ABSTRACT
Base editors (BEs) enable efficient, programmable installation of point mutations while avoiding the use of double-strand breaks. Simultaneous application of two or more different BEs, such as an adenine BE (which converts A·T base pairs to G·C) and a cytosine BE (which converts C·G base pairs to T·A), is not feasible because guide RNA crosstalk results in non-orthogonal editing, with all BEs modifying all target loci. Here we engineer both adenine BEs and cytosine BEs that can be orthogonally multiplexed by using RNA aptamer-coat protein systems to recruit the DNA-modifying enzymes directly to the guide RNAs. We generate four multiplexed orthogonal BE systems that enable rates of precise co-occurring edits of up to 7.1% in the same DNA strand without enrichment or selection strategies. The addition of a fluorescent enrichment strategy increases co-occurring edit rates up to 24.8% in human cells. These systems are compatible with expanded protospacer adjacent motif and high-fidelity Cas9 variants, function well in multiple cell types, have equivalent or reduced off-target propensities compared with their parental systems and can model disease-relevant point mutation combinations.
ABSTRACT
Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. EPAS1, a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations and validation in a lowland population. Although this genocopy of relatively lower hematocrit in Andean highlanders parallels well-replicated findings in Tibetans, it likely involves distinct pathway responses based on a protein-coding versus noncoding variants, respectively. These findings illuminate how unique variants at EPAS1 contribute to the same phenotype in Tibetans and a subset of Andean highlanders despite distinct evolutionary trajectories.
Subject(s)
Adaptation, Physiological , Altitude , Hematocrit , South American People , Humans , Adaptation, Physiological/genetics , Adaptation, Physiological/physiology , East Asian People , Hypoxia/genetics , Hypoxia/metabolism , Mutation, Missense/genetics , South American People/geneticsABSTRACT
BACKGROUND: The chronic hypoxia of high-altitude residence poses challenges for tissue oxygen supply and metabolism. Exposure to high altitude during pregnancy increases the incidence of hypertensive disorders of pregnancy and fetal growth restriction and alters placental metabolism. High-altitude ancestry protects against altitude-associated fetal growth restriction, indicating hypoxia tolerance that is genetic in nature. Yet, not all babies are protected and placental pathologies associated with fetal growth restriction occur in some Andean highlanders. METHODS: We examined placental metabolic function in 79 Andeans (18-45 years; 39 preeclamptic and 40 normotensive) living in La Paz, Bolivia (3600-4100 m) delivered by unlabored Cesarean section. Using a selection-nominated approach, we examined links between putatively adaptive genetic variation and phenotypes related to oxygen delivery or placental metabolism. RESULTS: Mitochondrial oxidative capacity was associated with fetal oxygen delivery in normotensive but not preeclamptic placenta and was also suppressed in term preeclamptic pregnancy. Maternal haplotypes in or within 200 kb of selection-nominated genes were associated with lower placental mitochondrial respiratory capacity (PTPRD [protein tyrosine phosphatase receptor-δ]), lower maternal plasma erythropoietin (CPT2 [carnitine palmitoyl transferase 2], proopiomelanocortin, and DNMT3 [DNA methyltransferase 3]), and lower VEGF (vascular endothelial growth factor) in umbilical venous plasma (TBX5 [T-box transcription factor 5]). A fetal haplotype within 200 kb of CPT2 was associated with increased placental mitochondrial complex II capacity, placental nitrotyrosine, and GLUT4 (glucose transporter type 4) protein expression. CONCLUSIONS: Our findings reveal novel associations between putatively adaptive gene regions and phenotypes linked to oxygen delivery and placental metabolic function in highland Andeans, suggesting that such effects may be of genetic origin. Our findings also demonstrate maladaptive metabolic mechanisms in the context of preeclampsia, including dysregulation of placental oxygen consumption.
