{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T12:27:29Z","timestamp":1788956849320,"version":"build-2803163510"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T00:00:00Z","timestamp":1664841600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011858","name":"African Academy of Sciences","doi-asserted-by":"publisher","award":["107740\/Z\/15\/Z"],"award-info":[{"award-number":["107740\/Z\/15\/Z"]}],"id":[{"id":"10.13039\/501100011858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:italic>Plasmodium falciparum<\/jats:italic> malaria cases in Africa represent over 90% of the global burden with Mali being amongst the 11 highest burden countries that account for 70% of this annual incidence. The persistence of <jats:italic>P. falciparum<\/jats:italic> despite massive global interventions is because of its genetic diversity that drives its ability to adapt to environmental changes, develop resistance to drugs, and evade the host immune system. Knowledge on <jats:italic>P. falciparum<\/jats:italic> genetic diversity across populations and intervention landscape is thus critical for the implementation of new strategies to eliminate malaria. This study assessed genetic variation with 12,177 high-quality SNPs from 830 Malian <jats:italic>P. falciparum<\/jats:italic> isolates collected between 2007 and 2017 from seven locations. The complexity of infections remained high, varied between sites, and showed a trend toward overall decreasing complexity over the decade. Though there was no significant substructure, allele frequencies varied geographically, partly driven by temporal variance in sampling, particularly for drug resistance and antigen loci. Thirty-two mutations in known drug resistance markers (<jats:italic>pfcrt<\/jats:italic>, <jats:italic>pfdhps<\/jats:italic>, <jats:italic>pfdhfr<\/jats:italic>, <jats:italic>pfmdr1<\/jats:italic>, <jats:italic>pfmdr2,<\/jats:italic> and <jats:italic>pfk13<\/jats:italic>) attained a frequency of at least 2% in the populations. SNPs within and around the major markers of resistance to quinolines (<jats:italic>pfmdr1<\/jats:italic> and <jats:italic>pfcrt<\/jats:italic>) and antifolates (<jats:italic>pfdhfr<\/jats:italic> and <jats:italic>pfdhps<\/jats:italic>) varied temporally and geographically, with strong linkage disequilibrium and signatures of directional selection in the genome. These geo-temporal populations also differentiated at alleles in immune-related loci, including, <jats:italic>protein E140<\/jats:italic>, <jats:italic>pfsurfin8<\/jats:italic>, <jats:italic>pfclag8<\/jats:italic>, and <jats:italic>pfceltos<\/jats:italic>, as well as <jats:italic>pftrap<\/jats:italic>, which showed signatures of haplotype differentiation between populations<jats:italic>.<\/jats:italic> Several regions across the genomes, including five known drug resistance loci, showed signatures of differential positive selection. These results suggest that drugs and immune pressure are dominant selective forces against <jats:italic>P. falciparum<\/jats:italic> in Mali, but their effect on the parasite genome varies temporally and spatially. Interventions interacting with these genomic variants need to be routinely evaluated as malaria elimination strategies are implemented.<\/jats:p>","DOI":"10.3389\/fgene.2022.943445","type":"journal-article","created":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T04:24:55Z","timestamp":1664857495000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Genome-wide SNP analysis of Plasmodium falciparum shows differentiation at drug-resistance-associated loci among malaria transmission settings in southern Mali"],"prefix":"10.3389","volume":"13","author":[{"given":"Aoua","family":"Coulibaly","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mouhamadou Fadel","family":"Diop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aminatou","family":"Kone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Dara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amed","family":"Ouattara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Mulder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivo","family":"Miotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahamadou","family":"Diakite","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdoulaye","family":"Djimde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred","family":"Amambua-Ngwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1126\/science.aav5427","article-title":"Major subpopulations of Plasmodium falciparum in sub-Saharan Africa","volume":"365","author":"Amambua-Ngwa","year":"2019","journal-title":"Science"},{"key":"B2","doi-asserted-by":"publisher","first-page":"9687","DOI":"10.1038\/s41598-018-28017-5","article-title":"Consistent signatures of selection from genomic analysis of pairs of temporal and spatial Plasmodium falciparum populations from the Gambia","volume":"8","author":"Amambua-Ngwa","year":"2018","journal-title":"Sci. Rep."