Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum
Malaria infection with the human pathogen Plasmodium falciparum results in almost a million deaths each year, mostly in African children. Efforts to eliminate malaria are underway, but the parasite is adept at eluding both the human immune response and antimalarial treatments. Thus, it is important to understand how the parasite becomes resistant to drugs and to develop strategies to overcome resistance mechanisms. Toward this end, we used population genetic strategies to identify genetic loci that contribute to parasite adaptation and to identify candidate genes involved in drug resistance. We examined over 17,000 genetic variants across the parasite genome in over 50 strains in which we also measured responses to many known antimalarial compounds. We found a number of genetic loci showing signs of recent natural selection and a number of loci potentially involved in modulating the parasite's response to drugs. We further demonstrated that one of the novel candidate genes (PF10_0355) modulates resistance to the antimalarial compounds halofantrine, mefloquine, and lumefantrine. Overall, this study confirms that we can use genome-wide approaches to identify clinically relevant genes and demonstrates through functional testing that at least one of these candidate genes is indeed involved in antimalarial drug resistance.