Subject(s)
Placenta , Pre-Eclampsia , Humans , Pregnancy , Female , Placenta/metabolism , Cesarean Section , Fetal Growth Retardation , Vascular Endothelial Growth Factor A/metabolism , Hypoxia/metabolism , Oxygen/metabolism , Phenotype , GenomicsABSTRACT
STUDY OBJECTIVES: The coexistence of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) in a single individual, also known as overlap syndrome (OVS), is associated with higher cardiovascular risk and mortality than either OSA or COPD alone. However, the underlying mechanisms remain unclear. We hypothesized that patients with OVS have elevated systemic inflammatory biomarkers relative to patients with either disease alone, which could explain greater cardiovascular risk observed in OVS. METHODS: We included 255 participants in the study, 55 with COPD alone, 100 with OSA alone, 50 with OVS, and 50 healthy controls. All participants underwent a home sleep study, spirometry, and a blood draw for high-sensitivity C-reactive protein and total blood count analysis. In a randomly selected subset of 186 participants, inflammatory protein profiling was performed using Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assays. Biomarker level differences across groups were identified using a mixed linear model. RESULTS: Levels of interleukin 6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and granulocyte colony stimulating factor (G-CSF) were higher in participants with OVS and COPD compared with healthy controls and participants with OSA. Furthermore, participants with OVS had higher circulating levels of leukocytes and neutrophils than those with COPD, OSA, and controls. CONCLUSIONS: COPD and OVS are associated with higher systemic inflammation relative to OSA and healthy controls. This work proposes the potential utilization of interleukin 6, granulocyte colony stimulating factor, and high-sensitivity C-reactive protein as screening biomarkers for COPD in patients with OSA. Inflammatory pathways may not fully explain the higher cardiovascular risk observed in OVS, indicating the need for further investigation. CITATION: Sanchez-Azofra A, Gu W, Masso-Silva JA, et al. Inflammation biomarkers in OSA, chronic obstructive pulmonary disease, and chronic obstructive pulmonary disease/OSA overlap syndrome. J Clin Sleep Med. 2023;19(8):1447-1456.
Subject(s)
Autoimmune Diseases , Pulmonary Disease, Chronic Obstructive , Sleep Apnea Syndromes , Sleep Apnea, Obstructive , Humans , C-Reactive Protein , Interleukin-6 , Sleep Apnea, Obstructive/diagnosis , Sleep Apnea Syndromes/complications , Pulmonary Disease, Chronic Obstructive/complications , Inflammation/complications , Biomarkers , Autoimmune Diseases/complications , Granulocyte Colony-Stimulating FactorABSTRACT
OBJECTIVES: To determine in patients with acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) whether reducing driving pressure (ΔP) would decrease plasma biomarkers of inflammation and lung injury (interleukin-6 [IL-6], IL-8, and the soluble receptor for advanced glycation end-products sRAGE). DESIGN: A single-center prospective physiologic study. SETTING: At a single university medical center. PARTICIPANTS: Adult patients with severe COVID-19 ARDS on VV ECMO. INTERVENTIONS: Participants on VV ECMO had the following biomarkers measured: (1) pre-ECMO with low-tidal-volume ventilation (LTVV), (2) post-ECMO with LTVV, (3) during low-driving-pressure ventilation (LDPV), (4) after 2 hours of very low driving-pressure ventilation (V-LDPV, main intervention ΔP = 1 cmH2O), and (5) 2 hours after returning to LDPV. MAIN MEASUREMENTS AND RESULTS: Twenty-six participants were enrolled; 21 underwent V-LDPV. There was no significant change in IL-6, IL-8, and sRAGE from LDPV to V-LDPV and from V-LDPV to LDPV. Only participants (9 of 21) with nonspontaneous breaths had significant change (p < 0.001) in their tidal volumes (Vt) (mean ± SD), 1.9 ± 0.5, 0.1 ± 0.2, and 2.0 ± 0.7 mL/kg predicted body weight (PBW). Participants with spontaneous breathing, Vt were unchanged-4.5 ± 3.1, 4.7 ± 3.1, and 5.6 ± 2.9 mL/kg PBW (p = 0.481 and p = 0.065, respectively). There was no relationship found when accounting for Vt changes and biomarkers. CONCLUSIONS: Biomarkers did not significantly change with decreased ΔPs or Vt changes during the first 24 hours post-ECMO. Despite deep sedation, reductions in Vt during V-LDPV were not reliably achieved due to spontaneous breaths. Thus, patients on VV ECMO for ARDS may have higher Vt (ie, transpulmonary pressure) than desired despite low ΔPs or Vt.