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e1002992","DOI":"10.1371\/journal.pgen.1002992","article-title":"Population genomic scan for candidate signatures of balancing selection to guide antigen characterization in malaria parasites","volume":"8","author":"Amambua-Ngwa","year":"2012","journal-title":"PLoS Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/nature12876","article-title":"A molecular marker of artemisinin-resistant Plasmodium falciparum malaria","volume":"505","author":"Ariey","year":"2014","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/s0035-9203(01)90140-3","article-title":"Diversity of Plasmodium falciparum populations and complexity of infections in relation to transmission intensity and host age: A study from the usambara mountains, Tanzania","volume":"95","author":"Bendixen","year":"2001","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"B6","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/s12916-020-1494-3","article-title":"The duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of pfmdr1 86Y and pfcrt 76T: A meta-analysis of individual patient data","volume":"18","author":"Bretscher","year":"2020","journal-title":"BMC Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1111\/1755-0998.12471","article-title":"TESS3: Fast inference of spatial population structure and genome scans for selection","volume":"16","author":"Caye","year":"2016","journal-title":"Mol. Ecol. Resour."},{"key":"B8","doi-asserted-by":"publisher","first-page":"8271","DOI":"10.1038\/s41598-022-11974-3","article-title":"Stratification at the health district level for targeting malaria control interventions in Mali","volume":"12","author":"Cissoko","year":"2022","journal-title":"Sci. Rep."},{"key":"B9","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1056\/NEJM200101253440403","article-title":"A molecular marker for chloroquine-resistant falciparum malaria","volume":"344","author":"Djimde","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1111\/j.1574-695X.2009.00641.x","article-title":"A molecular map of chloroquine resistance in Mali","volume":"58","author":"Djimde","year":"2010","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1056\/NEJMoa0808859","article-title":"Artemisinin resistance in Plasmodium falciparum malaria","volume":"361","author":"Dondorp","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"15763","DOI":"10.1038\/s41598-018-34078-3","article-title":"Multi-population genomic analysis of malaria parasites indicates local selection and differentiation at the gdv1 locus regulating sexual development","volume":"8","author":"Duffy","year":"2018","journal-title":"Sci. Rep."},{"key":"B13","doi-asserted-by":"publisher","first-page":"m4711","DOI":"10.1136\/bmj.m4711","article-title":"African malaria deaths set to dwarf Covid-19 fatalities as pandemic hits control efforts, WHO warns","volume":"371","author":"Dyer","year":"2020","journal-title":"BMJ"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e2100685118","DOI":"10.1073\/pnas.2100685118","article-title":"Mapping partner drug resistance to guide antimalarial combination therapy policies in sub-Saharan Africa","volume":"118","author":"Ehrlich","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B15","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1006\/expr.1995.1096","article-title":"Plasmodium falciparum: Malaria morbidity is associated with specific merozoite surface antigen 2 genotypes","volume":"81","author":"Engelbrecht","year":"1995","journal-title":"Exp. Parasitol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/s1097-2765(05)00077-8","article-title":"Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance","volume":"6","author":"Fidock","year":"2000","journal-title":"Mol. Cell"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.4269\/ajtmh.21-0788","article-title":"Differential incidence of malaria in neighboring villages in a high-transmission setting of southern Mali","volume":"106","author":"Fofana","year":"2022","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"B18","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/1755-0998.12509","article-title":"pophelper: an R package and web app to analyse and visualize population structure","volume":"17","author":"Francis","year":"2017","journal-title":"Mol. Ecol. Resour."