Tracing the evolutionary path of the CCR5delta32 deletion via ancient and modern genomes

The chemokine receptor variant CCR5delta32 is linked to HIV-1 infection resistance and other pathological conditions. In European populations, the allele frequency ranges from 10-16%, and its evolution has been extensively debated throughout the years. 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 for this deletion across 860 low-coverage ancient genomes and we found evidence that CCR5delta32 arose at least 7,000 years BP, with a likely origin somewhere in the Western Eurasian Steppe region. We further show evidence that the CCR5delta32 haplotype underwent positive selection between 7,000-2,000 BP in Western Eurasia and that the presence of the haplotype in Latin America can be explained by post-Columbian genetic exchanges. Finally, we point to new complex CCR5delta32 genotype-haplotype-phenotype relationships, which demand consideration when targeting the CCR5 receptor for therapeutic strategies.