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

Area of Science:

• Human adaptation to extreme environments
• Population genomics and genetics
• Physiological responses to hypoxia

Background:

• High-altitude hypoxia poses significant challenges to human survival and reproduction.
• Andean populations exhibit unique physiological adaptations to hypoxia, including elevated hemoglobin concentration ([Hb]).
• Previous studies on natural selection shaping Andean [Hb] have yielded conflicting results.

Purpose of the Study:

• To investigate the role of natural selection in shaping hemoglobin concentration ([Hb]) in Andean populations.
• To identify specific genes and genomic regions under selection associated with [Hb] in Peruvians.
• To understand the mechanisms by which natural selection may be influencing [Hb] levels.

Main Methods:

• Genome-wide array data analysis from Peruvian Andeans.
• Identification of genomic regions and genes associated with [Hb] using statistical association.
• Whole Genome Sequencing (WGS) data analysis combined with publicly available expression and Hi-C data.

Main Results:

• Two genomic regions, including PDE1B, PPP1R1A, and RASGEF1B, showed evidence of recent positive selection associated with [Hb].
• Andean alleles within these selected regions were linked to lower [Hb] levels, suggesting selection for reduced hemoglobin.
• A selective sweep favoring PDE1B expression-decreasing alleles was identified near hemoglobin-linked genes.

Conclusions:

• Novel evidence suggests polygenic natural selection is actively lowering hemoglobin concentration ([Hb]) in Andean populations.
• This adaptive response in Andeans is phenotypically convergent with the adaptation observed in Tibetan populations.
• Understanding these genetic mechanisms is crucial for comprehending human resilience in high-altitude environments.