Whole genome sequence-based haplotypes reveal single origin of the sickle allele during the Holocene Wet Phase

Five classical designations of sickle haplotypes are based on the presence/absence of restriction sites and named after ethnic groups or geographic regions from which patients originated. Each haplotype is thought to represent an independent occurrence of the sickle mutation. We investigated the origins of the sickle mutation using whole genome sequence data. We identified 156 carriers from the 1000 Genomes Project, the African Genome Variation Project, and Qatar. We defined a new haplotypic classification using 27 polymorphisms in linkage disequilibrium with rs334. Network analysis revealed a common haplotype that differed from the ancestral haplotype only by the derived sickle mutation at rs334 and correlated collectively with the Central African Republic/Bantu, Cameroon, and Arabian/Indian designations. Other haplotypes were derived from this haplotype and fell into two clusters, one comprised of haplotypes correlated with the Senegal designation and the other comprised of haplotypes correlated with both the Benin and Senegal designations. The near-exclusive presence of the original sickle haplotype in the Central African Republic, Kenya, Uganda, and South Africa is consistent with this haplotype predating the Bantu Expansion. Modeling of balancing selection indicated that the heterozygote advantage was 15.2%, an equilibrium frequency of 12.0% was reached after 87 generations, and the selective environment predated the mutation. The posterior distribution of the ancestral recombination graph yielded an age of the sickle mutation of 259 generations, corresponding to 7,300 years and the Holocene Wet Phase. These results clarify the origin of the sickle allele and improve and simplify the classification of sickle haplotypes.