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1554","DOI":"10.1093\/molbev\/msw037","article-title":"Combinatorial genetic modeling of pfcrt-mediated drug resistance evolution in Plasmodium falciparum","volume":"33","author":"Gabryszewski","year":"2016","journal-title":"Mol. Biol. Evol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.molbiopara.2004.12.010","article-title":"Implication of a Plasmodium falciparum gene in the switch between asexual reproduction and gametocytogenesis","volume":"140","author":"Gardiner","year":"2005","journal-title":"Mol. Biochem. Parasitol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1093\/bioinformatics\/bts115","article-title":"rehh: an R package to detect footprints of selection in genome-wide SNP data from haplotype structure","volume":"28","author":"Gautier","year":"2012","journal-title":"Bioinformatics"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1617","DOI":"10.3389\/fmicb.2016.01617","article-title":"Immune escape strategies of malaria parasites","volume":"7","author":"Gomes","year":"2016","journal-title":"Front. Microbiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1093\/trstmh\/tru181","article-title":"Home treatments alone or mixed with modern treatments for malaria in finkolo AC, South Mali: Reported use, outcomes and changes over 10 years","volume":"109","author":"Graz","year":"2015","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"B24","volume-title":"Trends in and factors associated with malaria prevention in Mali: Further analysis of the Mali demographic and health surveys and malaria indicator surveys 2006-2018","author":"Hannah Keonker","year":"2020"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e1002380","DOI":"10.1371\/journal.pbio.1002380","article-title":"Tools and strategies for malaria control and elimination: What do we need to achieve a grand convergence in malaria?","volume":"14","author":"Hemingway","year":"2016","journal-title":"PLoS Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1111\/1755-0998.12663","article-title":"The empirical Bayes estimators of fine-scale population structure in high gene flow species","volume":"17","author":"Kitada","year":"2017","journal-title":"Mol. Ecol. Resour."},{"key":"B27","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1186\/s12936-020-03202-y","article-title":"Effect of routine seasonal malaria chemoprevention on malaria trends in children under 5 years in Dangassa, Mali","volume":"19","author":"Konate","year":"2020","journal-title":"Malar. J."},{"key":"B28","volume-title":"moimix: an R package for assessing clonality in high-througput sequencing data","author":"Lee","year":"2016"},{"key":"B29","doi-asserted-by":"publisher","first-page":"6057","DOI":"10.3390\/ijms22116057","article-title":"Selection of pfcrt K76 and pfmdr1 N86 coding alleles after uncomplicated malaria treatment by artemether-lumefantrine in Mali","volume":"22","author":"Maiga","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"42","DOI":"10.12688\/wellcomeopenres.16168.2","article-title":"An open dataset of Plasmodium falciparum genome variation in 7, 000 worldwide samples","volume":"6","author":"MalariaGen","year":"2021","journal-title":"Wellcome Open Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1038\/nature11174","article-title":"Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing","volume":"487","author":"Manske","year":"2012","journal-title":"Nature"},{"key":"B32","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.actatropica.2009.07.008","article-title":"Origins and spread of pfdhfr mutant alleles in Plasmodium falciparum","volume":"114","author":"Mita","year":"2010","journal-title":"Acta Trop."},{"key":"B33","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1186\/1475-2875-11-223","article-title":"Population genetic structure of Plasmodium falciparum across a region of diverse endemicity in West Africa","volume":"11","author":"Mobegi","year":"2012","journal-title":"Malar. J."},{"key":"B34","doi-asserted-by":"publisher","first-page":"15178","DOI":"10.1073\/pnas.1520426112","article-title":"Plasmodium evasion of mosquito immunity and global malaria transmission: The lock-and-key theory","volume":"112","author":"Molina-Cruz","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B35","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1001\/jama.1989.03430020087034","article-title":"The spread of chloroquine-resistant malaria in Africa. Implications for travelers","volume":"262","author":"Moran","year":"1989","journal-title":"JAMA"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.4269\/ajtmh.12-0739","article-title":"Selection of antimalarial drug resistance after intermittent preventive treatment of infants and children (IPTi\/c) in Senegal","volume":"88","author":"Ndiaye","year":"2013","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"B37","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.ijpddr.2021.06.001","article-title":"A review of the