Subject(s)
COVID-19 , Extracorporeal Membrane Oxygenation , Respiratory Distress Syndrome , Adult , Humans , Respiration, Artificial , Prospective Studies , Interleukin-6 , Receptor for Advanced Glycation End Products , Interleukin-8 , COVID-19/complications , COVID-19/therapy , Respiratory Distress Syndrome/therapy , BiomarkersABSTRACT
In chronic mountain sickness (CMS), increased blood oxygen (O2)-carrying capacity due to excessive erythrocytosis (EE, [Hb] ≥ 21 g/dL) could be offset, especially during exercise by both impaired cardiac output (QÌt) and O2 diffusion limitation in lungs and muscle. We hypothesized that EE results in reduced peak VÌo2 despite increased blood O2-carrying capacity, and that isovolumic hemodilution (IVHD) improves exercise capacity. In 14 male residents of Cerro de Pasco, Peru (4,340 m), six with and eight without EE, we measured peak cycle-exercise capacity, VÌo2, QÌt, arterial blood gas parameters, and (resting) blood volume. This was repeated for participants with EE after IVHD, reducing hematocrit by 20% (from 67% to 53%). From these data, we quantified the major O2 transport pathway components (ventilation, pulmonary alveolar-capillary diffusion, QÌt, and blood-muscle mitochondria diffusion). Participants with EE had similar peak VÌo2, systemic O2 delivery, and O2 extraction as non-EE controls, however, with lower QÌt and higher arterial [O2]. After IVHD, peak VÌo2 was preserved (but not enhanced), with lower O2 delivery (despite higher QÌt) balanced by greater O2 extraction. The considerable variance in exercise capacity across the 14 individuals was explained essentially completely by differences in both pulmonary and muscle O2 diffusional conductances and not by any differences in ventilation, [Hb], nor QÌt. In conclusion, EE does not result in lower peak VÌo2 in Andean males, and IVHD maintains, but does not enhance, exercise capacity.NEW & NOTEWORTHY Male Andean highlanders with and without excessive erythrocytosis (EE) have similar peak VÌo2 at 4,340 m, with higher arterial [O2] in EE and lower cardiac output (QÌt), thus maintaining similar O2 delivery. Peak VÌo2 in participants with EE was unaffected by isovolumic hemodilution (hematocrit reduced from 67% to 53%), with lower O2 delivery balanced by slightly increased QÌt and greater O2 extraction. Differences in lung and muscle diffusing capacity, and not hematocrit variation, accounted for essentially all interindividual variance in peak VÌo2.
Subject(s)
Altitude Sickness , Polycythemia , Humans , Male , Altitude , Exercise Tolerance , Hemodilution , Oxygen/metabolism , Oxygen ConsumptionABSTRACT
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.
ABSTRACT
STUDY OBJECTIVES: Chronic mountain sickness (CMS) is commonly observed among Andean and other highland populations. Sleep-disordered breathing (SDB) is highly prevalent at high altitude, and SDB and nocturnal hypoxemia have been observed in CMS. Phlebotomy is commonly performed to treat CMS, but it is unknown whether reducing hematocrit improves SDB. We hypothesized that isovolemic hemodilution (IVHD) in CMS would reduce SBD severity and improve sleep efficiency. METHODS: Six participants with CMS and 8 without CMS, all residents of Cerro de Pasco, Peru (altitude 4340 m), completed baseline nocturnal sleep studies. CMS participants then underwent IVHD, and nocturnal sleep studies were repeated 24-48 hours after IVHD. We analyzed sleep apnea severity, nocturnal oxygenation, and sleep quality in those with CMS relative to those without CMS, and the effects of IVHD in CMS participants. RESULTS: Participants with CMS did not have altered sleep architecture, sleep apnea severity, or nocturnal oxygenation relative to non-CMS participants. However, IVHD in CMS increased apnea-hypopnea index (40.9 ± 6.9 events/h to 61.5 ± 7.7 events/h, P = .009). IVHD increased oxyhemoglobin desaturation index (P = .008) and the percentage of sleep time spent with oxyhemoglobin saturation at or below 80% (P = .012). There was no effect of IVHD on sleep efficiency, arousal index, or sleep staging. CONCLUSIONS: In this cohort, CMS was not associated with worsened SDB or changes in sleep architecture. IVHD, a putative therapeutic option for participants with CMS, appears to worsen nocturnal oxygenation and SDB within 48 hours post-IVHD. CITATION: Sanchez-Azofra A, Villafuerte FC, DeYoung PN, et al. Isovolemic hemodilution in chronic mountain sickness acutely worsens nocturnal oxygenation and sleep apnea severity. J Clin Sleep Med. 2022;18(10):2423-2432.
