Quantitative mRNA expression measurement at home.

mRNA measurement is dominated by RT-PCR, which requires expensive laboratory equipment and personnel with advanced degrees. Loop-mediated isothermal amplification (LAMP) is a versatile technique for detecting target DNA and RNA. The sensitivity of LAMP in early reports has been below that of the standard RT-PCR tests. Here, we report the use of a fluorescence-based RT-LAMP protocol to measure CDX2 expression patterns, which match extremely well to the standards of sophisticated RT-PCR techniques (r = 0.99, p < 0.001). The assay works on diverse sample types such as cDNA, mRNA, and direct tissue sample testing in 25 min compared to more than 3 h for RT-PCR. We have developed a new protocol for designing RT-LAMP primers that reduce false positives due to self-amplification and improve quantification. A simple device with a 3D-printed box enables the measurement of mRNA expression at home, outdoors, and point-of-care setting.

The Pupa Stage Is the Most Sensitive to Hypoxia in Drosophila melanogaster.

Hypoxia not only plays a critical role in multiple disease conditions; it also influences the growth and development of cells, tissues and organs. To identify novel hypoxia-related mechanisms involved in cell and tissue growth, studying a precise hypoxia-sensitive time window can be an effective approach. Drosophila melanogaster has been a useful model organism for studying a variety of conditions, and we focused in this study on the life cycle stages of Drosophila to investigate their hypoxia sensitivity. When normoxia-grown flies were treated with 4% O2 at the pupa stage for 3, 2 and 1 day/s, the eclosion rates were 6.1%, 66.7% and 96.4%, respectively, and, when 4% O2 was kept for the whole pupa stage, this regimen was lethal. Surprisingly, when our hypoxia-adapted flies who normally live in 4% O2 were treated with 4% O2 at the pupa stage, no fly eclosed. Within the pupa stage, the pupae at 2 and 3 days after pupae formation (APF), when treated for 2 days, demonstrated 12.5 ± 8.5% and 23.6 ± 1.6% eclosion, respectively, but this was completely lethal when treated for 3 days. We conclude that pupae, at 2 days APF and for a duration of a minimum of 2 days, were the most sensitive to hypoxia. Our data from our hypoxia-adapted flies clearly indicate that epigenetic factors play a critical role in pupa-stage hypoxia sensitivity.

Starch wall of urea: Facile starch modification to residue-free stable urea coating for sustained release and crop productivity.

Quick leaching of urea fertilizer encourages different coatings, but achieving a stable coating without toxic linkers is still challenging. Here, the naturally abundant bio-polymer, i.e., starch, has been groomed to form a stable coating through phosphate modification and the support of eggshell nanoparticles (ESN) as a reinforcement agent. The ESN offers a calcium ion binding site for the phosphate to cause bio-mimetic folding. This coating retains hydrophilic ends in the core and gives an excellent hydrophobic surface (water contact angle 123°). Further, the phosphorylated starch+ESN led the coating to release only ∼30 % of the nutrient in the initial ten days and sustained for up to 60 days to show ∼90 % release. The stability of the coating has been attributed to its resistance to major soil factors viz., acidity and amylase degradation. The ESN also increases elasticity, cracking control, and self-repairing capacity by serving as buffer micro-bots. The coated urea enhanced the yield of rice grain by ∼10%.

A Boolean approach for novel hypoxia-related gene discovery.

Hypoxia plays a major role in the etiology and pathogenesis of most of the leading causes of morbidity and mortality, whether cardiovascular diseases, cancer, respiratory diseases or stroke. Despite active research on hypoxia-signaling pathways, the understanding of regulatory mechanisms, especially in specific tissues, still remain elusive. With the accessibility of thousands of potentially diverse genomic datasets, computational methods are utilized to generate new hypotheses. Here we utilized Boolean implication relationship, a powerful method to probe symmetrically and asymmetrically related genes, to identify novel hypoxia related genes. We used a well-known hypoxia-responsive gene, VEGFA, with very large human expression datasets (n = 25,955) to identify novel hypoxia-responsive candidate gene/s. Further, we utilized in-vitro analysis using human endothelial cells exposed to 1% O2 environment for 2, 8, 24 and 48 hours to validate top candidate genes. Out of the top candidate genes (n = 19), 84% genes were previously reported as hypoxia related, validating our results. However, we identified FAM114A1 as a novel candidate gene significantly upregulated in the endothelial cells at 8, 24 and 48 hours of 1% O2 environment. Additional evidence, particularly the localization of intronic miRNA and numerous HREs further support and strengthen our finding. Current results on FAM114A1 provide an example demonstrating the utility of powerful computational methods, like Boolean implications, in playing a major role in hypothesis building and discovery.

