High-altitude environments and spleen function in humans

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Some humans living in mountainous regions of the world are adapted to the low oxygen conditions of high-altitude, particularly notable during mountaineering activity. The main goal of this project is to examine the role of the human spleen in exercise tolerance at altitude, and to assess the ways in which this pressure has shaped the function of the spleen in populations who have lived and exercised at altitude for thousands of years. The spleen regulates circulating red blood cells and thus the oxygen carrying capacity of the blood; in other species (e.g., diving mammals, racehorses) research has shown that the spleen plays a critical role in individuals engaging in activity with high metabolic demand when oxygen is a limiting factor. This could also be true for humans, as prior work has documented larger spleens and significantly enhanced spleen function in some high-altitude populations compared to those living closer to sea level. The current project will measure spleen function during exercise in high- and low-altitude living populations over a length of time in which both groups are exercising at increasingly high altitudes. This project is linked to a study-abroad course which offers research opportunities for both graduate and undergraduate students, and the research also directly engages local community members and implementing partners. Highland native populations have been exposed to hypobaric hypoxia for millennia. In some such populations, natural selection has acted on genes which are associated with lower circulating hemoglobin concentration [Hb]. In hypoxia tolerant species like diving mammals, circulating [Hb] is dynamically regulated by contraction of the spleen to elevate circulating red blood cells (RBCs) during high metabolic demand. Splenic contraction also occurs in humans with exercise and hypoxia exposure. The researchers have documented that some high-altitude adapted populations have 19-35% larger resting spleen volume and 5-fold greater splenic contraction compared to controls. This is similar to the 35% larger spleen volume documented in breath-hold diving marine hunter-gatherer populations; genomic analysis of breath-hold diving populations suggest positive selection on spleen volume and/or the human diving response. This study tests the hypothesis that natural selection has modified spleen size and splenic contraction to optimize aerobic performance at altitude in the context of an incremental 7-day ascent to altitude from 1,440 to 4,370 meters where spleen volume, splenic contraction, changes in [Hb], and other features of the hemodynamic system during this time period will be assessed. Whole genome sequence data will be used to explore selection at loci of a priori interest and across the genome broadly. The approach will be to conduct association analyses of splenic and hematological phenotypes with previously identified candidate genes as well as the top selection-nominated genes identified via population genetic statistical tests used to identify genomic signatures of directional selection. Positive research findings could be transformative and would open avenues for future physiological and genomic work on the adaptive response of highland native populations around the world.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.