{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:55:15Z","timestamp":1791258915662,"version":"4.1.0"},"reference-count":30,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T00:00:00Z","timestamp":1609372800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"\n Plasmodium falciparum<\/jats:italic>\n parasites resistant to antimalarial treatments have hindered malaria disease control. Sulfadoxine-pyrimethamine (SP) was used globally as a first-line treatment for malaria after wide-spread resistance to chloroquine emerged and, although replaced by artemisinin combinations, is currently used as intermittent preventive treatment of malaria in pregnancy and in young children as part of seasonal malaria chemoprophylaxis in sub-Saharan Africa. The emergence of SP-resistant parasites has been predominantly driven by cumulative build-up of mutations in the dihydrofolate reductase (\n pfdhfr<\/jats:italic>\n ) and dihydropteroate synthetase (\n pfdhps<\/jats:italic>\n ) genes, but additional amplifications in the folate pathway rate-limiting\n pfgch1<\/jats:italic>\n gene and promoter, have recently been described. However, the genetic make-up and prevalence of those amplifications is not fully understood. We analyse the whole genome sequence data of 4,134\n P. falciparum<\/jats:italic>\n isolates across 29 malaria endemic countries, and reveal that the\n pfgch1<\/jats:italic>\n gene and promoter amplifications have at least ten different forms, occurring collectively in 23% and 34% in Southeast Asian and African isolates, respectively. Amplifications are more likely to be present in isolates with a greater accumulation of\n pfdhfr<\/jats:italic>\n and\n pfdhps<\/jats:italic>\n substitutions (median of 1 additional mutations; P<0.00001), and there was evidence that the frequency of\n pfgch1<\/jats:italic>\n variants may be increasing in some African populations, presumably under the pressure of SP for chemoprophylaxis and anti-folate containing antibiotics used for the treatment of bacterial infections. The selection of\n P. falciparum<\/jats:italic>\n with\n pfgch1<\/jats:italic>\n amplifications may enhance the fitness of parasites with\n pfdhfr<\/jats:italic>\n and\n pfdhps<\/jats:italic>\n substitutions, potentially threatening the efficacy of this regimen for prevention of malaria in vulnerable groups. Our work describes new\n pfgch1<\/jats:italic>\n amplifications that can be used to inform the surveillance of SP drug resistance, its prophylactic use, and future experimental work to understand functional mechanisms.\n <\/jats:p>","DOI":"10.1371\/journal.pgen.1009268","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T13:34:08Z","timestamp":1609421648000},"page":"e1009268","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":29,"title":["Genetic diversity of the Plasmodium falciparum GTP-cyclohydrolase 1, dihydrofolate reductase and dihydropteroate synthetase genes reveals new insights into sulfadoxine-pyrimethamine antimalarial drug resistance"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7829-1683","authenticated-orcid":true,"given":"Anna","family":"Turkiewicz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7405-6523","authenticated-orcid":true,"given":"Emilia","family":"Manko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1592-6407","authenticated-orcid":true,"given":"Colin J.","family":"Sutherland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4313-4290","authenticated-orcid":true,"given":"Ernest","family":"Diez Benavente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1403-6138","authenticated-orcid":true,"given":"Susana","family":"Campino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8985-9265","authenticated-orcid":true,"given":"Taane G.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,12,31]]},"reference":[{"issue":"1","key":"pgen.1009268.ref001","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1186\/s12936-016-1634-6","article-title":"Characterizing the impact of sustained sulfadoxine\/pyrimethamine use upon the Plasmodium falciparum population in Malawi","volume":"15","author":"M Ravenhall","year":"2016","journal-title":"Malaria Journal"},{"issue":"1","key":"pgen.1009268.ref002","doi-asserted-by":"crossref","first-page":"8287","DOI":"10.1038\/s41598-019-44599-0","article-title":"An analysis of large structural variation in global Plasmodium falciparum isolates identifies a novel duplication of the chloroquine resistance associated gene","volume":"9","author":"M Ravenhall","year":"2019","journal-title":"Scientific