Time Domains of Hypoxia Responses and -Omics Insights.

The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research.

Morphological, Molecular, and Biochemical Characterization of a Unique Lentil (Lens culinaris Medik.) Genotype Showing Seed-Coat Color Anomalies Due to Altered Anthocyanin Pathway.

This study reports the identification of a unique lentil (Lens culinaris Medik.) genotype L4717-NM, a natural mutant (NM) derived from a variety L4717, producing brown, black, and spotted seed-coat colored seeds in a single plant, generation after generation, in different frequencies. The genetic similarity of L4717 with that of L4717-NM expressing anomalous seed-coat color was established using 54 SSR markers. In addition, various biochemical parameters such as TPC (total phenolic content), TFC (total flavonoid content), DPPH (2,2-diphenyl-1-picrylhydrazyl), FRAP (ferric reducing antioxidant power), H2O2 (peroxide quantification), TCC (total carotenoids content), TAC (total anthocyanin content), and TAA (total ascorbic acid) were also studied in the seeds, sprouts, and seedlings of L4717, brown, black, and spotted seed-coat colored seeds. Stage-specific variations for the key biochemical parameters were recorded, and seedling stage was found the best for many parameters. Moreover, seeds with black seed coat showed better nutraceutical values for most of the studied traits. A highly significant (p ≤ 0.01) and positive correlation was observed between DPPH and TPC, TAA, TFC, etc., whereas, protein content showed a negative correlation with the other studied parameters. The seed coat is maternal tissue and we expect expression of seed-coat color as per the maternal genotype. However, such an anomalous seed-coat expression, which seems to probably be governed by some transposable element in the identified genotype, warrants more detailed studies involving exploitation of the anthocyanin pathway.

Yield optimization, microbial load analysis, and sensory evaluation of mungbean (Vigna radiata L.), lentil (Lens culinaris subsp. culinaris), and Indian mustard (Brassica juncea L.) microgreens grown under greenhouse conditions.

Microgreens have been used for raw consumption and are generally viewed as healthy food. This study aimed to optimize the yield parameters, shelf life, sensory evaluation and characterization of total aerobic bacteria (TAB), yeast and mold (Y&M), Escherichia coli, Salmonella spp., and Listeria spp. incidence in mungbean (Vigna radiata (L.) Wilczek), lentil (Lens culinaris Medikus subsp. culinaris), and Indian mustard (Brassica juncea (L.) Czern & Coss.) microgreens. In mungbean and lentil, seeding-density of three seed/cm2, while in Indian mustard, eight seed/cm2 were recorded as optimum. The optimal time to harvest mungbean, Indian mustard, and lentil microgreens were found as 7th, 8th, and 9th day after sowing, respectively. Interestingly, seed size was found highly correlated with the overall yield in both mungbeans (r2 = .73) and lentils (r2 = .78), whereas no such relationship has been recorded for Indian mustard microgreens. The target pathogenic bacteria such as Salmonella spp. and Listeria spp. were not detected; while TAB, Y&M, Shigella spp., and E. coli were recorded well within the limit to cause any human illness in the studied microgreens. Washing with double distilled water for two minutes has shown some reduction in the overall microbial load of these microgreens. The results provided evidence that microgreens if grown and stored properly, are generally safe for human consumption. This is the first study from India on the safety of mungbean, lentils, and Indian mustard microgreens.

Heterozygous Tropomodulin 3 mice have improved lung vascularization after chronic hypoxia.

