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The chemokine receptor variant CCR5delta32 is linked to HIV-1 resistance and other conditions. Its evolutionary history and allele frequency (10%–16%) in European populations have been extensively debated. We provide a detailed perspective of the evolutionary history of the deletion through time and space. We discovered that the CCR5delta32 allele arose on a pre-existing haplotype consisting of 84 variants. Using this information, we developed a haplotype-aware probabilistic model to screen 934 low-coverage ancient genomes and traced the origin of the CCR5delta32 deletion to at least 6,700 years before the present (BP) in the Western Eurasian Steppe region. Furthermore, we present strong evidence for positive selection acting upon the CCR5delta32 haplotype between 8,000 and 2,000 years BP in Western Eurasia and show that the presence of the haplotype in Latin America can be explained by post-Columbian genetic exchanges. Finally, we point to complex CCR5delta32 genotype-haplotype-phenotype relationships, which demand consideration when targeting the CCR5 receptor for therapeutic strategies.
4.6
11 reviews