Mosquito Sex Ratio Distortion

First sex ratio disruption is an important general topic in population biology. An allele which causes

I note that I have been (ignorantly) discussing this topic for more than 10 years

“A disrupted sex ratio can, in principle, drive a species extinct. Consider an abnormal genome which causes a male to produce only male sperm. This could, in principle spread through a population causing a shortage of females and reduced fitness. The key point is that males are healthy (well some are) but that the number of females typically limits total reproduction.”

Here the point is that the allele causes males to have more male offspring so the fraction of males with the allele increases. This can be true even if the allele causes fewer members of the species — see “The Selfish Gene”.

One question is why doesn’t this eliminate species (another is has this eliminated species — would we know). The reason is as follows (this is due to R A Fisher who was both a top population biologist/evolutionary biologist — the main founder of conventional adaptationist evolutionary biology and the main founder of conventional (frequentist that is non Bayesian) statistics). If there are more males than females then the average female has more offspring than the average male (exact same numerator different denominators) so something which causes more female descendents is selected. So the sex ratio goes to 1:1. This is true even though the species would produce more total offspring with if there were more females than males.

How does this selection stop the male plague which can (in theory) cause extinction ? In practice, known sex ratio disruptors (citations very needed but no links here) work by destroying female chromasomes (for us it would be the X chromasome — I am going to be sloppy and call it the X chromasome from now on even though there are different letters used for different species) in spermatocytes (the diploid cells which will become spermatazoa through meiosis). This just requires a gene activated only in spermatocytes which cuts the female chromasome (that is cuts DNA with a sequence found only on the female chromasome). Such genes exist in nature and have been artificially created for Anopheles gambiae the number one malaria vector (they are mentioned a bit disrespectfully in this article about a different approach to using genetic engineering of mosquitoes to eliminate malaria).

Now consider a female which has an X chromasome without that sequence. If the male plague has spread, it is likely that the male which mates with her will have only male spermatazoa so she will have no daughters. However, the x chromasome cutter will not cut the x chromasomes in her sons, so she will have grand-daughters. They will reproduce a lot compared to males, because so many males are competing to impregnate the few remaining females. So the new X chromasome is selected and the male plague is stopped.

There are two ways to avoid this if we want to eliminate a species. One is to target a sequence that evolves very slowely, because any change massively reduces fitness. This is the sequence of ribosomal RNA which evolves very very slowly and is useful for determining how many hundreds of millions of years have passed since two species had a common ancestor. The reason is that ribosomeal RNA includes areas where it sticks to itself creating a secondary structure. For a new mutant ribosome to work, both of the sequences which stick together have to change so they still stick together. Such mutations don’t occure often — almost certainly not in a mere million years. If the X chromasome contains the ribosomal RNA gene and the sex ratio disruptor cuts a suquence which must stick to another sequence, then the X prottecting mutation might not occur before the species is extinct. In fact in Anopheles gambiae the ribosomal RNA genes are on the X chromasomes, so it is possible to discrut sex ratios targetting a gene which necessarily evolves very slowly.

There is another approach to preventing the escape from the male plague by selection of mutant X chromasomes. There are alleles which specifically cause female infertility. It is possible to make a gene drive system such that the allele ends up on both of a pair of chromasomes and is transmitted to all offspring. Gene drive is explained in the first article to which I link. basically it has to do with cutting a specific DNA sequence again. If the sequence is on an autosome (a not sex chromasome of which there are two copies) the break is repaired by splicing in the sequence from the sister chromasome. If the gene we want to spread is inserted in that sequence, then it spreads (sortof like a benign virus). So say there is sequence ABC on wild time chromasomes. If we make one chromasome with AD(cutB)C then it will cut B and then the repair will consist of a new copy of AD(cutB)C. The sequence D will spread to the whole population.

If the sequence D makes females sterile, the spread of the (only male offspring) allele will not be affected by the spread of AD(cutB)C. However, a mutation which creates X chromasomes which are invulnerable to the only male offspring DNA cutter will not be selected. The mutant female will have grandaughters – sterile grandaughters.

