Driving Antipathogenic Effector Genes into Vector Populations

A selfish gene (blue) “spreading” through a mosquito population. Such selfish genetic systems are now more easily created using RNA-guided endonucleases.  Beaghton et al. modeled this type of drive system and its use to introduce anti-parasite effector genes into mosquito populations.

Beaghton and colleagues have reported in Genetics their modeling efforts where they examine drive systems intended to modify standing populations of vectors by introgressing genes that affect vector competency.

Genetic systems for rapidly increasing the frequency of desired alleles or genotypes in populations by biasing the outcomes of meiosis (gene drives) are of increased interest today by vector biologists and others because RNA-guided DNA endonucleases are making it possible to readily create synthetic homing-based drive systems.

A recent scheme showing the consequences of distorting mosquito sex ratios using a “precision” drive system. This drive system will result in local erradication of the target  mosquito population.  Although not the focus of Beaghton et al. (2017) such systems have also been modeled

There are two general approaches to gene drive being considered for controlling pathogen transmission by mosquitoes:  Population modification and the use gene drive systems to reduce or even eliminate vector populations.

Developing these technologies to the point where they might become the basis for an operational vector/malaria transmission control program will require considerable effort in understanding what technical characteristics  the drive systems should have in order to persist long enough in the environment to result in a meaningful change in disease transmission.

Beaghton et al. create two models, each modeling a different strategy for affecting population modification.

The first strategy involves linking the effector gene to the sequence specific endonuclease that is at the heart of the drive system while the second strategy links the effector gene to an endonuclease-resistant target gene and knocking out the native target gene with a target-gene specific endonuclease.

The models consist of a system of 15 equations with some 20 parameters.

RNA-guided endonuclease-based drive systems function like homing endonucleases to ‘drive’ genes into populations

The investigators ran each model while varying one parameter and keeping the other parameters at their baseline value. This enabled the authors to see which parameters within the models are most influential under these simple conditions.

The models yield similar results with notable differences that are worth exploring by carefully reading this paper.

The models were particularly sensitive to three parameters. First, the probability of repair following endonuclease cleavage not resulting in homologous recombination. Second, the fitness costs associated with effector gene expression. Third, the fitness costs of endonuclease expression (Model 1) and the probability that the effector gene will mutate and become ineffective (Model 2).

guide RNA relative to target sequence.  These programmable endonuclease systems are particularly useful for creating homing-like drive systems.

With both models, given enough time, resistance alleles will become frequent after an initial rapid increase in the frequency of the effector gene. In the case of Model 1 this required about 100 generations and for Model 2 this required about 200 generations.

However, during the 100 generations or so the vectorial capacity is significantly reduced. This is a significant amount of time (~15 generations per year in Africa) and this could contribute significantly to an integrated program of malaria transmission reduction, for example.

This is an interesting paper that compares two basic strategies for increasing an effector gene’s frequency in a population. It also further illuminates characteristics of gene drives that might be important when designing systems intended ultimately for release into a target environment – something that is many years down the road.

Andrea Beaghton, Andrew Hammond, Tony Nolan, Andrea Crisanti, H. Charles J. Godfray, Austin Burt (2017) Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing.




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