The molecular mechanisms leading to high-altitude pulmonary hypertension (HAPH) remains poorly understood. We previously analyzed the whole genome sequence of Kyrgyz highland population and identified eight genomic intervals having a potential role in HAPH. Tropomodulin 3 gene (TMOD3), which encodes a protein that binds and caps the pointed ends of actin filaments and inhibits cell migration, was one of the top candidates. Here we systematically sought additional evidence to validate the functional role of TMOD3. In-silico analysis reveals that some of the SNPs in HAPH associated genomic intervals were positioned in a regulatory region that could result in alternative splicing of TMOD3. In order to functionally validate the role of TMOD3 in HAPH, we exposed Tmod3-/+ mice to 4 weeks of constant hypoxia, i.e. 10% O2 and analyzed both functional (hemodynamic measurements) and structural (angiography) parameters related to HAPH. The hemodynamic measurements, such as right ventricular systolic pressure, a surrogate measure for pulmonary arterial systolic pressure, and right ventricular contractility (RV- ± dP/dt), increases with hypoxia did not separate between Tmod3-/+ and control mice. Remarkably, there was a significant increase in the number of lung vascular branches and total length of pulmonary vascular branches (P < 0.001) in Tmod3-/+ after 4 weeks of constant hypoxia as compared with controls. Notably, the Tmod3-/+ endothelial cells migration was also significantly higher than that from the wild-type littermates. Our results indicate that, under chronic hypoxia, lower levels of Tmod3 play an important role in the maintenance or neo-vascularization of pulmonary arteries.

Diversity in Phytochemical Composition, Antioxidant Capacities, and Nutrient Contents Among Mungbean and Lentil Microgreens When Grown at Plain-Altitude Region (Delhi) and High-Altitude Region (Leh-Ladakh), India.

Mungbeans and lentils are relatively easily grown and cheaper sources of microgreens, but their phytonutrient diversity is not yet deeply explored. In this study, 20 diverse genotypes each of mungbean and lentil were grown as microgreens under plain-altitude (Delhi) and high-altitude (Leh) conditions, which showed significant genotypic variations for ascorbic acid, tocopherol, carotenoids, flavonoid, total phenolics, DPPH (1, 1-diphenyl-2-picrylhydrazyl), FRAP (ferric-reducing antioxidant power), peroxide activity, proteins, enzymes (peroxidase and catalase), micronutrients, and macronutrients contents. The lentil and mungbean genotypes L830 and MH810, respectively, were found superior for most of the studied parameters over other studied genotypes. Interestingly, for most of the studied parameters, Leh-grown microgreens were found superior to the Delhi-grown microgreens, which could be due to unique environmental conditions of Leh, especially wide temperature amplitude, photosynthetically active radiation (PAR), and UV-B content. In mungbean microgreens, total phenolics content (TPC) was found positively correlated with FRAP and DPPH, while in lentil microgreens, total flavonoid content (TFC) was found positively correlated with DPPH. The most abundant elements recorded were in the order of K, P, and Ca in mungbean microgreens; and K, Ca, and P in the lentil microgreens. In addition, these Fabaceae microgreens may help in the nutritional security of the population residing in the high-altitude regions of Ladakh, especially during winter months when this region remains landlocked due to heavy snowfall.

Effect of shading and high temperature amplitude in greenhouse on growth, photosynthesis, yield and phenolic contents of tomato (Lycopersicum esculentum Mill.).

Low temperature is the major environmental factor that limits the optimal field production of tomato in the high altitude mountain regions. Studies were conducted to determine the feasibility of growing tomato, a temperature sensitive crop, in a naturally ventilated passive solar greenhouse with high temperature amplitude (24.7 ± 3.0 °C). The study also aimed to determine the application of shade net combined with low-cost greenhouse technology. Despite the temperature fluctuation from 6.6 ± 2.1 °C at night to 39.1 ± 4.7 °C day temperature, flowering and fruiting were observed under the greenhouse conditions. The marketable yield inside the greenhouse was 1.8-times higher compared to open-field. Shading significantly affected the photosynthesis and results in increased sub-stomatal CO2 concentration. Shading resulted in delayed flowering and 48% reduction in marketable yield. Total phenolic contents (TPC) of tomato grown under open-field and greenhouse conditions were similar. However, greenhouse conditions resulted in a 35% decrease in total flavonoid contents (TFC) of tomato fruit. Shading reduced the TPC and TFC by 29 and 16%, respectively under greenhouse conditions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-021-01032-z.

Multiple mechanisms drive genomic adaptation to extreme O2 levels in Drosophila melanogaster.

