Genomic Evidence for Natural Selection Underlying High-Altitude Adaptive Hemoglobin Levels Among Peruvian Andeans

Zhu K.; Jorgensen K.C.; Weinstein J.; Kiyamu M.; Elías G.; Isherwood J.L.; Breidenstein A.M.; Garcia O.A.; Gerdes G.; Pearson L.N.; Lee F.S.; Rivera-Ch M.; Leon-Velarde F.; Brutsaert T.D.; Bigham A.W. · Genome Biology and Evolution (2026) · DOI: 10.1093/gbe/evag164

Resumen

High-altitude hypoxia presents an extreme environmental pressure that challenges human survival, growth, and reproduction. Despite this challenge, humans have thrived on the Andean Altiplano for millennia, displaying several unique physiological responses to hypoxia such as elevated hemoglobin concentration ([Hb]). This trait closely resembles the acclimatization response observed among high-altitude sojourners but is distinct from the sea-level normative [Hb] that characterizes the Tibetan adaptive response. As recent candidate-gene efforts to understand the role of natural selection in shaping Andean [Hb] have produced conflicting results, it remains unclear what role natural selection may have played in shaping this unique hematopoietic response. Using genome-wide array data from Peruvian Andeans, we identified two genomic regions containing three genes, PDE1B, PPP1R1A, and RASGEF1B, that show evidence of recent positive selection and are associated with [Hb]. Importantly, Andean alleles within these regions are associated with lowered [Hb], suggesting that recent polygenic selection may be acting to reduce [Hb] within this population. We observe the greatest divergence of Andean allele frequencies from other global populations within the PDE1B/PPP1R1A region and use WGS data and publicly available expression and Hi-C data to more closely identify how natural selection may be acting within this region to impact [Hb]. We identify a selective sweep that favors 11 PDE1B expression-decreasing alleles and is located at the boundary of a topologically associating domain spanning several hemoglobin-linked genes. In sum, this study provides novel evidence that polygenic natural selection may be acting to lower Andean [Hb] in a manner phenotypically convergent with Tibetan populations. © The Author(s) 2026. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

Instituciones: Universidad Peruana Cayetano Heredia