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 only well characterised in few model organisms. In malaria parasites, sexual reproduction coincides with transmission to the vector host. Sex determination is epigenetic, with a single haploid parasite in the human host capable of producing either a male or a female gametocyte. Mechanisms underlying sex specification and maintenance of sexual identity have not been elucidated. Here we show that Md1 is both necessary and sufficient for male fate determination in the human malaria parasite Plasmodium falciparum. We show that Md1 has a dual function: in sex determination from its N-terminus and in male development from its conserved C-terminal LOTUS/OST-HTH domain, which remarkably is also associated with germline development in metazoans. We further identify a bistable genetic switch at the md1 locus which is coupled with the sex determining event and ensures the male determining gene is not expressed in the female lineage. We describe one of only few known non-genetic mechanisms of sex determination in a eukaryote, characterise a new gene expression regulatory switch in Plasmodium and highlight Md1 as a potential target for interventions blocking malaria transmission.