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This study was conducted in an area of high seasonal malaria transmission in Bongo District, Ghana. IRS was implemented during the dry season (November\u2013May) in three consecutive years between 2013 and 2015 to reduce transmission and attempt to bottleneck the parasite population in humans towards lower diversity with greater linkage disequilibrium. The study was done against a background of widespread use of long\u2010lasting insecticidal nets, typical for contemporary malaria control in West Africa. Microsatellite genotyping with 10\u00a0loci was used to construct 392 <jats:italic>P<\/jats:italic>.\u00a0<jats:italic>falciparum<\/jats:italic> multilocus infection haplotypes collected from two age\u2010stratified cross\u2010sectional surveys at the end of the wet seasons pre\u2010 and post\u2010IRS. Three\u2010rounds of IRS, under operational conditions, led to a &gt;90% reduction in transmission intensity and a 35.7% reduction in the <jats:italic>P<\/jats:italic>.\u00a0<jats:italic>falciparum<\/jats:italic> prevalence (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.001). Despite these declines, population genetic analysis of the infection haplotypes revealed no dramatic changes with only a slight, but significant increase in genetic diversity (<jats:italic>H<\/jats:italic><jats:sub>e<\/jats:sub>: pre\u2010IRS\u00a0=\u00a00.79 vs. post\u2010IRS = 0.81, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.048). Reduced relatedness of the parasite population (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.001) was observed post\u2010IRS, probably due to decreased opportunities for outcrossing. Spatiotemporal genetic differentiation between the pre\u2010 and post\u2010IRS surveys (<jats:italic>D<\/jats:italic>\u00a0=\u00a00.0329 [95% CI: 0.0209 \u2013 0.0473], <jats:italic>p<\/jats:italic>\u00a0=\u00a0.034) was identified. These data provide a genetic explanation for the resilience of <jats:italic>P.\u00a0falciparum<\/jats:italic> to short\u2010term IRS programmes in high\u2010transmission settings in sub\u2010Saharan Africa.<\/jats:p>","DOI":"10.1111\/mec.16029","type":"journal-article","created":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T15:13:57Z","timestamp":1624029237000},"page":"3974-3992","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The impact of indoor residual spraying on <i>Plasmodium falciparum<\/i> microsatellite variation in an area of high seasonal malaria transmission in Ghana, West Africa"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8068-0215","authenticated-orcid":false,"given":"Dionne C.","family":"Argyropoulos","sequence":"first","affiliation":[{"name":"School of BioSciences Bio21 Institute The University of Melbourne Melbourne Vic. 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Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4191-7419","authenticated-orcid":false,"given":"Abraham R.","family":"Oduro","sequence":"additional","affiliation":[{"name":"Navrongo Health Research Centre Ghana Health Service Navrongo Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4105-1010","authenticated-orcid":false,"given":"Samuel K.","family":"Dadzie","sequence":"additional","affiliation":[{"name":"Noguchi Memorial Institute for Medical Research University of Ghana Legon Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maxwell A.","family":"Appawu","sequence":"additional","affiliation":[{"name":"Noguchi Memorial Institute for Medical Research University of Ghana Legon Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor","family":"Asoala","sequence":"additional","affiliation":[{"name":"Navrongo Health Research Centre Ghana Health Service Navrongo Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3575-7233","authenticated-orcid":false,"given":"Mercedes","family":"Pascual","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution University of Chicago Chicago USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4274-6516","authenticated-orcid":false,"given":"Kwadwo A.","family":"Koram","sequence":"additional","affiliation":[{"name":"Noguchi Memorial Institute for Medical Research University of Ghana Legon Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6115-6135","authenticated-orcid":false,"given":"Karen P.","family":"Day","sequence":"additional","affiliation":[{"name":"School of BioSciences Bio21 Institute The University of Melbourne Melbourne Vic. 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