Reports"},{"issue":"8","key":"pgen.1009268.ref003","first-page":"917","article-title":"Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic","volume":"23","year":"2017","journal-title":"Parasite Biology To the Clinic. Nature Medicine"},{"issue":"8","key":"pgen.1009268.ref004","doi-asserted-by":"crossref","first-page":"3405","DOI":"10.1128\/AAC.00024-09","article-title":"Novel pfdhps haplotypes among imported cases of Plasmodium falciparum malaria in the United Kingdom","volume":"53","author":"CJ Sutherland","year":"2009","journal-title":"Antimicrobial Agents and Chemotherapy"},{"issue":"3","key":"pgen.1009268.ref005","first-page":"220","article-title":"Molecular determinants of sulfadoxine-pyrimethamine resistance in Plasmodium falciparum in Nigeria and the regional emergence of dhps 431V","volume":"6","author":"MC Oguike","year":"2016","journal-title":"International Journal for Parasitology: Drugs and Drug Resistance"},{"issue":"5","key":"pgen.1009268.ref006","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/S1473-3099(18)30732-1","article-title":"Effect of Plasmodium falciparum sulfadoxine-pyrimethamine resistance on the effectiveness of intermittent preventive therapy for malaria in pregnancy in Africa: a systematic review and meta-analysis","volume":"19","author":"AM van Eijk","year":"2019","journal-title":"The Lancet Infectious Diseases"},{"issue":"3","key":"pgen.1009268.ref007","first-page":"1","article-title":"The prevalence and antifolate drug resistance profiles of Plasmodium falciparum in study participants randomized to discontinue or continue cotrimoxazole prophylaxis","volume":"13","author":"DW Juma","year":"2018","journal-title":"PLoS Neglected Tropical Diseases"},{"issue":"10","key":"pgen.1009268.ref008","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1000243","article-title":"Adaptive copy number evolution in malaria parasites","volume":"4","author":"S Nair","year":"2008","journal-title":"PLoS Genetics"},{"issue":"1","key":"pgen.1009268.ref009","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12936-020-03176-x","article-title":"Molecular characterization of Plasmodium falciparum antifolate resistance markers in Thailand between 2008 and 2016","volume":"19","author":"R Sugaram","year":"2020","journal-title":"Malaria Journal"},{"issue":"9","key":"pgen.1009268.ref010","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0204871","article-title":"Amplification of GTP-cyclohydrolase 1 gene in plasmodium falciparum isolates with the quadruple mutant of dihydrofolate reductase and dihydropteroate synthase genes in Ghana","volume":"13","author":"M Osei","year":"2018","journal-title":"PLoS ONE"},{"key":"pgen.1009268.ref011","article-title":"An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples","author":"MalariaGEN Plasmodium falciparum Community Project","year":"2019","journal-title":"bioRxiv"},{"issue":"9","key":"pgen.1009268.ref012","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1093\/bioinformatics\/btu005","article-title":"EstMOI: Estimating multiplicity of infection using parasite deep sequencing data","volume":"30","author":"SA Assefa","year":"2014","journal-title":"Bioinformatics"},{"issue":"1","key":"pgen.1009268.ref013","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-33767-3","article-title":"Global genetic diversity of var2csa in Plasmodium falciparum with implications for malaria in pregnancy and vaccine development","volume":"8","author":"ED Benavente","year":"2018","journal-title":"Scientific Reports"},{"issue":"6455","key":"pgen.1009268.ref014","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1126\/science.aav5427","article-title":"Major subpopulations of Plasmodium falciparum in sub-Saharan Africa","volume":"365","author":"A Amambua-Ngwa","year":"2019","journal-title":"Science"},{"issue":"4254","key":"pgen.1009268.ref015","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1126\/science.781840","article-title":"Human malaria parasites in continuous culture","volume":"193","author":"W Trager","year":"1976","journal-title":"Science"},{"issue":"May","key":"pgen.1009268.ref016","first-page":"1","article-title":"Long read assemblies of geographically dispersed Plasmodium falciparum isolates reveal highly structured subtelomeres [version 1; referees: 3 approved]","volume":"3","author":"TD Otto","year":"2018","journal-title":"Wellcome Open Research"},{"key":"pgen.1009268.ref017","first-page":"1394","article-title":"Implicitfunction.Pdf","volume":"14","author":"ACE Darling","year":"2004","journal-title":"Genome Research"},{"issue":"11","key":"pgen.1009268.ref018","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.pt.2012.08.002","article-title":"PfCRT