Uncovering Signals of Positive Selection in Peruvian Populations from Three Ecological Regions.

Peru hosts extremely diverse ecosystems which can be broadly classified into the following three major ecoregions: the Pacific desert coast, the Andean highlands, and the Amazon rainforest. Since its initial peopling approximately 12,000 years ago, the populations inhabiting such ecoregions might have differentially adapted to their contrasting environmental pressures. Previous studies have described several candidate genes underlying adaptation to hypobaric hypoxia among Andean highlanders. However, the adaptive genetic diversity of coastal and rainforest populations has been less studied. Here, we gathered genome-wide single-nucleotide polymorphism-array data from 286 Peruvians living across the three ecoregions and analyzed signals of recent positive selection through population differentiation and haplotype-based selection scans. Among highland populations, we identify candidate genes related to cardiovascular function (TLL1, DUSP27, TBX5, PLXNA4, SGCD), to the Hypoxia-Inducible Factor pathway (TGFA, APIP), to skin pigmentation (MITF), as well as to glucose (GLIS3) and glycogen metabolism (PPP1R3C, GANC). In contrast, most signatures of adaptation in coastal and rainforest populations comprise candidate genes related to the immune system (including SIGLEC8, TRIM21, CD44, and ICAM1 in the coast; CBLB and PRDM1 in the rainforest; and BRD2, HLA-DOA, HLA-DPA1 regions in both), possibly as a result of strong pathogen-driven selection. This study identifies candidate genes related to human adaptation to the diverse environments of South America.

Genome-wide CNV analysis reveals variants associated with high-altitude adaptation and meat traits in Qaidam cattle

BACKGROUND Qaidam cattle are local breeds that habitats in northwest China. It has many excellent characteristics, such as high cold and roughage tolerance, low oxygen adaptability, and tender meat quality. Copy number variation (CNV) can induce phenotypic changes in animals by a variety of effects, and thus affects the biological functions of the animals. To explore the molecular mechanism of its adaptation to extreme cold weather and muscle fat development, the CNV variations in the genome of three Qaidam cattle were detected by whole-genome sequencing, in this study. RESULTS : A total of 16,743 CNVs and 9498 copy number variable regions (CNVRs) were obtained after the screening, which accounts for 2.18% of the bovine genome. The CNVR length detected ranged from 0.3 KB to 10.77 KB, with a total length of 58.17 MB and an average length of 6.12 KB/ CNVR. Through functional enrichment of CNVR related genes, LDHB, and ME1 genes were screened as the key genes for Qaidam cattle to adapt to the cold and low oxygen environments, whereas KIT and FGF18 genes might be related to the coat color and growth. In the CNVR overlapped with QTLs, variation in CAPN1 and CAST genes might be closely related to the tender meat quality of Qaidam cattle. CONCLUSIONS Therefore, this study provides new genetic insights on the environmental adaptability and important economic traits of Qaidam cattle

Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes.

High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled nitric oxide also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.

Individual variations and sex differences in hemodynamics with percutaneous arterial oxygen saturation (SpO2) in young Andean highlanders in Bolivia.

BACKGROUND: Many studies have reported specific adaptations to high altitude, but few studies have focused on physiological variations in high-altitude adaptation in Andean highlanders. This study aimed to investigate the relationships between SpO2 and related factors, including individual variations and sex differences, in Andean highlanders. METHODS: The participants were community-dwelling people in La Paz, Bolivia, aged 20 years and over (age range 20-34 years). A total of 50 men and 50 women participated in this study. Height, weight, SpO2, hemoglobin concentration, finger temperature, heart rate, and blood pressure were measured. Information about lifestyle was also obtained by interview. RESULTS: There were individual variations of SpO2 both in men (mean 89.9%, range 84.0-95.0%) and women (mean 91.0%, range 84.0-96.0%). On Student's t test, men had significantly lower heart rate (p = 0.046) and SpO2 (p = 0.030) than women. On the other hand, men had significantly higher SBP (p < 0.001), hemoglobin (p < 0.001), and finger temperature (p = 0.004). In men, multiple stepwise regression analysis showed that a higher SpO2 was correlated with a lower heart rate (ß = - 0.089, p = 0.007) and a higher finger temperature (ß = 0.308, p = 0.030) (r2 for model = 0.18). In women, a higher SpO2 was significantly correlated with a higher finger temperature (ß = 0.391, p = 0.015) (r2 for model = 0.12). A higher SpO2 was related to a higher finger temperature (ß = 0.286, p = 0.014) and a lower heart rate (ß = - 0.052, p = 0.029) in all participants (r2 for model = 0.21). Residual analysis showed that individual SpO2 values were randomly plotted. CONCLUSION: Random plots of SpO2 on residual analysis indicated that these variations were random error, such as biological variation. A higher SpO2 was related to a lower heart rate and finger temperature in men, but a higher SpO2 was related to finger temperature in women. These results suggest that there are individual variations and sex differences in the hemodynamic responses of high-altitude adaptation in Andean highlanders.

