Mosquito eradication with sterility gene - how does it work?

There is now the possibility of eradicating particular mosquito species by releasing genetically engineered mosquito that have a recessive female sterility gene (cite).

Forget the rights and wrongs of it for this thread.
I still can’t get my head around how it would supposedly spread rapidly through a population.

The linked article alludes to the fact that we’d normally expect such a deleterious gene to be wiped out by natural selection, even though it’s recessive. But apparently, no, because <reasons I don’t follow>.

Can someone explain it please, at the level of Alice and Bob mosquito (who are very much in love) and what genes they have and what genes their babies have :slight_smile:

I’m not a geneticist or even particularly good at biology, so take this with a grain of salt: the genetically modified gene is able to replicate more than a normal gene because it contains instructions for modifying the “healthy” version of the gene when it is paired with it.

Because the gene only makes females infertile, but will be carried by males too, it will eventually spread throughout the mosquito population. If it made both sexes infertile, obviously the gene itself would not survive through more than one or two generations.

I imagine that while mosquitoes with two alleles are sterile, variants with one allele have greatly increases fecundity, largely because it causes an army of apes to help them breed and protect their offspring from predators before releasing them into the wild, in hopes that the overall strategy will protect those apes from malaria.

:confused: :dubious:

Anyways, apparently in that mosquito there are three genes that control fertility (at least in females). Female mosquitoes need two defective genes to be sterile, one gene won’t cut it. But there is an addendum machinery (that is supposed to help) that is being used, and it can create another defective copy of the gene. I’m assuming the original idea was to repair a defective copy into a good one, or replicate a good gene, but in this case it has been altered to replicate the bad gene.

This way, the mosquitoes carry only one defective (causing sterility) gene, plus the gene to create the cellular machinery that will make another defective gene from that copy (ideally). I am guessing this second gene is dominant, so that the machinery can be thus created in each generation.

So say if Bob the mosquito has the defective gene and the machinery gene, and meets Alice, Alice not having any alterations… Then say about half of all their offspring will have the defective sterility gene and the “create another sterility copy machinery” gene. These will have no effect of the males, but at least half of his daughters will be sterile. Going on with his grandkids, he will get more grandkids from his sons that from his daughters, and once more, the female grandkids will be affected and many will again become sterile, while the male grandkids will carry the defects on.

Hence, it is reducing the population slowly each generation. Also, I’m not an expert on mosquito sexuality and mating habits, but maybe the sterile female mosquitoes can still attempt to breed, causing potentially fertile males to “waste” energy in breeding with her, also then lowering their own chances of passing their genes to the next group (because no new mosquitoes will come from the sterile female).

I don’t think this is quite right. There are potentially many other genes controlling fertility but they chose three and these were tested separately. Disrupting both copies of any one of the genes is sufficient to cause sterility.

Otherwise, I think KarlGrenze and Really Not All That Bright have the mechanism right. Bob’s sperm carrying the defective version of the gene fertilises one of Alice’s eggs containing the functional version of the gene (gametes having only one version of each gene). Bob’s defective version contains instructions for making an enzyme (Cas9) and a guide to lead it to the normal version of the gene. In the zygote, Bob’s enzyme finds the normal version and cuts it in the middle.

The normal cellular repair mechanisms then repair the cut using the only template available - the defective version on Bob’s DNA. So now the zygote has two defective versions, both carrying the enzyme and guide DNA.

As noted, in male offspring there’s no effect because the genes are involved in follicle development, so males will continue to mate and pass the defective genes on to all of their offspring and so on for following generations.

The original study is here.

Thanks everyone. The article makes more sense to me now, but still overall I’m having trouble grokking this.

So say the ecosystem can support 8 mosquitoes.

And right now we have 2 normal females (NF), 2 normal males (NM), 2 infertile females (IF) and 2 carrier males (CM).

Let’s forget about the IF: it’s true some males may waste time trying to mate with them but knowing how big an effect that would make means knowing about mosquito mating habits.

So of our 2 NF, 1 on average will mate with a NM, 1 will mate with a CM. If they breed enough to have a replacement population, then next generation we have:

NF x NM gives 2 NM, 2 NF on average
NF x CM gives 2 CM, 2 IF on average

…which is exactly what we had in the last generation. What am I missing?

The concept is called “gene drive”. Wikipedia has an explanation of the mechanism that I find relatively easy to grasp.

