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1. Larger spleens and greater splenic contraction during exercise may be an adaptive characteristic of Nepali Sherpa at high‐altitude

   https://doi.org/10.1002/ajhb.24090  

   Brutsaert, Tom D; Harman, Taylor Shay; Bigham, Abigail W; Kalker, Anne; Jorgensen, Kelsey C; Zhu, Kimberly T; Steiner, Bethany C; Hawkins, Ella; Day, Trevor A; Kunwar, Ajaya J; et al (May 2024, American Journal of Human Biology)

   Abstract ObjectivesThe Sherpa ethnic group living at altitude in Nepal may have experienced natural selection in response to chronic hypoxia. We have previously shown that Sherpa in Kathmandu (1400 m) possess larger spleens and a greater apnea‐induced splenic contraction compared to lowland Nepalis. This may be significant for exercise capacity at altitude as the human spleen responds to stress‐induced catecholamine secretion by an immediate contraction, which results in transiently elevated hemoglobin concentration ([Hb]). MethodsTo investigate splenic contraction in response to exercise at high‐altitude (4300 m; P_b = ~450 Torr), we recruited 63 acclimatized Sherpa (29F) and 14 Nepali non‐Sherpa (7F). Spleen volume was measured before and after maximal exercise on a cycle ergometer by ultrasonography, along with [Hb] and oxygen saturation (SpO₂). ResultsResting spleen volume was larger in the Sherpa compared with Nepali non‐Sherpa (237 ± 62 vs. 165 ± 34 mL,p < .001), as was the exercise‐induced splenic contraction (Δspleen volume, 91 ± 40 vs. 38 ± 32 mL,p < .001). From rest to exercise, [Hb] increased (1.2 to 1.4 g.dl⁻¹), SpO₂decreased (~9%) and calculated arterial oxygen content (CaO₂) remained stable, but there were no significant differences between groups. In Sherpa, both resting spleen volume and the Δspleen volume were modest positive predictors of the change (Δ) in [Hb] and CaO₂with exercise (p‐values from .026 to .037 and R²values from 0.059 to 0.067 for the predictor variable). ConclusionsLarger spleens and greater splenic contraction may be an adaptive characteristic of Nepali Sherpa to increase CaO₂during exercise at altitude, but the direct link between spleen size/function and hypoxia tolerance remains unclear. 

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2. Genetic variation in haemoglobin is associated with evolved changes in breathing in high-altitude deer mice

   https://doi.org/10.1242/jeb.243595  

   Ivy, Catherine M.; Wearing, Oliver H.; Natarajan, Chandrasekhar; Schweizer, Rena M.; Gutiérrez-Pinto, Natalia; Velotta, Jonathan P.; Campbell-Staton, Shane C.; Petersen, Elin E.; Fago, Angela; Cheviron, Zachary A.; et al (January 2022, Journal of Experimental Biology)

   ABSTRACT Physiological systems often have emergent properties but the effects of genetic variation on physiology are often unknown, which presents a major challenge to understanding the mechanisms of phenotypic evolution. We investigated whether genetic variants in haemoglobin (Hb) that contribute to high-altitude adaptation in deer mice (Peromyscus maniculatus) are associated with evolved changes in the control of breathing. We created F2 inter-population hybrids of highland and lowland deer mice to test for phenotypic associations of α- and β-globin variants on a mixed genetic background. Hb genotype had expected effects on Hb–O2 affinity that were associated with differences in arterial O2 saturation in hypoxia. However, high-altitude genotypes were also associated with breathing phenotypes that should contribute to enhancing O2 uptake in hypoxia. Mice with highland α-globin exhibited a more effective breathing pattern, with highland homozygotes breathing deeper but less frequently across a range of inspired O2, and this difference was comparable to the evolved changes in breathing pattern in deer mouse populations native to high altitude. The ventilatory response to hypoxia was augmented in mice that were homozygous for highland β-globin. The association of globin variants with variation in breathing phenotypes could not be recapitulated by acute manipulation of Hb–O2 affinity, because treatment with efaproxiral (a synthetic drug that acutely reduces Hb–O2 affinity) had no effect on breathing in normoxia or hypoxia. Therefore, adaptive variation in Hb may have unexpected effects on physiology in addition to the canonical function of this protein in circulatory O2 transport. 

