A transcriptional switch controls sex determination in Plasmodium falciparum

Sexual reproduction and meiotic sex are deeply rooted in the eukaryotic tree of life, but mechanisms determining sex or mating types are extremely varied and are only well characterized in a few model organisms(1). In malaria parasites, sexual reproduction coincides with transmission to the vector host. Sex determination is non-genetic, with each haploid parasite capable of producing either a male or a female gametocyte in the human host(2). The hierarchy of events and molecular mechanisms that trigger sex determination and maintenance of sexual identity are yet to be elucidated. Here we show that the male development 1 (md1) gene is both necessary and sufficient for male fate determination in the human malaria parasite Plasmodium falciparum. We show that Md1 has a dual function stemming from two separate domains: in sex determination through its N terminus and in male development from its conserved C-terminal LOTUS/OST-HTH domain. We further identify a bistable switch at the md1 locus, which is coupled with sex determination and ensures that the male-determining gene is not expressed in the female lineage. We describe one of only a few known non-genetic mechanisms of sex determination in a eukaryote and highlight Md1 as a potential target for interventions that block malaria transmission.