It’s a very powerful concept. It’s also a bit frightening. It’s a mechanism by which maladaptive genes can actually overcome natural selection. Once released into the wild, it’s difficult or impossible to stop. This might be a good thing for some pests but a knowledgeable small group, or maybe even an individual, could in theory begin the destruction of a species on a whim.

I am not a Luddite. I am not anti-GMO. But this technology troubles me.

Not that we should ban it. You can’t, because it’s knowledge, and once we have knowledge we can’t unlearn it. But if someone wants to abuse it, someone eventually will.

I’m a huge fan of synthetic biology in general and CRISPR/Cas9 in particular. It has the potential to do wonderful things for the world. But add me to the list of people who are frightened by gene drive. The proponents argue that they can program in safeguards and shut things down if it gets out of control. I’m skeptical. Biology is just too unpredictable.

Even if they can successfully program in safeguards, what about those who want to use if for nefarious purposes and don’t bother with or even want safeguards? What about religious fanatics who want to bring on an apocalypse, or radical environmentalists who think that they know better than the experts?

Hopefully someone will come along and explain to us why there’s nothing to worry about and why there’s no reason for concern.

You are assuming that the ecosystem is the only thing limiting the population. Your birth rate is double what it was before to fill up the 8 slots in your ecosystem.

If you assume that the population is stable because the birth rate equals the death rate, then your population will halve with each generation.

NF x NM gives 1 NM, 1 NF on average
NF x CM gives 1 CM, 1 IF on average
IF x NM gives nothing.
IF x CM gives nothing.

If the environment is a partial factor, and the birth/death rate is also a partial factor, then you could end up with something more like this:

NF x NM gives 1.5 NM, 1.5 NF on average
NF x CM gives 1.5 CM, 1.5 IF on average
IF x NM gives nothing.
IF x CM gives nothing.

This is still a 75% survival rate. 8 becomes 6 then 4.5 then 3.375 etc. It’s a slower extinction rate, but it still ends in extinction. After 10 generations you’ve wiped out close to 95% of the population.

What you’re saying here makes sense but I haven’t read this explanation anywhere else. In fact I haven’t been able to find any detailed explanations that would answer Mijin’s question.

The study in question shows increased frequency of the CRISPR allele from 50% to 70-75% over four generations in cage experiments but doesn’t seem to discuss changes in total mosquito numbers.

But that’s typically how it is, especially for insects, no? Many more individuals born than will go on to reproduce.

So, imagining we have no GM mosquitos, the reality would be some thing like:

Start with 4 NF, 4 NM breeding adults
NF x NM = 5 NF, 5 NM offspring per pair = 20 NF, 20 NM total
20% survival rate
= 4 NF, 4 NM breeding adults, population is at equilibrium.

In my prior example the proportion of breeding females is less, but if they still have a large number of offspring, and the environmental pressure is the same, it looks like the proportion of fertile / infertile is not changing :confused:

This is concerning that it is not even mentioned in passage, as that would be a very important phenotype.

But it seems that to keep a stable cage population, since what they were checking was how long the mutations would last “in the wild”, and how much they would spread, they controlled for the amount of mosquitoes, so that it would be the same each generation (probably to help with the statistics they needed). Each generation thus was 600 mosquitoes.

Still, they could’ve said “hey, the number of eggs produced decreased by each generation”.

The closest they did say was that the female mosquito assays revealed that the female mosquitoes with the infertility gene combos either did not lay eggs or laid eggs that didn’t hatch.

Here is my explanation post of how this works:

GM Mosquitoes - what say you?

Also, GM sterile mosquitoes (RIDL) are NOT gene drive.

RIDL aims to suppress the mosquito population below some threshold necessary to maintain pathogen transmission. In principle, its identical to traditional the sterile insect technique where they use radiation to sterilize the males, and very similar in effect to pesticide usage.

Gene drive aims NOT to suppress the population, but rather to replace the mosquitoes that are capable of transmitting pathogens with mosquitoes that are unable to transmit pathogens.

CRISPR/Cas9 is the new flavor of the month to do this, but people have been talking about doing “Population Replacement” strategies for almost 60 years. Its amazing what the old guys were able to do without modern genetic engineering technologies (it was all based on radio-mutagenesis and classical crossing/selective breeding).

One day I’ll have to write a post on it. It was phenomenal work.