Mosquito transmission of the deadly malaria parasite Plasmodium falciparum is mediated by mature sexual forms (gametocytes). Circulating in the vertebrate host, relatively few intraerythrocytic gametocytes are picked up during a bloodmeal to continue sexual development in the mosquito vector. Human-to-vector transmission thus represents an infection bottleneck in the parasite’s life cycle for therapeutic interventions to prevent malaria. Even though recent progress has been made in the identification of genetic factors linked to gametocytogenesis, a plethora of genes essential for sexual-stage development are yet to be unraveled. In this review, we revisit P. falciparum transmission biology by discussing targetable features of gametocytes and provide a perspective on a forward-genetic approach for identification of novel transmission-blocking candidates in the future.

Resistance to antimalarial drugs, and in particular to the artemisinin derivatives and their partner drugs, threatens recent progress toward regional malaria elimination and eventual global malaria eradication. Population-level studies utilizing whole-genome sequencing approaches have facilitated the identification of regions of the parasite genome associated with both clinical and in vitro drug-resistance phenotypes. However, the biological relevance of genes identified in these analyses and the establishment of a causal relationship between genotype and phenotype requires functional characterization. Here we examined data from population genomic and transcriptomic studies in the context of data generated from recent functional studies, using a new population genetic approach designed to identify potential favored mutations within the region of a selective sweep (iSAFE). We identified several genes functioning in pathways now known to be associated with artemisinin resistance that were supported in early population genomic studies, as well as potential new drug targets/pathways for further validation and consideration for treatment of artemisinin-resistant Plasmodium falciparum. In addition, we establish the utility of iSAFE in identifying positively-selected mutations in population genomic studies, potentially accelerating the time to functional validation of candidate genes.