Subject(s)
Altitude Sickness , Sleep Apnea Syndromes , Altitude , Altitude Sickness/complications , Altitude Sickness/therapy , Chronic Disease , Hemodilution , Humans , Oxyhemoglobins , Sleep Apnea Syndromes/complications , Sleep Apnea Syndromes/therapyABSTRACT
Hypoxia triggers complex inter- and intracellular signals that regulate tissue oxygen (O2) homeostasis, adjusting convective O2 delivery and utilization (i.e., metabolism). Human populations have been exposed to high-altitude hypoxia for thousands of years and, in doing so, have undergone natural selection of multiple gene regions supporting adaptive traits. Some of the strongest selection signals identified in highland populations emanate from hypoxia-inducible factor (HIF) pathway genes. The HIF pathway is a master regulator of the cellular hypoxic response, but it is not the only regulatory pathway under positive selection. For instance, regions linked to the highly conserved Notch signaling pathway are also top targets, and this pathway is likely to play essential roles that confer hypoxia tolerance. Here, we explored the importance of the Notch pathway in mediating the cellular hypoxic response. We assessed transcriptional regulation of the Notch pathway, including close cross-talk with HIF signaling, and its involvement in the mediation of angiogenesis, cellular metabolism, inflammation, and oxidative stress, relating these functions to generational hypoxia adaptation.
ABSTRACT
BACKGROUND: A consensus group recently proposed the term progressive collapsing foot deformity (PCFD) and a new classification with 2 stages plus 5 classes to describe the complex array of flatfoot deformities. This study aimed to validate different diagnostic accuracy rates of the PCFD classification. METHODS: This was a survey-based study distributed among 13 foot and ankle fellowship programs for 3 groups of participants with varied experience in practice (group 1: fellows in training, group 2: surgeons in practice for 1-4 years, and group 3: surgeons in practice for ≥5 years). Each participant was asked to assign 20 different cases of flatfoot deformity to the appropriate classes and stages using the PCFD classification. The overall diagnostic accuracy, class, and stage diagnostic accuracy rates for the 20 cases were calculated first for the entire cohort and then compared among the 3 groups. The misdiagnosis rate for each class of deformity (the sum of overdiagnosis and underdiagnosis rates) of the entire cohort was calculated and compared with the other classes. Mean and standard evidence were used to describe numerical data. One-way analysis of variance was used to compare values among the 3 groups and the 5 classes. P <.05 was considered statistically significant. RESULTS: For the whole cohort, the overall diagnostic accuracy, class diagnostic accuracy, and stage diagnostic accuracy rates were 71.0%, 78.3%, and 81.7%, respectively There was a statistically significant difference between group 1 and 2, and group 1 and 3, in overall diagnostic accuracy and class diagnostic accuracy, with no significant difference among the 3 groups regarding stage diagnostic accuracy. Class B had a significantly higher overdiagnosis rate than the rest of the classes, whereas class D was significantly underdiagnosed than others. The misdiagnosis rates for classes A to E were 3.3%, 17.5%, 11.1%, 26.0%, and 3.7%, respectively. CONCLUSION: The PCFD classification showed overall fair diagnostic accuracy rates. The highest diagnostic accuracy was for "hindfoot valgus deformity" and "ankle instability." Further content validation of the PCFD classification is needed to examine the terminology and interpretation of those classes with low diagnostic accuracy including "midfoot/forefoot abduction deformity," "forefoot varus deformity/medial column instability," and "peritalar subluxation/dislocation."Level of Evidence: Level II, prospective comparative study.
Subject(s)
Flatfoot , Foot Deformities , Joint Dislocations , Ankle Joint , Flatfoot/diagnosis , Foot Deformities/diagnosis , Foot Deformities/surgery , Humans , Prospective Studies , Weight-BearingABSTRACT
Erythrocytosis, or increased production of red blood cells, is one of the most well-documented physiological traits that varies within and among in high-altitude populations. Although a modest increase in blood O2-carrying capacity may be beneficial for life in highland environments, erythrocytosis can also become excessive and lead to maladaptive syndromes such as chronic mountain sickness (CMS).