To detect the genomic mechanisms underlying evolutionary dynamics of adaptation in sexually reproducing organisms, we analyze multigenerational whole genome sequences of Drosophila melanogaster adapting to extreme O2 conditions over an experiment conducted for nearly two decades. We develop methods to analyze time-series genomics data and predict adaptive mechanisms. Here, we report a remarkable level of synchronicity in both hard and soft selective sweeps in replicate populations as well as the arrival of favorable de novo mutations that constitute a few asynchronized sweeps. We additionally make direct experimental observations of rare recombination events that combine multiple alleles on to a single, better-adapted haplotype. Based on the analyses of the genes in genomic intervals, we provide a deeper insight into the mechanisms of genome adaptation that allow complex organisms to survive harsh environments.

Genetic interactions regulate hypoxia tolerance conferred by activating Notch in excitatory amino acid transporter 1-positive glial cells in Drosophila melanogaster.

Hypoxia is a critical pathological element in many human diseases, including ischemic stroke, myocardial infarction, and solid tumors. Of particular significance and interest of ours are the cellular and molecular mechanisms that underlie susceptibility or tolerance to low O2. Previous studies have demonstrated that Notch signaling pathway regulates hypoxia tolerance in both Drosophila melanogaster and humans. However, the mechanisms mediating Notch-conferred hypoxia tolerance are largely unknown. In this study, we delineate the evolutionarily conserved mechanisms underlying this hypoxia tolerant phenotype. We determined the role of a group of conserved genes that were obtained from a comparative genomic analysis of hypoxia-tolerant D.melanogaster populations and human highlanders living at the high-altitude regions of the world (Tibetans, Ethiopians, and Andeans). We developed a novel dual-UAS/Gal4 system that allows us to activate Notch signaling in the Eaat1-positive glial cells, which remarkably enhances hypoxia tolerance in D.melanogaster, and, simultaneously, knock down a candidate gene in the same set of glial cells. Using this system, we discovered that the interactions between Notch signaling and bnl (fibroblast growth factor), croc (forkhead transcription factor C), or Mkk4 (mitogen-activated protein kinase kinase 4) are important for hypoxia tolerance, at least in part, through regulating neuronal development and survival under hypoxic conditions. Becausethese genetic mechanisms are evolutionarily conserved, this group of genes may serve as novel targets for developing therapeutic strategies and have a strong potential to be translated to humans to treat/prevent hypoxia-related diseases.

High fat diet induces sex-specific differential gene expression in Drosophila melanogaster.

Currently about 2 billion adults globally are estimated to be overweight and ~13% of them are obese. High fat diet (HFD) is one of the major contributing factor to obesity, heart disease, diabetes and cancer. Recent findings on the role of HFD in inducing abnormalities in neurocognition and susceptibility to Alzheimer's disease are highly intriguing. Since fundamental molecular pathways are often conserved across species, studies involving Drosophila melanogaster as a model organism can provide insight into the molecular mechanisms involving human disease. In order to study some of such mechanisms in the central nervous system as well in the rest of the body, we investigated the effect of HFD on the transcriptome in the heads and bodies of male and female flies kept on either HFD or regular diet (RD). Using comprehensive genomic analyses which include high-throughput transcriptome sequencing, pathway enrichment and gene network analyses, we found that HFD induces a number of responses that are sexually dimorphic in nature. There was a robust transcriptional response consisting of a downregulation of stress-related genes in the heads and glycoside hydrolase activity genes in the bodies of males. In the females, the HFD led to an increased transcriptional change in lipid metabolism. A strong correlation also existed between the takeout gene and hyperphagic behavior in both males and females. We conclude that a) HFD induces a differential transcriptional response between males and females, in heads and bodies and b) the non-dimorphic transcriptional response that we identified was associated with hyperphagia. Therefore, our data on the transcriptional responses in flies to HFD provides potentially relevant information to human conditions including obesity.

Novel insight into the genetic basis of high-altitude pulmonary hypertension in Kyrgyz highlanders.