Convergent changes in muscle metabolism depend on duration of high-altitude ancestry across Andean waterfowl.

High-altitude environments require that animals meet the metabolic O2 demands for locomotion and thermogenesis in O2-thin air, but the degree to which convergent metabolic changes have arisen across independent high-altitude lineages or the speed at which such changes arise is unclear. We examined seven high-altitude waterfowl that have inhabited the Andes (3812-4806 m elevation) over varying evolutionary time scales, to elucidate changes in biochemical pathways of energy metabolism in flight muscle relative to low-altitude sister taxa. Convergent changes across high-altitude taxa included increased hydroxyacyl-coA dehydrogenase and succinate dehydrogenase activities, decreased lactate dehydrogenase, pyruvate kinase, creatine kinase, and cytochrome c oxidase activities, and increased myoglobin content. ATP synthase activity increased in only the longest established high-altitude taxa, whereas hexokinase activity increased in only newly established taxa. Therefore, changes in pathways of lipid oxidation, glycolysis, and mitochondrial oxidative phosphorylation are common strategies to cope with high-altitude hypoxia, but some changes require longer evolutionary time to arise.

The Genetic Architecture of Chronic Mountain Sickness in Peru.

Chronic mountain sickness (CMS) is a pathological condition resulting from chronic exposure to high-altitude hypoxia. While its prevalence is high in native Andeans (>10%), little is known about the genetic architecture of this disease. Here, we performed the largest genome-wide association study (GWAS) of CMS (166 CMS patients and 146 controls living at 4,380 m in Peru) to detect genetic variants associated with CMS. We highlighted four new candidate loci, including the first CMS-associated variant reaching GWAS statistical significance (rs7304081; P = 4.58 × 10-9). By looking at differentially expressed genes between CMS patients and controls around these four loci, we suggested AEBP2, CAST, and MCTP2 as candidate CMS causal genes. None of the candidate loci were under strong natural selection, consistent with the observation that CMS affects fitness mainly after the reproductive years. Overall, our results reveal new insights on the genetic architecture of CMS and do not provide evidence that CMS-associated variants are linked to a strong ongoing adaptation to high altitude.

Control of breathing and respiratory gas exchange in high-altitude ducks native to the Andes.

We examined the control of breathing and respiratory gas exchange in six species of high-altitude duck that independently colonized the high Andes. We compared ducks from high-altitude populations in Peru (Lake Titicaca at ∼3800 m above sea level; Chancay River at ∼3000-4100 m) with closely related populations or species from low altitude. Hypoxic ventilatory responses were measured shortly after capture at the native altitude. In general, ducks responded to acute hypoxia with robust increases in total ventilation and pulmonary O2 extraction. O2 consumption rates were maintained or increased slightly in acute hypoxia, despite ∼1-2°C reductions in body temperature in most species. Two high-altitude taxa - yellow-billed pintail and torrent duck - exhibited higher total ventilation than their low-altitude counterparts, and yellow-billed pintail exhibited greater increases in pulmonary O2 extraction in severe hypoxia. In contrast, three other high-altitude taxa - Andean ruddy duck, Andean cinnamon teal and speckled teal - had similar or slightly reduced total ventilation and pulmonary O2 extraction compared with low-altitude relatives. Arterial O2 saturation (SaO2 ) was elevated in yellow-billed pintails at moderate levels of hypoxia, but there were no differences in SaO2  in other high-altitude taxa compared with their close relatives. This finding suggests that improvements in SaO2  in hypoxia can require increases in both breathing and haemoglobin-O2 affinity, because the yellow-billed pintail was the only high-altitude duck with concurrent increases in both traits compared with its low-altitude relative. Overall, our results suggest that distinct physiological strategies for coping with hypoxia can exist across different high-altitude lineages, even among those inhabiting very similar high-altitude habitats.

