{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:21:44Z","timestamp":1790169704632,"version":"4.1.0"},"reference-count":26,"publisher":"National Academy of Sciences","issue":"50","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,12,15]]},"abstract":"<jats:p>Several human genetic disorders of hemoglobin have risen in frequency because of the protection they offer against death from malaria, sickle-cell anemia being a canonical example. Here we address the issue of why this highly protective mutant, present at high frequencies in subSaharan Africa, is uncommon in Mediterranean populations that instead harbor a diverse range of thalassemic hemoglobin disorders. We demonstrate that these contrasting profiles of malaria-protective alleles can arise and be stably maintained by two well-documented phenomena: an alleviation of the clinical severity of \u03b1- and \u03b2-thalassemia in compound thalassemic genotypes and a cancellation of malaria protection when \u03b1-thalassemia and the sickle-cell trait are coinherited. The complex distribution of globin mutants across Africa and the Mediterranean can therefore be explained by their specific intracellular interactions.<\/jats:p>","DOI":"10.1073\/pnas.0910840106","type":"journal-article","created":{"date-parts":[[2009,12,1]],"date-time":"2009-12-01T21:54:06Z","timestamp":1259704446000},"page":"21242-21246","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":53,"title":["Epistatic interactions between genetic disorders of hemoglobin can explain why the sickle-cell gene is uncommon in the Mediterranean"],"prefix":"10.1073","volume":"106","author":[{"given":"Bridget S.","family":"Penman","sequence":"first","affiliation":[{"name":"Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver G.","family":"Pybus","sequence":"additional","affiliation":[{"name":"Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Weatherall","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunetra","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,12,15]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-5223.1949.tb03339.x"},{"key":"e_1_3_3_2_2","first-page":"704","article-title":"Inherited haemoglobin disorders: An increasing global health problem","volume":"79","author":"Weatherall DJ","year":"2001","unstructured":"DJ Weatherall, JB Clegg, Inherited haemoglobin disorders: An increasing global health problem. 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