The Central Asian Kyrgyz highland population provides a unique opportunity to address genetic diversity and understand the genetic mechanisms underlying high-altitude pulmonary hypertension (HAPH). Although a significant fraction of the population is unaffected, there are susceptible individuals who display HAPH in the absence of any lung, cardiac or hematologic disease. We report herein the analysis of the whole-genome sequencing of healthy individuals compared with HAPH patients and other controls (total n = 33). Genome scans reveal selection signals in various regions, encompassing multiple genes from the first whole-genome sequences focusing on HAPH. We show here evidence of three candidate genes MTMR4, TMOD3 and VCAM1 that are functionally associated with well-known molecular and pathophysiological processes and which likely lead to HAPH in this population. These processes are (a) dysfunctional BMP signaling, (b) disrupted tissue repair processes and (c) abnormal endothelial cell function. Whole-genome sequence of well-characterized patients and controls and using multiple statistical tools uncovered novel candidate genes that belong to pathways central to the pathogenesis of HAPH. These studies on high-altitude human populations are pertinent to the understanding of sea level diseases involving hypoxia as a main element of their pathophysiology.

Cardiac-specific knockout and pharmacological inhibition of Endothelin receptor type B lead to cardiac resistance to extreme hypoxia.

Oxygen plays a central role in cardiac energy metabolism. At high altitude where the ambient oxygen level is low, we found EDNRB is associated with human hypoxia adaptation. Our subsequent study in global heterozygous knockout mice (Ednrb-/+) revealed that cardiac function was conserved in these mice when exposed to extreme hypoxia. The major goal of this study was (i) to determine the functional role of cardiomyocyte EdnrB in maintaining cardiac function under hypoxic stress and (ii) to validate the phenotypes we detected in Ednrb-/+ mice using EDNRB blockers. Unlike the global knockouts, cardiac-specific heterozygote (EdnrBflox/+) and homozygote (EdnrBflox/flox) EdnrB knockout mice were phenotypically normal. When treated with graded low levels of oxygen (10% and 5% O2), both EdnrBflox/+ and EdnrBflox/flox were hypoxia tolerant. The cardiac indexes at 10% and 5% O2 for EdnrBflox/+ were significantly higher and lactate levels were significantly lower when compared to the cre-negative controls (P < 0.05). Simultaneously, mice treated with BQ-788 (EDNRB-specific blocker) had a significantly higher cardiac index (P < 0.005) and significantly lower lactate levels (P < 0.0001) than in control mice. A similar result was obtained with mice treated with Bosentan (non-specific). These data indicate that a lower level or complete lack of EdnrB in the cardiomyocytes significantly improves cardiac performance under extreme hypoxia, a novel role of cardiomyocyte EdnrB in the regulation of cardiac function. Furthermore, this rescue under extreme hypoxia can also be achieved using EDNRB-specific pharmacological agents, e.g., BQ-788. This systematically confirms, both genetically and pharmacologically, the protective role of a lower EDNRB under extreme hypoxia stress. KEY MESSAGES: Under normal condition, cardiomyocytes-specific EdnrB knockout mice, both heterozygote and homozygote, are phenotypically normal. Under hypoxic condition, a lower level or complete deletion of cardiomyocyte EdnrB conserves cardiac function by maintaining high cardiac index. Similarly, mice treated with both specific (BQ-788) and non-specific (Bosentan) EDNRB blockers are tolerant to hypoxia by maintaining better cardiac function. The oxygen perfusion under extreme hypoxia is better in the mice with lower EDNRB, as depicted by lower lactate level at 5% oxygen. Our current study systematically confirms, both genetically and pharmacologically, the protective role of a lower EDNRB under extreme hypoxia stress. Overall, it supports our hypothesis that studies on human hypoxia adaptation provide new insight to common disease pathogenesis and treatments.

Ecofriendly Fruit Switches: Graphene Oxide-Based Wrapper for Programmed Fruit Preservative Delivery To Extend Shelf Life.

According to Food and Agriculture Organization 2015 report, post-harvest agricultural loss accounts for 20-50% annually; on the other hand, reports about preservatives toxicity are also increasing. Hence, preservative release with response to fruit requirement is desired. In this study, acid synthesized in the overripe fruits was envisaged to cleave acid labile hydrazone to release preservative salicylaldehyde from graphene oxide (GO). To maximize loading and to overcome the challenge of GO reduction by hydrazine, two-step activation with ethylenediamine and 4-nitrophenyl chloroformate respectively, are followed. The final composite shows efficient preservative release with the stimuli of the overripe fruit juice and improves the fruit shelf life. The composite shows less toxicity as compared to the free preservative along with the additional scope to reuse. The composite was vacuum-filtered through a 0.4 µm filter paper, to prepare a robust wrapper for the fruit storage.

Comparative de novo transcriptome analysis of male and female Sea buckthorn.