An end to the male plague requires a mutation of the X chromasome specific target sequence *and* of the sequence B. B can be any sequence on any autosome. It is possiblt to make genedrivers with A1B1C1 and A2B2C2 for any sequence and to introduce them for dozens of sequences.

I think this dooms a species which would be nice if it were Anopheles (any species) or Aedes aegypti (for which naturally occuring sex disruptors are known (no link)).

This was supposed ot be an introduction to a criticism of “The Gamble: Can Genetically Modified Mosquitoes end Disease” That article largely discusses using gene drive to make Anopheles mosquitoes resistant to malaria so they don’t transmit it (a kinder gentler genetic engineering strategy aimed only at extinction of protazoans not insects). I support this too (I so do all of them right now everywhere).

A critique of sex ratio disruption (which is valid for current disruptors) is

The University of California approach carries less risk, and less of the appearance of meddling with nature, said Arlindo Carvalho, a former health minister of São Tomé and Príncipe who now advises various malaria-control projects including this one.

“Not eradicating, but modifying — this is the most secure and sustainable path.” The modification approach can also work on multiple diseases and species. And it doesn’t require the repeated release of massive numbers of mosquitoes, or the infrastructure to breed and rear them.”

first I ask what risk ? I have read no story about how releasing artificially engineered sex disruptors could cause any harm of any kind. The logic is the precautionary principle which says that if we do not know something is safe, we should not do it (and we can’t *know* till we try so we should never do something very new). The assertion is that it is safe to allow 600,000 deaths a year than take a risk of some not even hypothetical disadvantage from doing something new. Not even hypothetical because no one has explained how there could be bad effects even hypothetically – there is also, for example, not even a unified field hypothesis which could be tested – the set of hypotheses created by humans is not limitless and does not (as far as I know) contain a hypothetical disadvantage of attempting sex ratio disruption of Anopheles gambiae.

The alleged point of this post (finally( is the “require the repeated release of massive numbers of mosquitoes”. That repeated release is required if the sex ratio disruptor is inserted on an autosome. It is not required if it is inserted on the Y chromasome. In that case, starting from few modified males one can naturally go to all modified males — because males with only sons have more sons. This has not even been proposed (or developed in the lab) because it is a more powerful approach and therefor scarier. The proposed (not approved) sex ratio disruptor is designed not to be selected. The required “repeated release of massive numbers of mosquitoes” is a feature not a bug (a feature because of fear of not even hypothetical risks).

Another way to eliminate a species without repeated massive release is to combine gene drive and sex ratio distruction. This is having the sex ratio disruptor sequence D in AD(cut B)C so it is A(cut x chromasomes only in spermatocytes)(cutB)C. This will spread and eliminate females therefore eliminating the species.

finally I go baroque and discuss a weird idea (if anyone has read this far, this might be a good place to stop). A problem with the sex ratio disruptor I described above is that, if there are two populations which are not quite isolated (as in one individual goes from one to the other every 10 generations) then the disruptor could eliminate one population before infecting the other. This does mean repeated release might be required.

This morning I thought of a silly idea. The disruption involves two molecules CRISPR and Cas. one is an RNA molecule which sticks to the target DNA sequence and also to CAS which is an enzyme which cuts the DNA. Neither does much along. So I have the idea of releasing two different modified mosquitoes (far from each other). One makes CAS and an RNA which targets an autosome (non sex chromasome which has a sister chromasome). It does this in spermatozoa precursors (some kind of tubulin something promoter). SO it spread and makes CAS in spermatozoa precursors.

The other has CAS with a promoter active in larvae, It is A CAS sequence1 C and spreads to replace ABC on an autosome. sequence one is the X targeting RNA with a promoter active only in Spermatazoa precursurs.

Each alone does nothing noticeable, but when they meet and hybridize, then you get sex ratio distortion males which have only sons.

This means that with dozens of (widely separated) releases, you will get new sex ratio disruptors and many different places (and different times).

This is crazy but it is another way to avoid the need to release massive numbers of mosquitoes.