Genetic Signatures of Positive Selection in Human Populations Adapted to High Altitude in Papua New Guinea.

Papua New Guinea (PNG) hosts distinct environments mainly represented by the ecoregions of the Highlands and Lowlands that display increased altitude and a predominance of pathogens, respectively. Since its initial peopling approximately 50,000 years ago, inhabitants of these ecoregions might have differentially adapted to the environmental pressures exerted by each of them. However, the genetic basis of adaptation in populations from these areas remains understudied. Here, we investigated signals of positive selection in 62 highlanders and 43 lowlanders across 14 locations in the main island of PNG using whole-genome genotype data from the Oceanian Genome Variation Project (OGVP) and searched for signals of positive selection through population differentiation and haplotype-based selection scans. Additionally, we performed archaic ancestry estimation to detect selection signals in highlanders within introgressed regions of the genome. Among highland populations we identified candidate genes representing known biomarkers for mountain sickness (SAA4, SAA1, PRDX1, LDHA) as well as candidate genes of the Notch signaling pathway (PSEN1, NUMB, RBPJ, MAML3), a novel proposed pathway for high altitude adaptation in multiple organisms. We also identified candidate genes involved in oxidative stress, inflammation, and angiogenesis, processes inducible by hypoxia, as well as in components of the eye lens and the immune response. In contrast, candidate genes in the lowlands are mainly related to the immune response (HLA-DQB1, HLA-DQA2, TAAR6, TAAR9, TAAR8, RNASE4, RNASE6, ANG). Moreover, we find two candidate regions to be also enriched with archaic introgressed segments, suggesting that archaic admixture has played a role in the local adaptation of PNG populations.

Preliminary study of identified novel susceptibility loci for HAPE risk in a Chinese male Han population.

High altitude pulmonary edema (HAPE) is a life-threatening form of non-cardiogenic pulmonary edema. In recent years, association studies have become the main method for identifying HAPE genetic loci. A genome-wide association study (GWAS) of HAPE risk-associated loci was performed in Chinese male Han individuals (164 HAPE cases and 189 healthy controls) by the Precision Medicine Diversity Array Chip with 2,771,835 loci (Applied Biosystems Axiom™). Eight overlapping candidate loci in CCNG2, RP11-445O3.2, NUPL1 and WWOX were finally selected. In silico functional analyses displayed the PPI network, functional enrichment and signal pathways related to CCNG2, NUPL1, WWOX and NRXN1. This study provides data supplements for HAPE susceptibility gene loci and new insights into HAPE susceptibility.

A time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues.

High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we use sheep as an animal model for low-to-high altitude translocation. We generate multi-omics data including whole-genome sequences, time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues as well as phenotypic data from 20 bio-indicators. We characterize transcriptional changes of all genes in each tissue, and examine multi-tissue temporal dynamics and transcriptional interactions among genes. Particularly, we identify critical functional genes regulating the short response to hypoxia in each tissue (e.g., PARG in the cerebellum and HMOX1 in the colon). We further identify TAD-constrained cis-regulatory elements, which suppress the transcriptional activity of most genes under hypoxia. Phenotypic and transcriptional evidence indicate that antenatal hypoxia could improve hypoxia tolerance in offspring. Furthermore, we provide time-series expression data of candidate genes associated with human mountain sickness (e.g., BMPR2) and high-altitude adaptation (e.g., HIF1A). Our study provides valuable resources and insights for future hypoxia-related studies in mammals.

Exome sequencing in extreme altitude mountaineers identifies pathogenic variants in RTEL1 and COL6A1 previously associated with respiratory failure.

Adaptation of humans to challenging environmental conditions, such as extreme temperature, malnutrition, or hypoxia, is an interesting phenomenon for both basic and applied research. Identification of the genetic factors contributing to human adaptation to these conditions enhances our understanding of the underlying molecular and physiological mechanisms. In our study, we analyzed the exomes of 22 high altitude mountaineers to uncover genetic variants contributing to hypoxic adaptation. To our surprise, we identified two putative loss-of-function variants, rs1385101139 in RTEL1 and rs1002726737 in COL6A1 in two extremely high altitude (personal record of more than 8500 m) professional climbers. Both variants can be interpreted as pathogenic according to medical geneticists' guidelines, and are linked to inherited conditions involving respiratory failure (late-onset pulmonary fibrosis and severe Ullrich muscular dystrophy for rs1385101139 and rs1002726737, respectively). Our results suggest that a loss of gene function may act as an important factor of human adaptation, which is corroborated by previous reports in other human subjects.

Phospholipase D regulates ferroptosis signal transduction in mouse spleen hypoxia response.

