HLA-G 3'UTR haplotype frequencies in highland and lowland South Native American populations.

Human Leukocyte Antigen (HLA)-G participates in several biological processes, including reproduction, vascular remodeling, immune tolerance, and hypoxia response. HLA-G is a potential candidate gene for high altitude adaptation since its expression is modulated in both micro and macro environment under hypoxia and constant cellular stress. Besides the promoter region, the HLA-G 3'untranslated region (UTR) influences HLA-G expression patterns through several post-transcriptional mechanisms. Currently, the 3'UTR genetic diversity in terms of altitude adaptation of Native American populations is still unexplored, particularly at high altitude ecoregions. Here, we evaluated 288 Native Americans from 9 communities located in the Andes [highland (HL); ≥2,500 m (range = 2,838-4,433 m)] and 8 populations located in lowland (LL) regions [<2,500 m (range = 80-431 m); Amazonian tropical forest, Brazilian central plateau, and Chaco] of South America. In total, nine polymorphic sites and ten haplotypes were observed. The most frequent haplotypes (UTR-1, UTR-2, and UTR-3) accounted for ∼ 77% of haplotypes found in LL, while in the HL, the same haplotypes reach ∼ 93%. Also, a remarkable high frequency of putative ancestral UTR-5 haplotype was observed in LL (21.5%), while in HL UTR-2 reaches up to 47%. Further, UTR-2 frequency positively correlates with altitude-related variables, while a negative correlation for UTR-5 was observed. From an evolutionary perspective, we observed a tendency towards balancing selection in HL and LL populations thus suggesting that haplotypes of ancient and more derived alleles may have been co-opted for relatively recent adaptations such as those experienced by modern humans in the highland and lowland of South America. We also discuss how long-term balancing selection can be a reservoir of genetic variants that can be positively selected. Finally, our study provides some pieces of evidence that HLA-G 3'UTR haplotypes may have contributed to high altitude adaptation in the Andes.

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Copyright © 2021 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

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Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.