and its role in antimalarial drug resistance","volume":"28","author":"A Ecker","year":"2012","journal-title":"Trends in Parasitology"},{"issue":"1","key":"pgen.1009268.ref019","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1475-2875-11-251","article-title":"The detection of pfcrt and pfmdr1 point mutations as molecular markers of chloroquine drug resistance, Pahang, Malaysia","volume":"11","author":"WM Atroosh","year":"2012","journal-title":"Malaria Journal"},{"issue":"10","key":"pgen.1009268.ref020","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0013281","article-title":"Chloroquine clinical failures in P. falciparum malaria are associated with mutant Pfmdr-1, not Pfcrt in madagascar","volume":"5","author":"V Andriantsoanirina","year":"2010","journal-title":"PLoS ONE"},{"issue":"3","key":"pgen.1009268.ref021","first-page":"1","article-title":"Artemisinin resistance-associated markers in Plasmodium falciparum parasites from the China-Myanmar border: Predicted structural stability of K13 propeller variants detected in a low-prevalence area","volume":"14","author":"Y He","year":"2019","journal-title":"PLoS ONE"},{"issue":"10","key":"pgen.1009268.ref022","doi-asserted-by":"crossref","first-page":"2704","DOI":"10.1093\/jac\/dky258","article-title":"Prevalence of plasmodium falciparum parasites resistant to sulfadoxine\/pyrimethamine in the democratic republic of the congo: Emergence of highly resistant PfdHFR\/PfdHps alleles","volume":"73","author":"PN Mandoko","year":"2018","journal-title":"Journal of Antimicrobial Chemotherapy"},{"issue":"1","key":"pgen.1009268.ref023","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12936-019-2734-x","article-title":"High prevalence of Pfdhfr-Pfdhps quadruple mutations associated with sulfadoxine-pyrimethamine resistance in Plasmodium falciparum isolates from Bioko Island, Equatorial Guinea","volume":"18","author":"T Jiang","year":"2019","journal-title":"Malaria Journal"},{"issue":"10","key":"pgen.1009268.ref024","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1016\/j.celrep.2016.02.025","article-title":"Landscape and Dynamics of Transcription Initiation in the Malaria Parasite Plasmodium falciparum","volume":"14","author":"SH Adjalley","year":"2016","journal-title":"Cell Reports"},{"issue":"4","key":"pgen.1009268.ref025","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1093\/nar\/gky1268","article-title":"Complex DNA structures trigger copy number variation across the Plasmodium falciparum genome","volume":"47","author":"AC Huckaby","year":"2019","journal-title":"Nucleic Acids Research"},{"issue":"1","key":"pgen.1009268.ref026","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1093\/infdis\/jit415","article-title":"Ordered accumulation of mutations conferring resistance to sulfadoxine-pyrimethamine in the plasmodium falciparum parasite","volume":"209","author":"T Mita","year":"2014","journal-title":"Journal of Infectious Diseases"},{"issue":"7","key":"pgen.1009268.ref027","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1093\/molbev\/msu140","article-title":"Origin of robustness in generating drug-resistant malaria parasites","volume":"31","author":"K K\u00fcmpornsin","year":"2014","journal-title":"Molecular Biology and Evolution"},{"key":"pgen.1009268.ref028","first-page":"609","article-title":"New England Journal CREST","author":"P Fong","year":"2010","journal-title":"Science"},{"issue":"9","key":"pgen.1009268.ref029","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/S1473-3099(18)30348-7","article-title":"The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis","volume":"18","author":"RJ Commons","year":"2018","journal-title":"The Lancet Infectious Diseases"},{"issue":"4","key":"pgen.1009268.ref030","doi-asserted-by":"crossref","DOI":"10.1111\/mmi.12162","article-title":"Direct evidence for the adaptive role of copy number variation on antifolate susceptibility in Plasmodium falciparum","volume":"88","author":"A Heinberg","year":"2013","journal-title":"Mol Microbiol"}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1009268","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T13:35:26Z","timestamp":1609421726000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1009268"}},"subtitle":[],"editor":[{"given":"Giorgio","family":"Sirugo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2020,12,31]]},"references-count":30,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12,31]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1009268","relation":{},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,31]]}}}