High-altitude hypoxia exposure can lead to phospholipase D-mediated lipid metabolism disorder in spleen tissues and induce ferroptosis. Nonetheless, the key genes underlying hypoxia-induced splenic phospholipase D and the ferroptosis pathway remain unclear. This study aimed to establish a hypoxia animal model. Combined transcriptomic and proteomic analyses showed that 95 predicted target genes (proteins) were significantly differentially expressed under hypoxic conditions. Key genes in phospholipase D and ferroptosis pathways under hypoxic exposure were identified by combining Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis techniques. Gene set enrichment analysis (GSEA) showed that the differential gene sets of the phospholipase D and ferroptosis signaling pathways were upregulated in the high-altitude hypoxia group. The genes in the phospholipase D signalling pathway were verified, and the expression levels of KIT and DGKG were upregulated in spleen tissues under hypoxic exposure. Subsequently, the mRNA and protein expression levels of genes from the exogenous pathway such as TFRC, SLC40A1, SLC7A11, TRP53, and FTH1 and those from the endogenous pathway such as GPX4, HMOX1, and ALOX15 differentials in the ferroptosis signalling pathway were verified, and the results indicated significant differential expression. In summary, exposure to high-altitude hypoxia mediated phospholipid metabolism disturbance through the phospholipase D signalling pathway and further induced ferroptosis, leading to splenic injury.

Hypobaric hypoxia modulated structural characteristics of circulating cell-free DNA in high-altitude pulmonary edema.

The utility of cell-free (cf) DNA has extended as a surrogate or clinical biomarker for various diseases. However, a more profound and expanded understanding of the diverse cfDNA population and its correlation with physiological phenotypes and environmental factors is imperative for using its full potential. The high-altitude (HA; altitude > 2,500 m above sea level) environment characterized by hypobaric hypoxia offers an observational case-control design to study the differential cfDNA profile in patients with high-altitude pulmonary edema (HAPE) (number of subjects, n = 112) and healthy HA sojourners (n = 111). The present study investigated cfDNA characteristics such as concentration, fragment length size, degree of integrity, and subfractions reflecting mitochondrial-cfDNA copies in the two groups. The total cfDNA level was significantly higher in patients with HAPE, and the level increased with increasing HAPE severity (P = 0.0036). A lower degree of cfDNA integrity of 0.346 in patients with HAPE (P = 0.001) indicated the prevalence of shorter cfDNA fragments in circulation in patients compared with the healthy HA sojourners. A significant correlation of cfDNA characteristics with the peripheral oxygen saturation levels in the patient group demonstrated the translational relevance of cfDNA molecules. The correlation was further supported by multivariate logistic regression and receiver operating characteristic curve. To our knowledge, our study is the first to highlight the association of higher cfDNA concentration, a lower degree of cfDNA integrity, and increased mitochondrial-derived cfDNA population with HAPE disease severity. Further deep profiling of cfDNA fragments, which preserves cell-type specific genetic and epigenetic features, can provide dynamic physiological responses to hypoxia.NEW & NOTEWORTHY This study observed altered cell-free (cf) DNA fragment patterns in patients with high-altitude pulmonary edema and the significant correlation of these patterns with peripheral oxygen saturation levels. This suggests deep profiling of cfDNA fragments in the future may identify genetic and epigenetic mechanisms underlying physiological and pathophysiological responses to hypoxia.

LncRNA and Protein Expression Profiles Reveal Heart Adaptation to High-Altitude Hypoxia in Tibetan Sheep.

The Tibetan sheep has an intricate mechanism of adaptation to low oxygen levels, which is influenced by both genetic and environmental factors. The heart plays a crucial role in the adaptation of Tibetan sheep to hypoxia. In the present study, we utilized transcriptomic and proteomic technologies to comprehensively analyze and identify the long non-coding RNAs (lncRNAs), genes, proteins, pathways, and gene ontology (GO) terms associated with hypoxic adaptation in Tibetan sheep at three different altitudes (2500 m, 3500 m, and 4500 m). By integrating the differentially expressed (DE) lncRNA target genes, differentially expressed proteins (DEPs), and differentially expressed genes (DEGs), we were able to identify and characterize the mechanisms underlying hypoxic adaptation in Tibetan sheep. Through this integration, we identified 41 shared genes/proteins, and functional enrichment analyses revealed their close association with lipid metabolism, glycolysis/gluconeogenesis, and angiogenesis. Additionally, significant enrichment was observed in important pathways such as the PPAR signaling pathway, glycolysis/gluconeogenesis, the oxoacid metabolic process, and angiogenesis. Furthermore, the co-expression network of lncRNAs and mRNAs demonstrated that lncRNAs (MSTRG.4748.1, ENSOART00020025894, and ENSOART00020036371) may play a pivotal role in the adaptation of Tibetan sheep to the hypoxic conditions of the plateau. In conclusion, this study expands the existing database of lncRNAs and proteins in Tibetan sheep, and these findings may serve as a reference for the prevention of altitude sickness in humans.