Neonatal anthropometry at 3400 m above sea level compared with INTERGROWTH 21st standards.

OBJECTIVE: To determine the 3rd, 10th, 50th, 90th and 97th percentile of weight, length and head circumference (HC) of male and female neonates born at 3400 m above sea level and compare with published INTERGROWTH 21st standards. METHODS: Observational, transverse analytical study conducted in the National Hospital Adolfo Guevara Velazco of the ESSALUD hospital system in Cusco, Peru, at 3400 m altitude, during the period of January 2005 to December 2010. Using inclusion criteria, 7635 newborns were selected. The 3rd, 10th, 50th, 90th and 97th percentiles for the anthropometric measurements of birthweight, length and HC were determined for each sex and the results analyzed via polynomial regression for each percentile in order to compare the results with INTERGROWTH 21st standards. RESULTS: No statistically significant difference was observed with the exception of female HC at the 97th percentile when compared with the INTERGROWTH 21st standards. CONCLUSIONS: Based on tables generated in the present study, neonatal anthropometric percentiles at term at 3400 m above sea level demonstrate no appreciable difference with INTERGROWTH 21st standards with the exception of female HC at the 97th percentile.

Genome of Plant Maca (Lepidium meyenii) Illuminates Genomic Basis for High-Altitude Adaptation in the Central Andes.

Maca (Lepidium meyenii Walp, 2n = 8x = 64), belonging to the Brassicaceae family, is an economic plant cultivated in the central Andes sierra in Peru (4000-4500 m). Considering that the rapid uplift of the central Andes occurred 5-10 million years ago (Ma), an evolutionary question arises regarding how plants such as maca acquire high-altitude adaptation within a short geological period. Here, we report the high-quality genome assembly of maca, in which two closely spaced maca-specific whole-genome duplications (WGDs; ∼6.7 Ma) were identified. Comparative genomic analysis between maca and closely related Brassicaceae species revealed expansions of maca genes and gene families involved in abiotic stress response, hormone signaling pathway, and secondary metabolite biosynthesis via WGDs. The retention and subsequent functional divergence of many duplicated genes may account for the morphological and physiological changes (i.e., small leaf shape and self-fertility) in maca in a high-altitude environment. In addition, some duplicated maca genes were identified with functions in morphological adaptation (i.e., LEAF CURLING RESPONSIVENESS) and abiotic stress response (i.e., GLYCINE-RICH RNA-BINDING PROTEINS and DNA-DAMAGE-REPAIR/TOLERATION 2) under positive selection. Collectively, the maca genome provides useful information to understand the important roles of WGDs in the high-altitude adaptation of plants in the Andes.

Repeated elevational transitions in hemoglobin function during the evolution of Andean hummingbirds.

Animals that sustain high levels of aerobic activity under hypoxic conditions (e.g., birds that fly at high altitude) face the physiological challenge of jointly optimizing blood-O2 affinity for O2 loading in the pulmonary circulation and O2 unloading in the systemic circulation. At high altitude, this challenge is especially acute for small endotherms like hummingbirds that have exceedingly high mass-specific metabolic rates. Here we report an experimental analysis of hemoglobin (Hb) function in South American hummingbirds that revealed a positive correlation between Hb-O2 affinity and native elevation. Protein engineering experiments and ancestral-state reconstructions revealed that this correlation is attributable to derived increases in Hb-O2 affinity in highland lineages, as well as derived reductions in Hb-O2 affinity in lowland lineages. Site-directed mutagenesis experiments demonstrated that repeated evolutionary transitions in biochemical phenotype are mainly attributable to repeated amino acid replacements at two epistatically interacting sites that alter the allosteric regulation of Hb-O2 affinity. These results demonstrate that repeated changes in biochemical phenotype involve parallelism at the molecular level, and that mutations with indirect, second-order effects on Hb allostery play key roles in biochemical adaptation.

Systems biology approach to study the high altitude adaptation in tibetans

The aim of this work was to study an integrative systems biology research strategy to construct a network including the protein-protein interactions (PPIs) and microRNAs (miRNAs) and identify the functional biological processes and pathways for high-altitude adaptation in Tibetans. The pathway enrichment analysis revealed that the genes in the network were mainly involved in signling the pathways and the function of microRNAs was concentrated in the signling pathways, which suggested that miRNAs might contribute to the Tibetans high-altitude adaptation through the participation in signaling pathway. These results contribute to better understanding on the high-altitude adaptation of the Tibetans.