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Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in<jats:italic>Plasmodium falciparum<\/jats:italic>. Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that<jats:italic>P. falciparum<\/jats:italic>utilizes before genetic modification of the cPRS<jats:italic>. P. falciparum<\/jats:italic>first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the<jats:italic>cPRS<\/jats:italic>gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the<jats:italic>cPRS<\/jats:italic>locus accounts for the majority of genetic adaptation to halofuginone in<jats:italic>P. falciparum<\/jats:italic>. We further validate that copy-number variations at the<jats:italic>cPRS<\/jats:italic>locus also contribute to halofuginone resistance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We provide a three-step model for multi-locus evolution of halofuginone drug resistance in<jats:italic>P. falciparum<\/jats:italic>. Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s13059-014-0511-2","type":"journal-article","created":{"date-parts":[[2014,11,14]],"date-time":"2014-11-14T21:32:33Z","timestamp":1416000753000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["A genomic and evolutionary approach reveals non-genetic drug resistance in malaria"],"prefix":"10.1186","volume":"15","author":[{"given":"Jonathan D","family":"Herman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel P","family":"Rice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf","family":"Ribacke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Silterra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy A","family":"Deik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli L","family":"Moss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate M","family":"Broadbent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E","family":"Neafsey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael M","family":"Desai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clary B","family":"Clish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Mazitschek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dyann F","family":"Wirth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,11,14]]},"reference":[{"key":"511_CR1","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/S0140-6736(12)60034-8","volume":"379","author":"CJL Murray","year":"2012","unstructured":"Murray CJL, Rosenfeld LC, Lim SS, Andrews KG, Foreman KJ, Haring D, Fullman N, Naghavi M, Lozano R, Lopez AD: Global malaria mortality between 1980 and 2010: a systematic analysis. 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