WE TEND to think of a genome as geared solely towards growing, feeding, and protecting its owner and the owner’s offspring. In actuality the genome is rather like a battleground, the site of both intragenomic and intergenomic warfare. The maternal and paternal genomes in a new zygote compete, with the maternal genome trying to limit resources contributed to the embryo while the paternal genome tries to wrestle away as many resources as possible for its offspring. Genetic parasites can join this war between the sexes with an ulterior motive–to propagate copies of themselves. This can be done through meiotic drive, in which an X chromosome harboring a driving gene prevents the transmission of Y chromosomes in meiosis, or through methods that actually result in the death of offspring that do not inherit the driving gene. Now some researchers are attempting to harness this genomic warfare in order to reduce the spread of malaria.

The tool to be used is a Medea (maternal-effect dominant embryonic arrest) element. This selfish genetic element drives its spread in a population at faster-than-Mendelian rates by killing embryos that do not inherit the trait. The lucky embryos carrying the element produce rescue activity that saves them. This ensures that every offspring of a mother carrying Medea will be either heterozygous or homozygous for the trait.

Bruce Hay and coworkers’ initial experiment is a proof-of-concept carried out in fruit flies:

To create a Medea-like maternal-effect selfish genetic element in Drosophila, we generated a P transposable element vector in which the maternal germline–specific bicoid (bic) promoter drives the expression of a polycistronic transcript encoding twomicroRNAs (miRNAs) designed to silence expression of myd88 (the gene producing the toxin) [Fig. 1B and (16)]. Maternal Myd88 is required for dorsal-ventral pattern formation in early embryo development. Females with germline loss-of-function mutations for myd88 give rise to embryos that lack ventral structures and thus fail to hatch, even when a wild-type (WT) paternal allele is present (17). This vector (known as Medea^myd88) also carries a maternal miRNA–insensitive myd88 transgene expressed under the control of the early embryo–specific bottleneck (bnk) promoter (the gene producing the zygotic antidote) (Fig. 1B). Our analysis focused on flies carrying a single autosomal insertion of this element, Medea^myd88-1.

The authors demonstrate that the synthetic Medea element is able to propagate rapidly through a population. In the initial version of the element there was no survival cost associated with inheritance of this element. However, when the authors addressed the possibility of recombination breaking the association between the toxin and effector genes by inserting the toxin (the suppressing microRNAs) into an intron of the antidote (the embryonic bnk-driven myd88) they found high lethality in offspring, probably caused by poor splicing and thus inefficient rescue. However, enough offspring survived to ensure ultimate fixation of the synthetic Medea element in the population.

The next step would be to create such an element for mosquitoes and insert some of the genes that confer malaria-resistance. Releasing a large number of mosquitoes carrying this element into a population could result in the spread of malarial resistance and eventual elimination of the vulnerable wild-type. The use of species-specific microRNAs should present the spread of the element into other species. This technique could result in the safe reduction of malaria transmission to humans during a time in which drug-resistant malaria is spreading.

Chen, C.; Huang, H.; Ward, C. M.; Su, J. T.; Schaeffer, L. V.; Guo, M.; Hay, B. A. “A synthetic maternal-effect selfish genetic element drives population replacement in Drosophila.” Science 2007, 316, 597.