Advances in Understanding Adaptive Hemoglobin Concentration at High Altitude

Abstract

Hb-­O2 affinity, and later through increases in red cell volume (Siebenmann et al. 2015). Among high-­altitude-­adapted populations, we see distinct hematological adaptations to hypoxia both between and in comparison to high-­altitude sojourners. Tibetans display a relatively low erythropoietic response and attendant low Hb concentration (Adams and Strang 1975; Beall and Goldstein 1987; Beall and Reichsman 1984). Andeans exhibit elevated concentrations with some individuals presenting with polycythemia, or the increase of hematocrit and/or Hb (Beall et al. 1990, 1998). Hematocrit is related to Hb concentration and measures the percentage of whole blood composed of red blood cells. High-­altitude Ethiopians of mainly Amharic ancestry show similar Hb concentrations compared to low-­altitude US residents (Beall et al. 2002), but high-­altitude Amhara and Oromo exhibit elevated Hb levels compared to their low-­altitude (< 1500 masl) counterparts (Scheinfeldt et al. 2012; Alkorta-­ Aranburu et al. 2012), with Oromo displaying twice the elevation in Hb level compared to Amhara (Alkorta-­A ranburu et al. 2012). Collectively, this physiological evidence demonstrates that modifications to Hb concentration play an important role in the biological response to hypoxia. A cohort of genome-­ w ide investigations published in 2010 demonstrated that Andeans and Tibetans have adapted by natural selection to high-­altitude hypoxia (Beall et al. 2010; Bigham et al. 2010; Simonson et al. 2010; Yi et al. 2010), and, among Tibetans, that adaptive genetic variation contributed to their blunted Hb phenotype. In particular, two genes central to the hypoxia inducible factor (HIF) pathway, an evolutionarily ancient transcriptional regulatory pathway for the cellular response to hypoxia (Semenza 2012), showed signatures of positive selection