Wolbachia Genes Responsible for Cytoplasmic Incompatibility – Will Synthetic CI Follow?

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Wolbachia-infected insect cell. Image Credit: Scott O’Neill – Genome Sequence of the Intracellular Bacterium Wolbachia. PLoS Biol 2/3/2004: e76. doi:10.1371/journal.pbio.0

Cytoplasmic incompatibility – a hallmark of some Wolbachia infections – has not only been of great biological interest but also of practical interest. LePage et al (2017) have elucidated the genetic basis for CI in Drosophila and report their results in Nature.

Cytoplasmic incompatibility refers to a form of reproductive manipulation in which embryonic lethality results from matings involving Wolbachia-infected males and non-infected females. The net effect of this manipulation is the rapid increase in the number of infected individuals in a population

Insect biologists have envisioned a number of applications for Wolbachia-induced CI including harnessing it to introgress genes into insect populations and to suppress insect populations by selectively releasing infected males into populations of uninfected insects causing reduced fitness.

The interest in Wolbachia-induced effects on reproduction also led to the fortuitous discovery that some Wolbachia-infected mosquitoes are immune to infection by certain human viral pathogens – the basis for a new strategy to control vector-borne diseases.

http://www.rochester.edu/college/BIO/labs/WerrenLab/WerrenLab-WolbachiaBiology_files/CIFULL.gif

Graphic illustration of Wolbachia-induced Cytoplasmic Incompatibility. Image Credit: from http://www.rochester.edu/college/BIO/labs/WerrenLab/WerrenLab-WolbachiaBiology.html An excellent website created by Jack Werren for all things Wolbachia.

But the genetic and biochemical bases of CI has remained a mystery. Until now.

Using a clever comparative genomics approach LePage et al were able to identify 2 genes in the Wolbachia strain that infects D. melanogaster (wMel) that appear almost certainly to be responsible for CI in this species.

First, the authors compared wMel’s genome to those of four other Wolbachia strains that cause CI and found 161 genes that were shared by all strains.   The authors reasoned that the “CI genes” were likely to be among this set of genes

They then narrowed the list of genes by looking at Wolbachia gene expression in the infected ovaries as well as the proteome of infected ovaries. In addition, they also compared their list of genes to those of a Wolbachia strain that does not cause CI. These multiple comparisons resulted in the identification of only 2 genes of the initial 161 that correlated as expected with the presence and absence of CI.

With candidate genes in hand the authors performed a number of tests of their hypothesis that these two genes were directly responsible for wMel-induced CI in Drosophila.

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This is an example of a Wolbachia-based strategy to suppress mosquito populations based on cytoplasmic incompatibility.  Image Credit: http://mosquitomate.com/

They looked at temporal and spatial expression patterns and these proved to be consistent with CI.

But more convincingly, the authors were able to recreate the CI phenotype by expressing the two candidate genes as transgenes in male gametes and showing embryonic lethality when mated to wild-type females. This CI-like lethality was not observed when transgenic males were mated with wMel-infected females. The cytological defects associated with the CI-like lethality also closely resembled those observed with wMel infections.  This all added up to the two genes LePage et al identified as being responsible for CI.

The two genes, cifA and cifB, were both necessary for inducing CI.

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This is an example of using Wolbachia-induced resistance to control mosquito transmission of Dengue virus. Image Credit: http://www.eliminatedengue.com/program

So what are these genes? Well, surprisingly they are not Wolbachia genes at all but are from a prophage, WO, present in the genomes of CI-inducing Wolbachia. The cif genes remain a mystery with respect to their gene products and functions and these, no doubt, will be clarified shortly.

It will be interesting and potentially important to move cifA and cifB into heterologous species to see if one can create synthetic CI, something that might find a number of uses in controlling insect pests.

 

LePage, DP, Metcalf, JA, Bordenstein, SR, On, J, Perlmutter, JI, Shropshire, JD, Layton, EM, Funkhouser-Jones, LJ, Beckmann, JF, Bordenstein, SR. Prophage WO genes recapitulate and enhance Wolbachia-induced cytoplasmic incompatibility. Nature 2017; 543:243-247. 

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