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Objectives: The 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]). Methods: To investigate splenic contraction in response to exercise at high‐altitude (4300 m; Pb = ~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). Results: Resting 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), SpO2 decreased (~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 CaO2 with exercise (p‐values from.026 to.037 and R2 values from 0.059 to 0.067 for the predictor variable). Conclusions: Larger spleens and greater splenic contraction may be an adaptive characteristic of Nepali Sherpa to increase CaO2 during exercise at altitude, but the direct link between spleen size/function and hypoxia tolerance remains unclear. [ABSTRACT FROM AUTHOR]

The human spleen contracts in response to stress‐induced catecholamine secretion, resulting in a temporary rise in haemoglobin concentration ([Hb]). Recent findings highlighted enhanced splenic response to exercise at high altitude in Sherpa, possibly due to a blunted splenic response to hypoxia. To explore the potential blunted splenic contraction in Sherpas at high altitude, we examined changes in spleen volume during hyperoxic breathing, comparing acclimatized Sherpa with acclimatized individuals of lowland ancestry. Our study included 14 non‐Sherpa (7 female) residing at altitude for a mean continuous duration of 3 months and 46 Sherpa (24 female) with an average of 4 years altitude exposure. Participants underwent a hyperoxic breathing test at altitude (4300 m; barrometric pressure = ∼430 torr; PO2${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ = ∼90 torr). Throughout the test, we measured spleen volume using ultrasonography and monitored oxygen saturation (SpO2${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$). During rest, Sherpa exhibited larger spleens (226 ± 70 mL) compared to non‐Sherpa (165 ± 34 mL; P < 0.001; effect size (ES) = 0.95, 95% CI: 0.3–1.6). In response to hyperoxia, non‐Sherpa demonstrated 22 ± 12% increase in spleen size (35 ± 17 mL, 95% CI: 20.7–48.9; P < 0.001; ES = 1.8, 95% CI: 0.93–2.66), while spleen size remained unchanged in Sherpa (−2 ± 13 mL, 95% CI: −2.4 to 7.3; P = 0.640; ES = 0.18, 95% CI: −0.10 to 0.47). Our findings suggest that Sherpa and non‐Sherpas of lowland ancestry exhibit distinct variations in spleen volume during hyperoxia at high altitude, potentially indicating two distinct splenic functions. In Sherpa, this phenomenon may signify a diminished splenic response to altitude‐related hypoxia at rest, potentially contributing to enhanced splenic contractions during physical stress. Conversely, non‐Sherpa experienced a transient increase in spleen size during hyperoxia, indicating an active tonic contraction, which may influence early altitude acclimatization in lowlanders by raising [Hb]. What is the central question of this study?Indigenous Sherpa exhibit greater spleen size and enhanced exercise‐induced contraction at high altitude compared to lowlanders: how does spleen size of Sherpa and lowlanders respond to hyperoxic breathing at high altitude?What is the main finding and its importance?Sherpa do not experience any changes in spleen size when subjected to hyperoxic breathing at high altitude, whereas lowlanders show a 20% increase in spleen size under similar conditions. This may represent adaptive traits in Sherpa, potentially enhancing the spleen's capacity for contractions during increased metabolic demands. [ABSTRACT FROM AUTHOR]

Objectives: Potatoes are an important staple crop across the world and particularly in the Andes, where they were cultivated as early as 10,000 years ago. Ancient Andean populations that relied upon this high‐starch food to survive could possess genetic adaptation(s) to digest potato starch more efficiently. Here, we analyzed genomic data to identify whether this putative adaptation is still present in their modern‐day descendants, namely Peruvians of Indigenous American ancestry. Materials and methods: We applied several tests to detect signatures of natural selection in genes associated with starch‐digestion, AMY1, AMY2, SI, and MGAM in Peruvians. These were compared to two populations who only recently incorporated potatoes into their diets, Han Chinese and West Africans. Results: Overlapping statistical results identified a regional haplotype in MGAM that is unique to Peruvians. The age of this haplotype was estimated to be around 9547 years old. Discussion: The MGAM haplotype in Peruvians lies within a region of high transcriptional activity associated with the REST protein. The timing of this haplotype suggests that it arose in response to increased potato cultivation and attendant consumption. For Peruvian populations that relied upon the high‐starch potato as a major source of nutrition, natural selection likely favored these MGAM variant(s) that led to more efficient digestion and increased glucose production. This research provides further support that detecting subtle shifts in human diet can be a major driver of human evolutionary change, as these results indicate that there is global variation in human ability to better digest high‐starch foods. [ABSTRACT FROM AUTHOR]

Objectives High-altitude hypoxia, or decreased oxygen levels caused by low barometric pressure, challenges the ability of humans to live and reproduce. Despite these challenges, human populations have lived on the Andean Altiplano and the Tibetan Plateau for millennia and exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. We and others have identified natural selection candidate genes and gene regions for these adaptations using dense genome scan data. One gene previously known to be important in cellular oxygen sensing, egl nine homolog 1 ( EGLN1), shows evidence of positive selection in both Tibetans and Andeans. Interestingly, the pattern of variation for this gene differs between the two populations. Continued research among Tibetan populations has identified statistical associations between hemoglobin concentration and single nucleotide polymorphism ( SNP) genotype at EGLN1 and a second gene, endothelial PAS domain protein 1 ( EPAS1). Methods To measure for the effects of EGLN1 and EPAS1 altitude genotypes on hemoglobin concentration among Andean highlanders, we performed a multiple linear regression analysis of 10 candidate SNPs in or near these two genes. Results Our analysis did not identify significant associations between EPAS1 or EGLN1 SNP genotypes and hemoglobin concentration in Andeans. Conclusions These results contribute to our understanding of the unique set of adaptations developed in different highland groups to the hypoxia of high altitude. Overall, the results provide key insights into the patterns of geneticadaptation to high altitude in Andean and Tibetan populations. Am. J. Hum. Biol. 25:190-197, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation-positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]