frequencies of Plasmodium falciparum Kelch 13 artemisinin resistance mutations in Africa","volume":"16","author":"Ndwiga","year":"2021","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2025","DOI":"10.1056\/NEJMoa1505819","article-title":"Genetic diversity and protective efficacy of the RTS, S\/AS01 malaria vaccine","volume":"373","author":"Neafsey","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"e1000055","DOI":"10.1371\/journal.pmed.1000055","article-title":"Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria","volume":"6","author":"Pearce","year":"2009","journal-title":"PLoS Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1093\/molbev\/msu136","article-title":"PopGenome: An efficient Swiss army knife for population genomic analyses in R","volume":"31","author":"Pfeifer","year":"2014","journal-title":"Mol. Biol. Evol."},{"key":"B41","first-page":"2021","volume-title":"President malaria initiative Mali operational plan, FY","year":"2020"},{"key":"B42","doi-asserted-by":"publisher","first-page":"e1005131","DOI":"10.1371\/journal.pgen.1005131","article-title":"Imputation-based population genetics analysis of Plasmodium falciparum malaria parasites","volume":"11","author":"Samad","year":"2015","journal-title":"PLoS Genet."},{"key":"B43","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1186\/s12936-021-03764-5","article-title":"Determinants of intermittent preventive treatment with sulfadoxine-pyrimethamine in pregnant women (IPTp-SP) in Mali, a household survey","volume":"20","author":"Sangho","year":"2021","journal-title":"Malar. J."},{"key":"B44","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1186\/s12936-017-2068-5","article-title":"Temporal dynamic of malaria in a suburban area along the Niger River","volume":"16","author":"Sissoko","year":"2017","journal-title":"Malar. J."},{"key":"B45","doi-asserted-by":"publisher","first-page":"e0232234","DOI":"10.1371\/journal.pone.0232234","article-title":"Novel malaria antigen Plasmodium yoelii E140 induces antibody-mediated sterile protection in mice against malaria challenge","volume":"15","author":"Smith","year":"2020","journal-title":"PLoS One"},{"key":"B46","doi-asserted-by":"publisher","first-page":"e21800","DOI":"10.1371\/journal.pone.0021800","article-title":"REVIGO summarizes and visualizes long lists of gene ontology terms","volume":"6","author":"Supek","year":"2011","journal-title":"PLoS One"},{"key":"B47","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1046\/j.1365-3156.2000.00652.x","article-title":"Child malaria treatment practices among mothers in the district of Yanfolila, Sikasso region, Mali","volume":"5","author":"Thera","year":"2000","journal-title":"Trop. Med. Int. Health"},{"key":"B48","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.parepi.2018.02.001","article-title":"School-aged children based seasonal malaria chemoprevention using artesunate-amodiaquine in Mali","volume":"3","author":"Thera","year":"2018","journal-title":"Parasite Epidemiol. Control"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e1001383","DOI":"10.1371\/journal.pgen.1001383","article-title":"Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum","volume":"7","author":"Van Tyne","year":"2011","journal-title":"PLoS Genet."},{"key":"B50","doi-asserted-by":"publisher","first-page":"833","DOI":"10.4269\/ajtmh.14-0031","article-title":"Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: Parasite risk factors that affect treatment outcomes for P. Falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine","volume":"91","author":"Venkatesan","year":"2014","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"B51","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1086\/322858","article-title":"Chloroquine-resistant malaria","volume":"184","author":"Wellems","year":"2001","journal-title":"J. Infect. Dis."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1111\/j.1755-0998.2012.03174.x","article-title":"Mmod: an R library for the calculation of population differentiation statistics","volume":"12","author":"Winter","year":"2012","journal-title":"Mol. Ecol. Resour."},{"key":"B53","volume-title":"Guidelines for the treatment of malaria","year":"2006"},{"key":"B54","volume-title":"World malaria Report 2021","year":"2021"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.943445\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T04:25:02Z","timestamp":1664857502000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.943445\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,4]]},"references-count":54,"alternative-id":["10.3389\/fgene.2022.943445"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.943445","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,4]]},"article-number":"943445"}}