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3. Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude

   https://doi.org/10.1073/pnas.1906171116  

   Brutsaert, Tom D.; Kiyamu, Melisa; Elias Revollendo, Gianpietro; Isherwood, Jenna L.; Lee, Frank S.; Rivera-Ch, Maria; Leon-Velarde, Fabiola; Ghosh, Sudipta; Bigham, Abigail W. (November 2019, Proceedings of the National Academy of Sciences)

   Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO 2 max) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated Egl-9 homolog 1 gene ( EGLN1 ) as a candidate gene. The encoded protein, EGLN1/PHD2, is an O 2 sensor that controls levels of the Hypoxia Inducible Factor-α (HIF-α), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 EGLN1 SNPs associated with higher VO 2 max (L⋅min −1 and mL⋅min −1 ⋅kg −1 ) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VO 2 max) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VO 2 max genotype categories differing by ∼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL⋅min −1 ⋅kg −1 vs. CC = 30.5 mL⋅min −1 ⋅kg −1 ). To guard against spurious association, we controlled for population stratification. Findings were replicated for EGLN1 SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at EGLN1 in Andeans, and support the hypothesis that natural selection has increased the frequency of an EGLN1 causal variant that enhances O 2 delivery or use during exercise at altitude in Peruvian Quechua. 

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4. The adaptive benefit of evolved increases in hemoglobin-O2 affinity is contingent on tissue O2 diffusing capacity in high-altitude deer mice

   https://doi.org/10.1186/s12915-021-01059-4  

   Wearing, Oliver H.; Ivy, Catherine M.; Gutiérrez-Pinto, Natalia; Velotta, Jonathan P.; Campbell-Staton, Shane C.; Natarajan, Chandrasekhar; Cheviron, Zachary A.; Storz, Jay F.; Scott, Graham R. (December 2021, BMC Biology)

   null (Ed.)

   Abstract Background Complex organismal traits are often the result of multiple interacting genes and sub-organismal phenotypes, but how these interactions shape the evolutionary trajectories of adaptive traits is poorly understood. We examined how functional interactions between cardiorespiratory traits contribute to adaptive increases in the capacity for aerobic thermogenesis (maximal O 2 consumption, V̇ O 2 max, during acute cold exposure) in high-altitude deer mice ( Peromyscus maniculatus ). We crossed highland and lowland deer mice to produce F 2 inter-population hybrids, which expressed genetically based variation in hemoglobin (Hb) O 2 affinity on a mixed genetic background. We then combined physiological experiments and mathematical modeling of the O 2 transport pathway to examine the links between cardiorespiratory traits and V̇ O 2 max. Results Physiological experiments revealed that increases in Hb-O 2 affinity of red blood cells improved blood oxygenation in hypoxia but were not associated with an enhancement in V̇ O 2 max. Sensitivity analyses performed using mathematical modeling showed that the influence of Hb-O 2 affinity on V̇ O 2 max in hypoxia was contingent on the capacity for O 2 diffusion in active tissues. Conclusions These results suggest that increases in Hb-O 2 affinity would only have adaptive value in hypoxic conditions if concurrent with or preceded by increases in tissue O 2 diffusing capacity. In high-altitude deer mice, the adaptive benefit of increasing Hb-O 2 affinity is contingent on the capacity to extract O 2 from the blood, which helps resolve controversies about the general role of hemoglobin function in hypoxia tolerance. 

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5. COVID-19 and silent hypoxemia in a minimal closed-loop model of the respiratory rhythm generator

   https://doi.org/10.1007/s00422-024-00989-w  

   Diekman, Casey O; Thomas, Peter J; Wilson, Christopher G (June 2024, Biological Cybernetics)

   Abstract Silent hypoxemia, or "happy hypoxia", is a puzzling phenomenon in which patients who have contracted COVID-19 exhibit very low oxygen saturation ( ${\text{SaO}}_2$< 80%) but do not experience discomfort in breathing. The mechanism by which this blunted response to hypoxia occurs is unknown. We have previously shown that a computational model of the respiratory neural network (Diekman et al. in J Neurophysiol 118(4):2194–2215, 2017) can be used to test hypotheses focused on changes in chemosensory inputs to the central pattern generator (CPG). We hypothesize that altered chemosensory function at the level of the carotid bodies and/or thenucleus tractus solitariiare responsible for the blunted response to hypoxia. Here, we use our model to explore this hypothesis by altering the properties of the gain function representing oxygen sensing inputs to the CPG. We then vary other parameters in the model and show that oxygen carrying capacity is the most salient factor for producing silent hypoxemia. We call for clinicians to measure hematocrit as a clinical index of altered physiology in response to COVID-19 infection. 

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