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Sickle Cell Origins Unraveled From Contemporary Genome Sequences

NEW YORK (GenomeWeb) – A new genomic analysis suggests that the sickle allele haplotypes in existing human populations arose just once, subsequently diversifying into three main haplotype clusters.  

By sorting through nearly 3,000 whole-genome sequences from the 1000 Genomes Project, the African Genome Variation Project, and a sequencing project in Qatar, researchers from the National Human Genome Research Institute focused on 156 individuals carrying sickle cell mutations. From haplotypes centered on 27 informative variants, they retraced sickle allele emergence — a single event that occurred in Africa roughly 7,300 years ago.

The team's results, published online today in the American Journal of Human Genetics, suggested that three haplotype clusters were ultimately derived from the original sickle allele, encompassing the five restriction site-based haplotypes that have traditionally been used to classify the genetic backgrounds of sickle alleles in different parts of the world.

"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 expansions," co-authors Daniel Shriner and Charles Rotimi, investigators at the NHGRI's Center for Research on Genomics and Global Health, wrote. "These results clarify the origin of the sickle allele and improve and simplify the classification of sickle haplotypes."

Hemoglobin gene mutations, including sickle cell-related mutations in the beta globin gene HBB, are present in numerous malaria-exposed human populations, the duo explained. Five HBB sickle allele backgrounds — known as the Arabian/Indian, Benin, Cameroon, Central African Republic, and Senegal haplotypes — were previously identified based on restriction site patterns near HBB, perhaps due to rampant recombination events at an upstream hotspot or multiple introductions of the allele.

"There are two models of the origins of the sickle allele," the authors explained. "The multicentric model posits five independent occurrences of the same mutation within the last few thousand years. The unicentric model posits a single occurrence and an older age."

In an effort to differentiate between these possibilities, the researchers began by characterizing sickle alleles present in whole-genome sequence data for 2,504 participants in the 1000 Genomes Project, 320 individuals profiled for the African Genome Variation Project, and 108 individuals sequenced from Qatar.

After folding in linkage disequilibrium, balancing selection, phylogenetic profiles, recombination patterns, and more, the researchers concluded that the original sickle mutation arose just once, around 259 generations ago — putting its emergence at roughly 7,300 years ago.

Since then, derived mutations appear to produced three sickle cell haplotype clusters, they reported: one derived mutation ultimately led to the sickle allele haplotypes in the Central African Republic, Cameroon, and Arabia/India, followed by diversifications producing one haplotype sub-cluster in Senegal and another spanning the Senegal and Benin haplotypes.

"[W]e found that the Senegal haplotype is sub-structured into two clusters, one containing only Senegal haplotypes and one containing Benin and Senegal haplotypes," the authors wrote. "This sub-structuring of haplotypes might have confounded previous assessments of clinical phenotype or disease severity."

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