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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement K.R., L.C., and S.R. were supported by the Novo Nordisk Foundation (grant NNF14CC0001 and NNF21SA0072102). E.K.I.P was supported by the Lundbeck Foundation (grant R302-2018-2155), and the Novo Nordisk Foundation (grant NNF18SA0035006). E.K.I.P. and R.M. were additionally supported by a Villum Young Investigator grant given to F.R. (project no. 00025300). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: 1000 Genomes Project Phase 3 (1KGP3, http://www.1000genomes.org/) Ancient data sets: ENA Project ID: PRJEB9021 https://www.ebi.ac.uk/ena/browser/view/PRJEB9021 ENA Project ID: PRJEB37976 https://www.ebi.ac.uk/ena/browser/view/PRJEB37976 One of the datasets, which is part of an ongoing study, has not yet been published. However, the data from the study can be found in the bioRxiv preprint with the following DOI: https://doi.org/10.1101/2022.05.04.490594. Additionally, the ENA Project ID for the dataset will be published soon. It is important to note that the first and last co-authors of the aforementioned paper, Eske Willerslev, and Morten E. Allentoft, are also among the co-authors on this dataset. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All datasets used in our study are available online, except for the Meso/Neo dataset (/doi.org/10.1101/2022.05.04.490594), which is soon to be published on The European Nucleotide Archive (ENA).