Novel Synthetic <i>Medea</i> Selfish Genetic Elements Drive Population Replacement in <i>Drosophila</i>; a Theoretical Exploration of <i>Medea</i>-Dependent Population Suppression

Insects act as vectors for diseases of plants, animals, and humans. Replacement of wild insect populations with genetically modified individuals unable to transmit disease provides a potentially self-perpetuating method of disease prevention. Population replacement requires a gene drive mechanism in order to spread linked genes mediating disease refractoriness through wild populations. We previously reported the creation of synthetic <i>Medea</i> selfish genetic elements able to drive population replacement in <i>Drosophila</i>. These elements use microRNA-mediated silencing of myd88, a maternally expressed gene required for embryonic dorso-ventral pattern formation, coupled with early zygotic expression of a rescuing transgene, to bring about gene drive. <i>Medea</i> elements that work through additional mechanisms are needed in order to be able to carry out cycles of population replacement and/or remove existing transgenes from the population, using second-generation elements that spread while driving first-generation elements out of the population. Here we report the synthesis and population genetic behavior of two new synthetic <i>Medea</i> elements that drive population replacement through manipulation of signaling pathways involved in cellular blastoderm formation or Notch signaling, demonstrating that in <i>Drosophila Medea</i> elements can be generated through manipulation of diverse signaling pathways. We also describe the mRNA and small RNA changes in ovaries and early embryos associated from <i>Medea</i>-bearing females. Finally, we use modeling to illustrate how <i>Medea</i> elements carrying genes that result in diapause-dependent female lethality could be used to bring about population suppression