A Systematic Map of Genetic Variation in Plasmodium falciparum

Abstract

Discovering novel genes involved in immune evasion and drug resistance in the human malaria parasite, Plasmodium falciparum, is of critical importance to global health. Such knowledge may assist in the development of new effective vaccines and in the appropriate use of antimalarial drugs. By performing a full-genome scan of allelic variability in 14 field and laboratory strains of P. falciparum, we comprehensively identified ≈500 genes evolving at higher than neutral rates. The majority of the most variable genes have paralogs within the P. falciparum genome and may be subject to a different evolutionary clock than those without. The group of 211 variable genes without paralogs contains most known immunogens and a few drug targets, consistent with the idea that the human immune system and drug use is driving parasite evolution. We also reveal gene-amplification events including one surrounding pfmdr1, the P. falciparum multidrug-resistance gene, and a previously uncharacterized amplification centered around the P. falciparum GTP cyclohydrolase gene, the first enzyme in the folate biosynthesis pathway. Although GTP cyclohydrolase is not the known target of any current drugs, downstream members of the pathway are targeted by several widely used antimalarials. We speculate that an amplification of the GTP cyclohydrolase enzyme in the folate biosynthesis pathway may increase flux through this pathway and facilitate parasite resistance to antifolate drugs. Variability in the genome of the human malaria parasite, Plasmodium falciparum, is key to the parasite's ability to cause disease and overcome therapeutic interventions such as drugs and vaccines. Elucidating the extent of genetic variation in the malaria parasite will therefore be central to decreasing the malaria disease burden. The authors performed a full-genome scan of variability in different strains of P. falciparum and observed a nonrandom distribution of variation. In particular, those genes that are predicted to have roles in evading the host immune response or antimalarial drugs show significantly higher levels of variation. In addition, the authors speculate that a previously unreported genome amplification in the folate biosynthesis pathway correlates with resistance to the antimalarial drug sulfadoxine. Such data enable hypotheses to be made about the function of many of the unknown elements in the parasite's genome, which may permit the identification of new targets that can be investigated for incorporation into a malaria vaccine and may aid in the understanding of how the parasite withstands drug pressure.