TY - JOUR T1 - Longitudinal genomic surveillance of <em>Plasmodium falciparum</em> malaria parasites reveals complex genomic architecture of emerging artemisinin resistance in western Thailand JF - bioRxiv DO - 10.1101/084897 SP - 084897 AU - Gustavo C. Cerqueira AU - Ian H. Cheeseman AU - Steve F. Schaffner AU - Shalini Nair AU - Marina McDew-White AU - Aung Pyae Phyo AU - Elizabeth A. Ashley AU - Alexandre Melnikov AU - Peter Rogov AU - Bruce W. Birren AU - François Nosten AU - Timothy J.C. Anderson AU - Daniel E. Neafsey Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/11/02/084897.abstract N2 - Background Artemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance (ART-R) has risen rapidly in in Southeast Asia over the last decade. Mutations in kelch13 have been associated with artemisinin (ART) resistance in this region. To explore the power of longitudinal genomic surveillance to detect signals in kelch13 and other loci that contribute to ART or partner drug resistance, we retrospectively sequenced the genomes of 194 P. falciparum isolates from five sites in Northwest Thailand, bracketing the era in which there was a rapid increase in ART-R in this region (2001–2014).Results We evaluated statistical metrics for temporal change in the frequency of individual SNPs, assuming that SNPs associated with resistance should increase frequency over this period. After Kelch13-C580Y, the strongest temporal change was seen at a SNP in phosphatidylinositol 4-kinase (PI4K), situated in a pathway recently implicated in the ART-R mechanism. However, other loci exhibit temporal signatures nearly as strong, and warrant further investigation for involvement in ART-R evolution. Through genome–wide association analysis we also identified a variant in a kelch-domain–containing gene on chromosome 10 that may epistatically modulate ART-R.Conclusions This analysis demonstrates the potential of a longitudinal genomic surveillance approach to detect resistance-associated loci and improve our mechanistic understanding of how resistance develops. Evidence for additional genomic regions outside of the kelch13 locus associated with ART-R parasites may yield new molecular markers for resistance surveillance and may retard the emergence or spread of ART-R in African parasite populations.ARTartemisininACTartemisinin combination therapySNPsingle nucleotide polymorphismGWASgenome-wide association studyNRAFnon-reference allele frequencyIBDidentical-by-descent ER -