Global-scale population genetic analysis of Plasmodium falciparum identifies country- and region-specific patterns of malaria parasite adaptation

To investigate the global evolution and adaptation of Plasmodium falciparum, we analysed 17,565 isolates collected over three decades from 39 countries. This large-scale genomic study integrates identity-by-descent (IBD) networks, population structure and multi-layered association analyses to explore patterns of selection, transmission and drug resistance. Strong selection signals were observed at known resistance loci (e.g. pfcrt, pfdhps) and in genes linked to immune evasion and drug efflux (e.g. pfABCK1, pfMC-2TM), with signals varying by geography and time. In Southeast Asia, clonal expansion of the pfkelch13-C580Y mutation occurred and multi-layered analysis revealed co-occurrence with mutations in pfarps10, pfrad5, and pfMyoF, supporting a polygenic model of artemisinin resistance. In South America and Horn of Africa, elevated IBD was found in pfKIC7 and pfKIC9, interactors of pfkelch13, suggesting convergent evolution under drug pressure. New data from Brazil and Vietnam enhance resolution of global parasite diversity, highlighting the role of genomic surveillance in malaria control.