Subject(s)
Altitude Sickness , Polycythemia , Altitude , Chronic Disease , Humans , PhenotypeABSTRACT
STUDY OBJECTIVES: Chronic obstructive pulmonary disease and obstructive sleep apnea overlap syndrome is associated with excess mortality, and outcomes are related to the degree of hypoxemia. People at high altitudes are susceptible to periodic breathing, and hypoxia at altitude is associated with cardio-metabolic dysfunction. Hypoxemia in these scenarios may be described as superimposed sustained hypoxia (SH) plus intermittent hypoxia (IH), or overlap hypoxia (OH), the effects of which have not been investigated. We aimed to characterize the cardio-metabolic consequences of OH in mice. METHODS: C57BL/6J mice were subjected to either SH (FiO2 = 0.10), IH (FiO2 = 0.21 for 12 h, and FiO2 oscillating between 0.21 and 0.06, 60 times/hour, for 12 h), OH (FiO2 = 0.13 for 12 h, and FiO2 oscillating between 0.13 and 0.06, 60 times/hour, for 12 h), or room air (RA), n = 8/group. Blood pressure and intraperitoneal glucose tolerance test were measured serially, and right ventricular systolic pressure (RVSP) was assessed. RESULTS: Systolic blood pressure transiently increased in IH and OH relative to SH and RA. RVSP did not increase in IH, but increased in SH and OH by 52% (p < .001) and 20% (p = .001). Glucose disposal worsened in IH and improved in SH, with no change in OH. Serum low- and very-low-density lipoproteins increased in OH and SH, but not in IH. Hepatic oxidative stress increased in all hypoxic groups, with the highest increase in OH. CONCLUSIONS: OH may represent a unique and deleterious cardio-metabolic stimulus, causing systemic and pulmonary hypertension, and without protective metabolic effects characteristic of SH.
Subject(s)
Hypoxia , Sleep Apnea, Obstructive , Animals , Disease Models, Animal , Humans , Mice , Mice, Inbred C57BL , Oxygen/metabolism , PhenotypeABSTRACT
Concern is often voiced over the ongoing loss of atmospheric O2. This loss, which is caused by fossil-fuel burning but also influenced by other processes, is likely to continue at least for the next few centuries. We argue that this loss is quite well understood, and the eventual decrease is bounded by the fossil-fuel resource base. Because the atmospheric O2 reservoir is so large, the predicted relative drop in O2 is very small even for extreme scenarios of future fossil-fuel usage which produce increases in atmospheric CO2 sufficient to cause catastrophic climate changes. At sea level, the ultimate drop in oxygen partial pressure will be less than 2.5 mm Hg out of a baseline of 159 mmHg. The drop by year 2300 is likely to be between 0.5 and 1.3 mmHg. The implications for normal human health is negligible because respiratory O2 consumption in healthy individuals is only weakly dependent on ambient partial pressure, especially at sea level. The impacts on top athlete performance, on disease, on reproduction, and on cognition, will also be very small. For people living at higher elevations, the implications of this loss will be even smaller, because of a counteracting increase in barometric pressure at higher elevations due to global warming.
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The clinical presentation of COVID-19 due to infection with SARS-CoV-2 is highly variable with the majority of patients having mild symptoms while others develop severe respiratory failure. The reason for this variability is unclear but is in critical need of investigation. Some COVID-19 patients have been labelled with 'happy hypoxia', in which patient complaints of dyspnoea and observable signs of respiratory distress are reported to be absent. Based on ongoing debate, we highlight key respiratory and neurological components that could underlie variation in the presentation of silent hypoxaemia and define priorities for subsequent investigation.
Subject(s)
COVID-19 , Dyspnea , Humans , Hypoxia , SARS-CoV-2ABSTRACT
Platelet-derived growth factor is one of the major growth factors found in human and mammalian serum and tissues. Abnormal activation of platelet-derived growth factor signaling pathway through platelet-derived growth factor receptors may contribute to the development and progression of pulmonary vascular remodeling and obliterative vascular lesions in patients with pulmonary arterial hypertension. In this study, we examined the expression of platelet-derived growth factor receptor isoforms in pulmonary arterial smooth muscle and pulmonary arterial endothelial cells and investigated whether platelet-derived growth factor secreted from pulmonary arterial smooth muscle cell or pulmonary arterial endothelial cell promotes pulmonary arterial smooth muscle cell proliferation. Our results showed that the protein expression of platelet-derived growth factor receptor α and platelet-derived growth factor receptor ß in pulmonary arterial smooth muscle cell was upregulated in patients with idiopathic pulmonary arterial hypertension compared to normal subjects. Platelet-derived growth factor activated platelet-derived growth factor receptor α and platelet-derived growth factor receptor ß in pulmonary arterial smooth muscle cell, as determined by phosphorylation of platelet-derived growth factor receptor α and platelet-derived growth factor receptor ß. The platelet-derived growth factor-mediated activation of platelet-derived growth factor receptor α/platelet-derived