Adaptively introgressed Neandertal haplotype at the OAS locus functionally 1

Title: Adaptively introgressed Neandertal haplotype at the OAS locus functionally 1 impacts innate immune responses in humans. 18. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not. doi: bioRxiv preprint first posted online May. 3, 2016;. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not. doi: bioRxiv preprint first posted online May. 3, 2016;. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not. doi: bioRxiv preprint first posted online May. 3, 2016;. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not. doi: bioRxiv preprint first posted online May. 3, 2016;. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not. doi: bioRxiv preprint first posted online May. 3, 2016;. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not. doi: bioRxiv preprint first posted online May. 3, 2016;. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not. Abstract 19 The 2'-5' oligoadenylate synthetase (OAS) locus encodes for three OAS enzymes 20 (OAS1-3) involved in innate immune response. This region harbors high amounts 21 of Neandertal ancestry in non-African populations; yet, strong evidence of positive 22 selection in the OAS region is still lacking. Here we used a combination of neutral 23 coalescent simulations and neutrality tests to firmly demonstrate a signal of 24 adaptive introgression at the OAS locus. Furthermore, we characterized the 25 functional consequences of the Neandertal haplotype in the transcriptional 26 regulation of OAS genes at baseline and infected conditions. We found that cells 27 from people with the Neandertal-like haplotype express lower levels of OAS3 28 upon infection, as well as distinct isoforms of OAS1 and OAS2. Notably, the 29 Neandertal-introgressed haplotype reintroduced an ancestral splice variant of 30 OAS1 encoding a more active protein, suggesting that adaptive introgression 31 occurred as a means to resurrect adaptive variation that had been lost outside 32 Africa.