{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:32:52Z","timestamp":1791235972590,"version":"4.1.0"},"reference-count":25,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2013,4,24]],"date-time":"2013-04-24T00:00:00Z","timestamp":1366761600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Microbiology"],"published-print":{"date-parts":[[2013,5]]},"abstract":"Summary<\/jats:title>Resistance to antimalarials targeting the folate pathway is widespread. GTP<\/jats:styled-content>\u2010cyclohydrolase (gch1<\/jats:italic>), the first enzyme in this pathway, exhibits extensive copy number variation (CN<\/jats:styled-content>) in parasite isolates from areas with a history of longstanding antifolate use. Increased CN<\/jats:styled-content> of gch1<\/jats:italic> is associated with a greater number of point mutations in enzymes targeted by the antifolates, pyrimethamine and sulphadoxine. While these observations suggest that increases in gch1<\/jats:italic> CN<\/jats:styled-content> are an adaptation to drug pressure, changes in CN<\/jats:styled-content> have not been experimentally demonstrated to directly alter drug susceptibility. To determine if changes in gch1<\/jats:italic> expression alone modify pyrimethamine sensitivity, we manipulated gch1<\/jats:italic> CN<\/jats:styled-content> in several parasite lines to test the effect on drug sensitivity. We report that increases in gch1<\/jats:italic> CN<\/jats:styled-content> alter pyrimethamine resistance in most parasites lines. However we find evidence of a detrimental effect of very high levels of gch1<\/jats:italic> overexpression in parasite lines with high endogenous levels of gch1<\/jats:italic> expression, revealing the importance of maintaining balance in the folate pathway and implicating changes in gch1<\/jats:italic> expression in preserving proper metabolic flux. This work expands our understanding of parasite adaptation to drug pressure and provides a possible mechanism for how specific mutations become fixed within parasite populations.<\/jats:p>","DOI":"10.1111\/mmi.12162","type":"journal-article","created":{"date-parts":[[2013,1,25]],"date-time":"2013-01-25T11:09:29Z","timestamp":1359112169000},"page":"702-712","source":"Crossref","is-referenced-by-count":60,"title":["Direct evidence for the adaptive role of copy number variation on antifolate susceptibility in P<\/scp>lasmodium falciparum<\/i>"],"prefix":"10.1111","volume":"88","author":[{"given":"Adina","family":"Heinberg","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology Weill Cornell Medical College New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin","family":"Siu","sequence":"additional","affiliation":[{"name":"Eck Institute for Global Health Department of Biology University of Notre Dame Notre Dame IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaya","family":"Stern","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Weill Cornell Medical College New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Lawrence","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Division of Infectious Diseases Weill Cornell Medical College New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Ferdig","sequence":"additional","affiliation":[{"name":"Eck Institute for Global Health Department of Biology University of Notre Dame Notre Dame IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk W.","family":"Deitsch","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Weill Cornell Medical College New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"Kirkman","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Weill Cornell Medical College New York NY USA"},{"name":"Department of Internal Medicine Division of Infectious Diseases Weill Cornell Medical College New York NY 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