growth factor receptor ß was enhanced in idiopathic pulmonary arterial hypertension-pulmonary arterial smooth muscle cell compared to normal cells. Expression level of platelet-derived growth factor-AA and platelet-derived growth factor-BB was greater in the conditioned media collected from idiopathic pulmonary arterial hypertension-pulmonary arterial endothelial cell than from normal pulmonary arterial endothelial cell. Furthermore, incubation of idiopathic pulmonary arterial hypertension-pulmonary arterial smooth muscle cell with conditioned culture media from normal pulmonary arterial endothelial cell induced more platelet-derived growth factor receptor α activation than in normal pulmonary arterial smooth muscle cell. Accordingly, the conditioned media from idiopathic pulmonary arterial hypertension-pulmonary arterial endothelial cell resulted in more pulmonary arterial smooth muscle cell proliferation than the media from normal pulmonary arterial endothelial cell. These data indicate that (a) the expression and activity of platelet-derived growth factor receptor are increased in idiopathic pulmonary arterial hypertension-pulmonary arterial smooth muscle cell compared to normal pulmonary arterial smooth muscle cell, and (b) pulmonary arterial endothelial cell from idiopathic pulmonary arterial hypertension patients secretes higher level of platelet-derived growth factor than pulmonary arterial endothelial cell from normal subjects. The enhanced secretion (and production) of platelet-derived growth factor from idiopathic pulmonary arterial hypertension-pulmonary arterial endothelial cell and upregulated platelet-derived growth factor receptor expression (and function) in idiopathic pulmonary arterial hypertension-pulmonary arterial smooth muscle cell may contribute to enhancing platelet-derived growth factor/platelet-derived growth factor receptor-associated pulmonary vascular remodeling in pulmonary arterial hypertension.
ABSTRACT
Over millions of years, vertebrate species populated vast environments spanning the globe. Among the most challenging habitats encountered were those with limited availability of oxygen, yet many animal and human populations inhabit and perform life cycle functions and/or daily activities in varying degrees of hypoxia today. Of particular interest are species that inhabit high-altitude niches, which experience chronic hypobaric hypoxia throughout their lives. Physiological and molecular aspects of adaptation to hypoxia have long been the focus of high-altitude populations and, within the past decade, genomic information has become increasingly accessible. These data provide an opportunity to search for common genetic signatures of selection across uniquely informative populations and thereby augment our understanding of the mechanisms underlying adaptations to hypoxia. In this review, we synthesize the available genomic findings across hypoxia-tolerant species to provide a comprehensive view of putatively hypoxia-adaptive genes and pathways. In many cases, adaptive signatures across species converge on the same genetic pathways or on genes themselves [i.e., the hypoxia inducible factor (HIF) pathway). However, specific variants thought to underlie function are distinct between species and populations, and, in most cases, the precise functional role of these genomic differences remains unknown. Efforts to standardize these findings and explore relationships between genotype and phenotype will provide important clues into the evolutionary and mechanistic bases of physiological adaptations to environmental hypoxia.
ABSTRACT
Heme oxygenase (HO) enzymes catalyze heme into biliverdin, releasing carbon monoxide (CO) and iron into circulation. These byproducts of heme degradation can have potent cytoprotective effects in the face of stressors such as hypoxia and ischemia-reperfusion events. The potential for exogenous use of CO as a therapeutic agent has received increasing attention throughout the past few decades. Further, HO and CO are noted as putatively adaptive in diving mammals and certain high-altitude human populations that are frequently exposed to hypoxia and/or ischemia-reperfusion events, suggesting that HO and endogenous CO afford an evolutionary advantage for hypoxia tolerance and are critical in cell survival and injury avoidance. Our goal is to describe the importance of examining HO and CO in several systems, the physiological links, and the genetic factors that underlie variation in the HO/CO pathway. Finally, we emphasize the ways in which evolutionary perspectives may enhance our understanding of the HO/CO pathway in the context of diverse clinical settings.
ABSTRACT
Human populations at high altitude exhibit both unique physiological responses and strong genetic signatures of selection thought to compensate for the decreased availability of oxygen in each breath of air. With the increased availability of genomic information from Tibetans, Andeans, and Ethiopians, much progress has been made to elucidate genetic adaptations to chronic hypoxia that have occurred throughout hundreds of generations in these populations. In this perspectives piece, we discuss specific hypoxia-pathway variants that have been identified in high-altitude populations and methods for functional investigation, which may be used to determine the underlying causal factors that afford adaptation to high altitude.