TY - JOUR T1 - Mapping the malaria parasite drug-able genome using <em>in vitro</em> evolution and chemogenomics JF - bioRxiv DO - 10.1101/139386 SP - 139386 AU - Annie N. Cowell AU - Eva S. Istvan AU - Amanda K. Lukens AU - Maria G. Gomez-Lorenzo AU - Manu Vanaerschot AU - Tomoyo Sakata-Kato AU - Erika L. Flannery AU - Pamela Magistrado AU - Matthew Abraham AU - Gregory LaMonte AU - Roy M. Williams AU - Virginia Franco AU - Maria Linares AU - Ignacio Arriaga AU - Selina Bopp AU - Victoria C. Corey AU - Nina F. Gnädig AU - Olivia Coburn-Flynn AU - Christin Reimer AU - Purva Gupta AU - James M. Murithi AU - Olivia Fuchs AU - Erika Sasaki AU - Sang W. Kim AU - Christine Teng AU - Lawrence T. Wang AU - Paul Willis AU - Dionicio Siegel AU - Olga Tanaseichuk AU - Yang Zhong AU - Yingyao Zhou AU - Sabine Ottilie AU - Francisco-Javier Gamo AU - Marcus C.S. Lee AU - Daniel E. Goldberg AU - David A. Fidock AU - Dyann F. Wirth AU - Elizabeth A. Winzeler Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/05/22/139386.abstract N2 - Chemogenetic characterization through in vitro evolution combined with whole genome analysis is a powerful tool to discover novel antimalarial drug targets and identify drug resistance genes. Our comprehensive genome analysis of 262 Plasmodium falciparum parasites treated with 37 diverse compounds reveals how the parasite evolves to evade the action of small molecule growth inhibitors. This detailed data set revealed 159 gene amplifications and 148 nonsynonymous changes in 83 genes which developed during resistance acquisition. Using a new algorithm, we show that gene amplifications contribute to 1/3 of drug resistance acquisition events. In addition to confirming known multidrug resistance mechanisms, we discovered novel multidrug resistance genes. Furthermore, we identified promising new drug target-inhibitor pairs to advance the malaria elimination campaign, including: thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This deep exploration of the P. falciparum resistome and drug-able genome will guide future drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms of the deadliest malaria parasite.One Sentence Summary Whole genome sequencing reveals how Plasmodium falciparum evolves resistance to diverse compounds and identifies new antimalarial drug targets. ER -