PMC:5985360 / 1869-4318 JSONTXT

{"project":"2_test","denotations":[{"id":"29526279-11423617-2046610","span":{"begin":186,"end":187},"obj":"11423617"},{"id":"29526279-12364370-2046611","span":{"begin":189,"end":190},"obj":"12364370"},{"id":"29526279-6583683-2046612","span":{"begin":868,"end":869},"obj":"6583683"},{"id":"29526279-6584911-2046613","span":{"begin":871,"end":872},"obj":"6584911"},{"id":"29526279-3752087-2046614","span":{"begin":874,"end":875},"obj":"3752087"},{"id":"29526279-2898142-2046615","span":{"begin":877,"end":878},"obj":"2898142"},{"id":"29526279-1376298-2046616","span":{"begin":880,"end":881},"obj":"1376298"},{"id":"29526279-17688704-2046617","span":{"begin":883,"end":884},"obj":"17688704"},{"id":"29526279-23542314-2046618","span":{"begin":886,"end":887},"obj":"23542314"},{"id":"29526279-281713-2046619","span":{"begin":1112,"end":1114},"obj":"281713"},{"id":"29526279-81926-2046620","span":{"begin":1116,"end":1118},"obj":"81926"},{"id":"29526279-6584911-2046621","span":{"begin":1351,"end":1352},"obj":"6584911"},{"id":"29526279-6268660-2046622","span":{"begin":1358,"end":1360},"obj":"6268660"},{"id":"29526279-11741197-2046623","span":{"begin":1362,"end":1364},"obj":"11741197"},{"id":"29526279-1569586-2046624","span":{"begin":1537,"end":1539},"obj":"1569586"},{"id":"29526279-8462981-2046625","span":{"begin":1541,"end":1543},"obj":"8462981"},{"id":"29526279-25748438-2046626","span":{"begin":1545,"end":1547},"obj":"25748438"},{"id":"29526279-4582014-2046627","span":{"begin":1600,"end":1602},"obj":"4582014"},{"id":"29526279-21260667-2046628","span":{"begin":1623,"end":1625},"obj":"21260667"},{"id":"29526279-28514091-2046629","span":{"begin":1627,"end":1629},"obj":"28514091"},{"id":"29526279-16501000-2046630","span":{"begin":1689,"end":1691},"obj":"16501000"},{"id":"29526279-6583683-2046631","span":{"begin":1805,"end":1806},"obj":"6583683"},{"id":"29526279-3177370-2046632","span":{"begin":1808,"end":1810},"obj":"3177370"},{"id":"29526279-10190321-2046633","span":{"begin":1812,"end":1814},"obj":"10190321"}],"text":"Introduction\nSeveral hereditary variants in the hemoglobin genes afford protection against malaria (MIM: 611162). Many such variants are thought to have evolved in the last 10,000 years.1, 2 In the beta globin gene HBB (MIM: 141900), the sickle (MIM: 603903) allele βS is under balancing selection because of heterozygote advantage, which results from protection against malaria caused by Plasmodium falciparum and recessive lethality. The chromosomal background of the βS allele has been classified on the basis of the presence or absence of a set of seven canonical restriction sites, 5′ ε HincII → Gγ1 HindIII → Aγ1 HindIII → ψβ HincII → 3′ ψβ HincII → β AvaII → 3′ β BamHI, yielding five haplotypes, Arabian/Indian, Benin, Cameroon, CAR, and Senegal, named after ethno-linguistic groups or geographic regions, as well as a sixth category for “atypical” haplotypes.3, 4, 5, 6, 7, 8, 9 These designations do not necessarily indicate where the haplotypes originated.\nWhether the βS allele has a recent or old origin has been debated since the development of restriction fragment length polymorphism (RFLP) data.10, 11 According to the multicentric model, the origin of the βS allele is recent—within the last few thousand years—and each haplotype represents an independent occurrence of the same exact mutation in the corresponding geographic region.4, 12, 13, 14 In contrast, according to the unicentric model, the origin of the βS allele is anywhere from tens to hundreds of thousands of years old, and the mutation occurred once.15, 16, 17, 18 Suggested places of origin include equatorial Africa19 and the Middle East.20, 21 A 1.2 kb recombination hotspot exists 1 kb upstream of HBB.22 Consequently, recombination and gene conversion, rather than de novo mutation, have generated several haplotypes.3, 23, 24\nWe investigated the origins of the sickle allele by using whole-genome-sequence data from a total of 2,932 individuals from the 1000 Genomes Project, the African Genome Variation Project, and Qatar. We identified a total of 156 sickle carriers. We classified haplotypes by using phased sequence data comprising diallelic sites (both single-nucleotide polymorphisms and short insertions or deletions). We then used a combination of forward time simulation, phylogenetic network analysis, and coalescent analysis to infer a single origin of the sickle allele approximately 7,300 years ago, during the Holocene Wet Phase or Green Sahara."}