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Unlike influenza and HIV, where diversity in immunodominant surface antigens is understood geographically to inform disease surveillance, relatively little is known about the global population structure of PfEMP1, the major variant surface antigen of the malaria parasite<jats:italic>Plasmodium falciparum<\/jats:italic>. The complexity of the<jats:italic>var<\/jats:italic>multigene family that encodes PfEMP1 and that diversifies by recombination, has so far precluded its use in malaria surveillance. Recent studies have demonstrated that cost-effective deep sequencing of the region of<jats:italic>var<\/jats:italic>genes encoding the PfEMP1 DBL\u03b1 domain and subsequent classification of within host sequences at 96% identity to define unique DBL\u03b1 types, can reveal structure and strain dynamics within countries. However, to date there has not been a comprehensive comparison of these DBL\u03b1 types between countries. By leveraging a bioinformatic approach (jumping hidden Markov model) designed specifically for the analysis of recombination within<jats:italic>var<\/jats:italic>genes and applying it to a dataset of DBL\u03b1 types from 10 countries, we are able to describe population structure of DBL\u03b1 types at the global scale. The sensitivity of the approach allows for the comparison of the global dataset to ape samples of<jats:italic>Plasmodium Laverania<\/jats:italic>species. Our analyses show that the evolution of the parasite population emerging out of Africa underlies current patterns of DBL\u03b1 type diversity. Most importantly, we can distinguish geographic population structure within Africa between Gabon and Ghana in West Africa and Uganda in East Africa. Our evolutionary findings have translational implications in the context of globalization. Firstly, DBL\u03b1 type diversity can provide a simple diagnostic framework for geographic surveillance of the rapidly evolving transmission dynamics of<jats:italic>P<\/jats:italic>.<jats:italic>falciparum<\/jats:italic>. It can also inform efforts to understand the presence or absence of global, regional and local population immunity to major surface antigen variants. Additionally, we identify a number of highly conserved DBL\u03b1 types that are present globally that may be of biological significance and warrant further characterization.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009269","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T18:26:26Z","timestamp":1614277586000},"page":"e1009269","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":27,"title":["Evolutionary analyses of the major variant surface antigen-encoding genes reveal population structure of Plasmodium falciparum within and between 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