Synthetic Interspecies-like Incompatibility

Engineered synthetic species-like barriers were recently described by Maselko et al (2017) in Nature Communications and the work has interesting implications for genetic control strategies and gene drive containment.

This is a well known example of hybrid incompatibility. Maselko et al. describe a specifically different but conceptually similar system.

There is an ever-increasing interest in manipulating natural populations using genetic approaches including the use of Sterile Insect Technology (SIT), SIT-like synthetic conditional lethals, underdominance and gene drive.

Maselko et al have created a synthetic hybrid incompatibility system with the genetic characteristics of interspecific hybrid incompatibility.

In this case, a synthetic dCas9-based transcription factor is used to over- or mis-express a gene that causes lethality. The synthetic transcription factor is inserted into a genome that has been rendered incapable of interacting with the gRNA used to guide the dCas9 transcription factor to the target gene. This is done by mutating the promoter region of the target gene so that it remains fully functional but contains a sequence polymorphism that prevents gRNA/dCas9 binding.

Introduction of the synthetic transcription factor into a wild-type genetic background will result in lethality.

Image result for dCas9

This is an example of a popular dCas9 Transcription factor showing how transcription activator domains are added to dCas9. Maselco et al. used a different but similar synthetic transcription factor. See their paper for details.

The authors demonstrate the feasibility of this system in yeast using actin as the target gene for over/mis-expression.

What is this synthetic incompatibility good for, potentially a number of things.

The synthetic incompatibility system behaves like an underdominance system and might be used to replace populations

Developing strong synthetic gene drive systems in the laboratory has led to some concerns about the effects of their unintentional release. Various forms of physical or environmental containment could go a long way to mitigating risks but where this is less feasible genetic incompatability could be an excellent additional measure.

A laboratory population with a synthetic incompatibility system would be a good host for an experimental gene drive system because if physical containment measures fail, the escaped insects would be unable to hybridize with wild-type insects. This would prevent the unwanted release of experimental gene drives prior to their planned release.

Image result for underdominance imgrs

The hybrid incompatibility system created by Maselko et al. has the genetic characteristics of a strong underdominance system.

Clever ways to enable the conditional removal of the incompatibility genetic cassette would enable deployment of the once experimental gene drive system into a target population.

This is an interesting concept and further shows the seemingly limitless possible uses of RNA-guided DNA endonuclease systems.

Maselko, M., Heinsch, S.C., Chacón, J. M. Harcombe, W. R., Smanski, M. J. (2017) Engineering species-like barriers to sexual reproduction. Nature Communications 8: 883, doi: 10.1038/s41467-017-01007-3

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