnessing a Sex-Linked Transgenic Drive System to Control Insect Populations

Josie Reinhardt, Ph.D., Department of Biology, University of Maryland College Park

Josie Reinhardt, Ph.D., Department of Biology, University of Maryland College Park

Segregation distorters (also known as drive genes) are selfish genetic elements with a natural fitness advantage – they are passed to greater than fifty percent of offspring in the next generation, breaking Mendel’s first law of inheritance.

In nature, drive genes may fix in populations, or be maintained through frequency dependent selection if they have a fitness cost or are suppressed by other genes.  If on a sex chromosome, spread of a drive gene could lead to local population extinction as the sex associated with the non-driving chromosome becomes rare.

Medusa of Greek Mythology

Medusa of Greek Mythology

In recent decades there has been interest in using drive genes in natural populations – particularly mosquitoes – as population control measures. Their natural fitness advantage, however, leads to a problem.

If unchecked, a drive gene could feasibly spread outside a target population, leading to unintended ecological consequences.  As a result, there is interest in creating transgenic drive systems containing a “check” so that impacts are kept local.

ToxicIn a recent paper, John Marshall and Bruce Hay (Marshall and Hay, 2014) propose the use of a synthetic two locus sex-linked drive system they call Medusa for control of Anopheles mosquitoes. Each sex chromosome carries a cassette expressing a toxin and an antidote to the toxin on the other chromosome.  On the X is a 2-gene transgene with a maternal toxin gene (MT1) and a zygotic antidote gene (ZA2).  On the Y is a 2-gene transgene consisting of a zygotic toxin gene (ZT2) and a zygotic antidote gene (ZA1).

ANTIDOTEHence, only males inheriting both transgenic chromosome are viable. Because the X toxin is expressed and deposited into eggs (maternal), female X carriers are viable, but will only produce offspring with males carrying the Y antidote/toxin, and all their surviving offspring will be male.

Thus, like natural sex-chromosome drive systems, Medusa can in principle cause a population crash by skewing the sex ratio. Sex linkage prevents recombination from creating resistant individuals and allows all-male releases to introduce the gene into populations, which is advantageous as male mosquitoes do not feed on blood and consequently are not disease vectors.

Figure 1 from Marshall and Hay, 2014.  See paper for details

Figure 1 from Marshall and Hay, 2014. See their paper for details

Using a modeling approach, Marshall and Hay demonstrate that Medusa should spread in target populations but fail to spread into non-target populations.

As the transgene pair spreads, the population will begin to skew towards males. When a threshold frequency is reached the will population crash.

At the same time, invasion of a few carriers of Medusa into a neighboring population should not occur, because the threshold for transgene spreading is fairly high: >42% of males must carry both transgenes, or Medusa will fail to spread because female carriers paired with wild type males produce no offspring.

Figure 2B from Marshall and Hay, 2014.  See their paper for details.

Figure 2B from Marshall and Hay, 2014. See their paper for details.

The introduction of an actual Medusa system into real populations remains to be done, however all of the components have been shown to function in Drosophila.

Marshall and Hay propose to keep the transgenes in a stock carrying both cassettes, with the addition of an antidote to each toxin also present on the same chromosome. However, the antidotes can be removed after tetracycline induction of a FLP recombinase, which will also induce expression of a different selectable marker (e.g. GFP/RFP) for the X and Y transgenic chromosomes. After induction, males expressing both markers will be viable, and can then be released.

This is an interesting and creative use of transgenic insect technologies.

Marshall JM, Hay BA (2014) Medusa: A Novel Gene Drive System for Confined Suppression of Insect Populations. PLoS ONE 9(7): e102694. doi:10.1371/journal.pone.0102694

Recent Related Posts in Technology Topics:

Transgenic Underdominance: Pushing Transgenes into Populations

The Road Ahead for Using Gene Drive Systems

Synthetic Selfish DNA as Genetic Technologies

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