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By contrast, Plasmodium falciparum parasites use multiple RBC receptors for invasion. Whether DARC is one of these receptors has never been systematically explored. We used flow cytometry and microscopy-based approaches to investigate whether P. falciparum parasites preferentially invade specific Duffy RBC phenotypes and explored 2 potential explanations for invasion preference\u2014differences in RBC biophysical properties and surface protein composition. P. falciparum parasites showed a consistent preference for Duffy-positive RBCs, and some biophysical properties and surface protein expression varied between Duffy-positive and Duffy-negative RBCs. We then used our in vitro invasion data to parametrize an evolutionary-epidemiological model of the relationship between P. falciparum and the FYBES allele. Our model accounts for immunity against P. falciparum virulence, gained through exposure, and thus mutations that impede infection are not always advantageous. The inhibition of P. falciparum invasion that we observed in vitro leads to FYBES frequencies increasing at low levels of P. falciparum transmission but decreasing at high levels of transmission. The impact of P. falciparum on the prevalence of Duffy negativity may therefore be most apparent in lower transmission settings. Our findings show a link between Duffy negativity and P. falciparum and suggest that DARC may directly or indirectly be involved in P. falciparum invasion of human RBCs which could, together with P. vivax, explain the distribution of Duffy negativity in sub-Saharan Africa.<\/jats:p>","DOI":"10.1093\/molbev\/msag033","type":"journal-article","created":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T12:39:07Z","timestamp":1769863147000},"source":"Crossref","is-referenced-by-count":0,"title":["Invasion preferences suggest a possible role for\n                    <i>Plasmodium falciparum<\/i>\n                    parasites in the expansion of Duffy negativity in West and Central Africa"],"prefix":"10.1093","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5391-6442","authenticated-orcid":false,"given":"Balanding","family":"Manneh","sequence":"first","affiliation":[{"name":"Cambridge Institute for Medical Research, University of Cambridge , Cambridge ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9012-4696","authenticated-orcid":false,"given":"Viola","family":"Introini","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research, University of Cambridge , Cambridge ,","place":["UK"]},{"name":"Cavendish Laboratory, University of Cambridge , Cambridge ,","place":["UK"]},{"name":"European Molecular Biology Laboratory , Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4441-9909","authenticated-orcid":false,"given":"James","family":"Reed","sequence":"additional","affiliation":[{"name":"Research Donors , London ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2832-2149","authenticated-orcid":false,"given":"Madalina","family":"Rotariu","sequence":"additional","affiliation":[{"name":"Research Donors , London ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8608-4011","authenticated-orcid":false,"given":"Robin","family":"Antrobus","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research, University of Cambridge , Cambridge ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9193-8496","authenticated-orcid":false,"given":"Pietro","family":"Cicuta","sequence":"additional","affiliation":[{"name":"Cavendish Laboratory, University of Cambridge , Cambridge ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3196-5545","authenticated-orcid":false,"given":"Michael P","family":"Weekes","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research, University of Cambridge , Cambridge ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9803-5209","authenticated-orcid":false,"given":"Bridget S","family":"Penman","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Oxford , Oxford ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9835-1014","authenticated-orcid":false,"given":"Julian C","family":"Rayner","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research, University of Cambridge , Cambridge ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"2026022404113821900_msag033-B1","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1074\/jbc.M309888200","article-title":"Human ABCA7 supports apolipoprotein-mediated release of cellular cholesterol and phospholipid to generate high density lipoprotein","volume":"279","author":"Abe-Dohmae","year":"2004","journal-title":"J Biol Chem"},{"key":"2026022404113821900_msag033-B2","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1136\/bmj.1.4857.290","article-title":"Protection afforded by sickle-cell trait against subtertian malarial infection","volume":"1","author":"Allison","year":"1954","journal-title":"Br Med J"},{"key":"2026022404113821900_msag033-B3","doi-asserted-by":"publisher","first-page":"24623","DOI":"10.1038\/srep24623","article-title":"Invasion characteristics of a Plasmodium knowlesi line newly isolated from a human","volume":"6","author":"Amir","year":"2016","journal-title":"Sci Rep"},{"key":"2026022404113821900_msag033-B4","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/1475-2875-7-37","article-title":"Malaria in rural Mozambique. 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