Alteraciones en el patron de apoptosis de celulas precursoras de eritrocitos en mujeres postmenopausicas con eitrocitosis patológica de la altura / Alteration in the Apoptosis pattern of erithocytes precursors Cells of postmenopausic women with high altitude erithrocytosis

Pregunta de investigación. ¿Existe alteraciones en el patrón de apoptisis de células precursoras de eritrocitos en mujeres postmenaopausicas con ertitrocitosis patológicas de la altura?. Objetivo. Determinar la existencia de alteraciones en el patrón de apoptosis de células precursoras de eritrocitos en mujeres postmenopausicas con eritrocitosis patológica de la altura. Diseño Corte transversal. Lugar. unidad de Biologia Molecular Paolo Belli, Instituto de Genética, Facultad de Medicina, UMSA. Poblacion. dos pacinetes mujeres postmenopausicas diagnosticadas con EPA según criterio clínico- laboratoriales, sin sobrepeso ni enfermedades cardiacorrespiratorias, no fumadoras y que no recibian tratamiento hormonal. El grupo control estuvo conformado por 4 mujeres de iguales características sin EPA. Metodos. Las células nononucleadas de la médula ósea fueron separadas en medio LSD y se cultivaron en medios líquidos en presencia y ausencia de Eritropoyetina. De estos cultivos se recuperaron las células a 1, 2, 7 y 14 días de ultivo, a partir de estas células se realizaron 2 frotis para la evaluación de la apoptosis por morfologia y el remanente celular fue empleado en el anális de la formación del DNA degradado. Finalmente los resultados fueron sujeto de test de significancia. Resultados. La morfología y el DNA degraado detectaron un retardo de patrón de apoptosis, de los progenitores eritroides, en las dos pacientes con EPA estudiadas; donde el porcentaje de células apoptosis tiende a mantenerse constante en función del tiempo, en lugar de incrementarse, como ocurre en los controles (p,00). el patrón de apoptosis en los controles es EPO dependiente, observandose una diferencia significativa ente los cultivos con y sin EPO (p0,00); mientras que en los pacientes es no EPO dependiente (p0,23). Conclusiones. El patron de aptosis modificado en los pacientes es indicativo de la presencia de alteraciones en la sobrevivencia celular y el incremento de la tasa de producción de progenitores eritroides durante la deferenciación EPO dependiente, posblemente sean factores etiopatogénicos de la eritrocitosis.

La hemoglobina, es un marcador genético invariable: hallazgos en la gallina criolla andina / The hemoglobin is a genetic marker invariability: Andean chicken finding

La gallina doméstica (Gallus gallus) fue inducida en Sud-América con la conquista española. Esta (Gal-NM), presenta una baja afinidad de la hemoglobina por el O2 (Hb-O2) e hipereritremia. Sin embargo hemos encontrado en Taraco (Puno, 4,000 m), y reproducido a nivel del mar, un grupo de gallinas con una alta afinidad de la Hb-O2 y ausencia de la hiperetremia (Gal-ALT). La afinidad de la Hb-O2(P50) fue determinada por el método de las mezclas en sangre total y en Hb libre de fosfatos (Hb-Lavada) antes y despúes de la adición de inositol hexafosfato (IHP) . La adición de la IHP se comportó de manera diferente en las dos hemoglobinas lavadas. La diferencia (Hb-lavada-Hb+IHP) fue 42.2 torr para Gal-NM y 26.3 torr para Gal-ALT, lo que es una indicación de que Hb de la Gal-ALT es fosfato-dependiente. Una mutación, Thr-->Ser, encontrada en la posición 69 de la cadena ß podría haber inducido la fosfato-dependencia. Nuestro hallazgo muestra un cambio en la función de la Hb, adquirido en un período evolutivo extremadamente corto de aproximadamente 500 años; muestra también, que individuos de una misma especie, que viven a NM y en la altura, pueden diferenciarse genéticamente mediante un cambio en la función de la Hb como reflejo de un cambio en su estructura.

Assesment of q-heterochromatin in patients with acute mountain sikness / En pacientes con el mal de montaña agudo

El presente estudio se ha diseñado para determinar marcadores genéticos del posible desarrollo del mal de montaña agudo (MMA), para lo cual se ha evaluado el número y distribución de las regiones cromosomiales específicas, nominalmente, las regiones de heterocromatina-Q (Q-HR) en 34 sujetos que desarrollaron MMA después de ascender a 3600 metros sobre el nivel del mar (Eastern Pamir). Los controles fueron 36 sujetos sin signos de MMA. El análisis de Q-HR se realizó utilizando la tinción de mostaza de propil quinacrina de las preparaciones cromosomales obtenidas de los cultivos de linfocitos. A diferencia de los controles, los sujetos con MMA mostraron ciertas diferencias en la distribución de características cuantitativas de la Variabilidad cromosomal Q-HR; el número total de Q-HR en sujetos con MMA fue de 2.15 +/- 0.19 en tanto que en los cointroles fue de 1.06 +/- 0.14 (P menor que 0,001). Estos datos sugieren el rol de la predisposición hereditaria en el desarrollo del mal de montaña agudo.