Fighting the dengue virus

There is an interesting paper by Alphey, Fu et al in the PNAS describing how genetic engineering could be used to fight the dengue virus

Here are some basic facts:
* Over 50 million people each year are infected by the dengue virus
* Only female mosquitoes bite ( suck blood ) and so they are the ones that can carry the infection to humans.
* There is only one species of mosquito that is responsible for dengue infections, it's called aedes aegypti.
* Fu, Alphey et al seem to have found a way of genetically engineer the males which cause their female offspring to be flightless, but their male offspring will be fine.
* Flightless females can't infect humans with dengue
* Flightless females won't be able to reproduce.

So let's see what would happen if we release some affected males into the wild. They will compete with the unaffected males for mates. There will be a reduction in the number of healthy females in the next generation who will be able to reproduce.
The male offspring of the affected males will be able to carry the genetic modification to the next generation and generations of males after that. At each generation there will be reduction in the number of healthy females.

It sounds like this could lead to the extinction of the (aedes aegypti) mosquito.

Alas, there is a little flaw in the logic...

We can look at this a few different ways:
1: Suppose in nature a genetic mutation can take place in the male of a species such that he'll produce healthy males with the same mutation and females that won't be able to reproduce. With the logic above that would suggest that that could lead to a reduction in healthy females in all future generations with potentially devastating consequences for the species. If just 3% are carriers and then we would have a reduction of approximately 3% in the population in every future generation. Sounds like extinction is on the way.
Well, I posit that such mutations are not uncommon in all species but yet we still have life on the planet. So they must be some flaw...

2: Let's look at it another way. Without going into the mathematics yet, if a creature has a gene which is severely detrimental to the procreation of its offspring. Then having that gene is a significant evolutionary handicap. And so you'd expect natural selection to mercilessly wipe out that gene. It is just survival of the fittest.

3: Let A be the affected gene, which is dominant over the unaffected gene U.

* Males with AA, AU and UU can reproduce
* Females with UU can reproduce
* Females with AA or AU can't

If we release some number of mosquitoes with AA genes into the wild. We'll call them generation 1. They'll mate with the wild UU females and produce AU male and female offspring. There will be no AA males in generation 2. Since to have AA male in generation 2 we'd need a female carrier of A to reproduce, but they can't. Only the pure UU females can reproduce.

The really key thing is that as we go from generation 2 to 3, the AU males will reproduce with the UU females, but only half of their male offspring will carry the A gene and similarly at each subsequent generation, the proportion of males with the A gene will be halved. In a few quick generation the A gene will have died out and we'll be left with a pure UU population of healthy flying male and female mosquitoes.

If you'd like to see a really simple mathematical model showing this in action,
have a look at the following spread-sheet:
* To see the calculation details, click here, requires (free) Google docs account.
* To view the results click here, no Google docs account required.

So what should we do: if we release some AA males into the wild, the effect on the native population will be rather small since the proportion of male carriers is going to halve in each generation subsequent to the second generation. So even if there is an enormous release of the AA males and they far outnumber the unaffacted males (UU), then within a few short generations we will still find that the A gene will be (almost) completely wiped out.
It would seem that a huge release of AA males every second generation would have some effect on the mosquito population, but it is rather impractical.

Bearing in mind that only half of the male offspring of AU males will carry the A gene, for the A gene to thrive into future generations, we would need the AU males to be far superior to the UU males when competing for mates. However if that could be achieved a future problem that we would face is that if there were any (UU) females that had a prefernce for UU males over AU males, then they would have an enormous evolutionary advantage and we would then find that in a few generations they would dominate thus wiping out the A gene once again.

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I got the following response from Luke Alphey:

You are both completely right and completely wrong at the same time!

Yes, the RIDL gene (A gene in your terminology) will be rapidly eliminated from the target population after a single initial introduction of the gene (e.g. in the form of released homozygous males). This puts this strategy, with other sterile-insect methods, in the class of 'self-limiting' genetic control strategies (in contrast to 'self-sustaining' or invasive strategies where the introduced gene has some method of spreading itself through the wild population, typically a selfish-DNA-based gene drive system).

However, the premise of a single release is incorrect. The key to sterile-male (or sterile-insect) methods is to establish a sufficient population of sterile males in the field to ensure that enough wild females mate a sterile male and then maintain this for at least several insect generations while the target population declines. For 'conventional' irradiated insects, it is even more obvious that the sterile insects will have no viable offspring at all, so the effect will only be for (approx) the lifespan of the released steriles. Therefore, periodic release is required, with a frequency less than the lifespan of the sterile males. This is perfectly practical, and there is plenty of precedent from the conventional Sterile Insect Technique, which uses radiation-sterilised insects to control a range of agricultural pests (e.g. New World screwworm and Mediterranean fruit fly).

The fact that the RIDL gene will disappear rapidly from the target population and is maintained only by periodic (effectively constant) release is often considered a desirable 'safety' feature. Though it is very hard to see how this approach could cause any undesirable side-effects, it is nonetheless reassuring to know that simply stopping releases would lead to rapid elimination of the gene from the population. This is in contrast to some other proposed methods using modified mosquitoes, such as refractory insect/gene drive systems or Wolbachia.

I'd be happy to discuss this further, but there are also a few papers you might like to look at.
Open access (some may ask your name, but they are free):
http://jbiol.com/content/8/4/40 short review which discusses self-limiting and self-sustaining methods
http://www.biomedcentral.com/content/pdf/1741-7007-5-11.pdf research article which models different genetic-sterility strategies
http://www.eurekah.com/chapter/3233 Book chapter discussing RIDL and SIT approaches, particularly in the context of mosquitoes

..(there is ) an earlier PNAS paper (2007) which models versions of this approach for dengue control and a review on sterile-male methods for mosquito control (from Vector-borne and Zoonotic Diseases, epub ahead of print).