Resistance afforded by the sickle-cell trait against severe malaria has led to high frequencies of the sickle-cell mutation [HBB; c.20T>A, p.Glu6Val; OMIM: 141900 (HBB-βS)] in most parts of Africa. High-coverage sequencing and genotype data have now confirmed the single African origin of the sickle-cell gene variant [HBB; c.20T>A, p.Glu6Val; OMIM: 141900 (HBB-βS)]. Nevertheless, the classical HBB-like genes cluster haplotypes remain a rich source of HBB-βS evolutionary information. The overlapping distribution of HBB-βS 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-βS 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-βS in these regions; (2) we discuss the time estimates of the emergence of HBB-βS in Africa and finally, (3) we discuss implications for genetic medicine in understanding complex epistatic interactions between HBB-βS and other gene variants selected under environmental pressure in Africa e.g. variants in HBB, HBA, G6PD, APOL1, APOE, OSBPL10 and RXRA.

中文翻译：

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镰状细胞突变的进化史：对全球遗传医学的影响


镰状细胞性状对严重疟疾的抵抗力导致了镰状细胞突变的高频率[HBB； c.20T>A，p.Glu6Val； OMIM：141900 (HBB-βS)]在非洲大部分地区。高覆盖率测序和基因型数据现已证实镰状细胞基因变体[HBB； c.20T>A，p.Glu6Val； OMIM：141900（HBB-βS）]。尽管如此，经典的 HBB 样基因簇单倍型仍然是 HBB-βS 进化信息的丰富来源。 HBB-βS 和其他疾病相关变异的重叠分布意味着必须同时研究它们的进化遗传学。在这篇综述中：（1）我们探讨了 HBB-βS 的进化史及其对理解非洲内外人类迁徙的影响：例如 HBB 单倍型和班图扩张的最近迁移路径，塞内加尔单倍型的出现率约为 7%安哥拉反映了人口/SCD 动态的变化，以及喀麦隆和埃及所有五种经典 HBB 单倍型的存在表明 HBB-βS 在这些地区的存在时间要长得多； (2) 我们讨论了 HBB-βS 在非洲出现的时间估计，最后，(3) 我们讨论了遗传医学在理解 HBB-βS 与非洲环境压力下选择的其他基因变体（例如变体）之间复杂的上位相互作用的影响在 HBB、HBA、G6PD、APOL1、APOE、OSBPL10 和 RXRA 中。