Sea buckthorn is a dioecious medicinal plant found at high altitude. The plant has both male and female reproductive organs in separate individuals. In this article, whole transcriptome de novo assemblies of male and female flower bud samples were carried out using Illumina NextSeq 500 platform to determine the role of the genes involved in sex determination. Moreover, genes with differential expression in male and female transcriptomes were identified to understand the underlying sex determination mechanism. The current study showed 63,904 and 62,272 coding sequences (CDS) in female and male transcriptome data sets, respectively. 16,831 common CDS were screened out from both transcriptomes, out of which 625 were upregulated and 491 were found to be downregulated. To understand the potential regulatory roles of differentially expressed genes in metabolic networks and biosynthetic pathways: KEGG mapping, gene ontology, and co-expression network analysis were performed. Comparison with Flowering Interactive Database (FLOR-ID) resulted in eight differentially expressed genes viz. CHD3-type chromatin-remodeling factor PICKLE (PKL), phytochrome-associated serine/threonine-protein phosphatase (FYPP), protein TOPLESS (TPL), sensitive to freezing 6 (SFR6), lysine-specific histone demethylase 1 homolog 1 (LDL1), pre-mRNA-processing-splicing factor 8A (PRP8A), sucrose synthase 4 (SUS4), ubiquitin carboxyl-terminal hydrolase 12 (UBP12), known to be broadly involved in flowering, photoperiodism, embryo development, and cold response pathways. Male and female flower bud transcriptome data of Sea buckthorn may provide comprehensive information at genomic level for the identification of genetic regulation involved in sex determination.

New Insights into the Genetic Basis of Monge's Disease and Adaptation to High-Altitude.

Human high-altitude (HA) adaptation or mal-adaptation is explored to understand the physiology, pathophysiology, and molecular mechanisms that underlie long-term exposure to hypoxia. Here, we report the results of an analysis of the largest whole-genome-sequencing of Chronic Mountain Sickness (CMS) and nonCMS individuals, identified candidate genes and functionally validated these candidates in a genetic model system (Drosophila). We used PreCIOSS algorithm that uses Haplotype Allele Frequency score to separate haplotypes carrying the favored allele from the noncarriers and accordingly, prioritize genes associated with the CMS or nonCMS phenotype. Haplotypes in eleven candidate regions, with SNPs mostly in nonexonic regions, were significantly different between CMS and nonCMS subjects. Closer examination of individual genes in these regions revealed the involvement of previously identified candidates (e.g., SENP1) and also unreported ones SGK3, COPS5, PRDM1, and IFT122 in CMS. Remarkably, in addition to genes like SENP1, SGK3, and COPS5 which are HIF-dependent, our study reveals for the first time HIF-independent gene PRDM1, indicating an involvement of wider, nonHIF pathways in HA adaptation. Finally, we observed that down-regulating orthologs of these genes in Drosophila significantly enhanced their hypoxia tolerance. Taken together, the PreCIOSS algorithm, applied on a large number of genomes, identifies the involvement of both new and previously reported genes in selection sweeps, highlighting the involvement of multiple hypoxia response systems. Since the overwhelming majority of SNPs are in nonexonic (and possibly regulatory) regions, we speculate that adaptation to HA necessitates greater genetic flexibility allowing for transcript variability in response to graded levels of hypoxia.

High-altitude adaptation in humans: from genomics to integrative physiology.

About 1.2 to 33% of high-altitude populations suffer from Monge's disease or chronic mountain sickness (CMS). Number of factors such as age, sex, and population of origin (older, male, Andean) contribute to the percentage reported from a variety of samples. It is estimated that there are around 83 million people who live at altitudes > 2500 m worldwide and are at risk for CMS. In this review, we focus on a human "experiment in nature" in various high-altitude locations in the world-namely, Andean, Tibetan, and Ethiopian populations that have lived under chronic hypoxia conditions for thousands of years. We discuss the adaptive as well as mal-adaptive changes at the genomic and physiological levels. Although different genes seem to be involved in adaptation in the three populations, we can observe convergence at genetic and signaling, as well as physiological levels. What is important is that we and others have shown that lessons learned from the genes mined at high altitude can be helpful in better understanding and treating diseases that occur at sea level. We discuss two such examples: EDNRB and SENP1 and their role in cardiac tolerance and in the polycythemic response, respectively.