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High-coverage sequencing and genotype data have now confirmed the single African origin of the sickle-cell gene variant [HBB; c.20T&amp;gt;A, p.Glu6Val; OMIM: 141900 (HBB-\u03b2S)]. Nevertheless, the classical HBB-like genes cluster haplotypes remain a rich source of HBB-\u03b2S evolutionary information. The overlapping distribution of HBB-\u03b2S and other disease-associated variants means that their evolutionary genetics must be investigated concurrently. In this review: (1) we explore the evolutionary history of HBB-\u03b2S and its implications in understanding human migration within and out of Africa: e.g. HBB haplotypes and recent migration paths of the Bantu expansion, occurrence of ~7% of the Senegal haplotype in Angola reflecting changes in population\/SCD dynamics, and existence of all five classical HBB haplotype in Cameroon and Egypt suggesting a much longer presence of HBB-\u03b2S in these regions; (2) we discuss the time estimates of the emergence of HBB-\u03b2S in Africa and finally, (3) we discuss implications for genetic medicine in understanding complex epistatic interactions between HBB-\u03b2S and other gene variants selected under environmental pressure in Africa e.g. variants in HBB, HBA, G6PD, APOL1, APOE, OSBPL10 and RXRA.<\/jats:p>","DOI":"10.1093\/hmg\/ddab004","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T07:19:21Z","timestamp":1609917561000},"page":"R119-R128","source":"Crossref","is-referenced-by-count":91,"title":["Evolutionary history of sickle-cell mutation: implications for global genetic medicine"],"prefix":"10.1093","volume":"30","author":[{"given":"Kevin","family":"Esoh","sequence":"first","affiliation":[{"name":"Division of Human Genetics, Department of Pathology, University of Cape Town, Cape Town, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ambroise","family":"Wonkam","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Department of Pathology, University of Cape Town, Cape Town, South Africa"},{"name":"Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,1,18]]},"reference":[{"key":"2021042610544767600_ref1","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.ajhg.2018.02.003","article-title":"Whole-genome-sequence-based haplotypes reveal single origin of the sickle allele during the Holocene wet phase","volume":"102","author":"Shriner","year":"2018","journal-title":"Am. 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