RT Journal Article SR Electronic T1 Mapping the malaria parasite drug-able genome using in vitro evolution and chemogenomics JF bioRxiv FD Cold Spring Harbor Laboratory SP 139386 DO 10.1101/139386 A1 Annie N. Cowell A1 Eva S. Istvan A1 Amanda K. Lukens A1 Maria G. Gomez-Lorenzo A1 Manu Vanaerschot A1 Tomoyo Sakata-Kato A1 Erika L. Flannery A1 Pamela Magistrado A1 Matthew Abraham A1 Gregory LaMonte A1 Roy M. Williams A1 Virginia Franco A1 Maria Linares A1 Ignacio Arriaga A1 Selina Bopp A1 Victoria C. Corey A1 Nina F. Gnädig A1 Olivia Coburn-Flynn A1 Christin Reimer A1 Purva Gupta A1 James M. Murithi A1 Olivia Fuchs A1 Erika Sasaki A1 Sang W. Kim A1 Christine Teng A1 Lawrence T. Wang A1 Paul Willis A1 Dionicio Siegel A1 Olga Tanaseichuk A1 Yang Zhong A1 Yingyao Zhou A1 Sabine Ottilie A1 Francisco-Javier Gamo A1 Marcus C.S. Lee A1 Daniel E. Goldberg A1 David A. Fidock A1 Dyann F. Wirth A1 Elizabeth A. Winzeler YR 2017 UL http://biorxiv.org/content/early/2017/05/22/139386.abstract AB 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.