scholarly journals EPAS1 Gain-of-Function Mutation Contributes to High-Altitude Adaptation in Tibetan Horses

2019 ◽  
Vol 36 (11) ◽  
pp. 2591-2603 ◽  
Author(s):  
Xuexue Liu ◽  
Yanli Zhang ◽  
Yefang Li ◽  
Jianfei Pan ◽  
Dandan Wang ◽  
...  
Keyword(s):  
High Altitude ◽  
Extreme Environments ◽  
Hypoxia Tolerance ◽  
Missense Mutations ◽  
Data Set ◽  
Genetic Changes ◽  
Genome Data ◽  
Hypoxic Conditions ◽  
Domestic Horses ◽  
Altitude Adaptation

Abstract High altitude represents some of the most extreme environments worldwide. The genetic changes underlying adaptation to such environments have been recently identified in multiple animals but remain unknown in horses. Here, we sequence the complete genome of 138 domestic horses encompassing a whole altitudinal range across China to uncover the genetic basis for adaptation to high-altitude hypoxia. Our genome data set includes 65 lowland animals across ten Chinese native breeds, 61 horses living at least 3,300 m above sea level across seven locations along Qinghai-Tibetan Plateau, as well as 7 Thoroughbred and 5 Przewalski’s horses added for comparison. We find that Tibetan horses do not descend from Przewalski’s horses but were most likely introduced from a distinct horse lineage, following the emergence of pastoral nomadism in Northwestern China ∼3,700 years ago. We identify that the endothelial PAS domain protein 1 gene (EPAS1, also HIF2A) shows the strongest signature for positive selection in the Tibetan horse genome. Two missense mutations at this locus appear strongly associated with blood physiological parameters facilitating blood circulation as well as oxygen transportation and consumption in hypoxic conditions. Functional validation through protein mutagenesis shows that these mutations increase EPAS1 stability and its hetero dimerization affinity to ARNT (HIF1B). Our study demonstrates that missense mutations in the EPAS1 gene provided key evolutionary molecular adaptation to Tibetan horses living in high-altitude hypoxic environments. It reveals possible targets for genomic selection programs aimed at increasing hypoxia tolerance in livestock and provides a textbook example of evolutionary convergence across independent mammal lineages.

scholarly journals De novo assembly of a Tibetan genome and identification of novel structural variants associated with high-altitude adaptation

2019 ◽  
Vol 7 (2) ◽  
pp. 391-402 ◽  
Author(s):  
Yaoxi He ◽  
Haiyi Lou ◽  
Chaoying Cui ◽  
Lian Deng ◽  
Yang Gao ◽  
...  
Keyword(s):  
High Altitude ◽  
De Novo Assembly ◽  
De Novo ◽  
Population Analysis ◽  
Extreme Environments ◽  
Structural Variants ◽  
Base Pairs ◽  
High Quality ◽  
Long Read ◽  
Altitude Adaptation

Abstract Structural variants (SVs) may play important roles in human adaptation to extreme environments such as high altitude but have been under-investigated. Here, combining long-read sequencing with multiple scaffolding techniques, we assembled a high-quality Tibetan genome (ZF1), with a contig N50 length of 24.57 mega-base pairs (Mb) and a scaffold N50 length of 58.80 Mb. The ZF1 assembly filled 80 remaining N-gaps (0.25 Mb in total length) in the reference human genome (GRCh38). Markedly, we detected 17 900 SVs, among which the ZF1-specific SVs are enriched in GTPase activity that is required for activation of the hypoxic pathway. Further population analysis uncovered a 163-bp intronic deletion in the MKL1 gene showing large divergence between highland Tibetans and lowland Han Chinese. This deletion is significantly associated with lower systolic pulmonary arterial pressure, one of the key adaptive physiological traits in Tibetans. Moreover, with the use of the high-quality de novo assembly, we observed a much higher rate of genome-wide archaic hominid (Altai Neanderthal and Denisovan) shared non-reference sequences in ZF1 (1.32%–1.53%) compared to other East Asian genomes (0.70%–0.98%), reflecting a unique genomic composition of Tibetans. One such archaic hominid shared sequence—a 662-bp intronic insertion in the SCUBE2 gene—is enriched and associated with better lung function (the FEV1/FVC ratio) in Tibetans. Collectively, we generated the first high-resolution Tibetan reference genome, and the identified SVs may serve as valuable resources for future evolutionary and medical studies.

scholarly journals Methylation studies in Peromyscus: aging, altitude adaptation, and monogamy

GeroScience ◽  
2021 ◽  
Author(s):  
Steve Horvath ◽  
Amin Haghani ◽  
Joseph A. Zoller ◽  
Asieh Naderi ◽  
Elham Soltanmohammadi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
High Altitude ◽  
Extreme Environments ◽  
Stress Factors ◽  
Deer Mice ◽  
Epigenetic Clock ◽  
Age Cohorts ◽  
Biomarkers Of Aging ◽  
Genome Wide ◽  
Altitude Adaptation

AbstractDNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how stress factors impact aging. Deer mice (Peromyscus) are long-living rodents that have emerged as an informative model to study aging, adaptation to extreme environments, and monogamous behavior. In the present study, we have undertaken an exhaustive, genome-wide analysis of DNA methylation in Peromyscus, spanning different species, stocks, sexes, tissues, and age cohorts. We describe DNA methylation-based estimators of age for different species of deer mice based on novel DNA methylation data generated on highly conserved mammalian CpGs measured with a custom array. The multi-tissue epigenetic clock for deer mice was trained on 3 tissues (tail, liver, and brain). Two human-Peromyscus clocks accurately measure age and relative age, respectively. We present CpGs and enriched pathways that relate to different conditions such as chronological age, high altitude, and monogamous behavior. Overall, this study provides a first step towards studying the epigenetic correlates of monogamous behavior and adaptation to high altitude in Peromyscus. The human-Peromyscus epigenetic clocks are expected to provide a significant boost to the attractiveness of Peromyscus as a biological model.

scholarly journals Transcriptomes of Saussurea (Asteraceae) Provide Insights into High-Altitude Adaptation

Plants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1715
Author(s):  
Xu Zhang ◽  
Yanxia Sun ◽  
Jacob B. Landis ◽  
Jun Shen ◽  
Huajie Zhang ◽  
...  
Keyword(s):  
High Altitude ◽  
High Throughput Sequencing ◽  
Extreme Environments ◽  
Tibet Plateau ◽  
Reference Level ◽  
High Altitude Adaptation ◽  
Genomic Resources ◽  
Ideal System ◽  
Alpine Species ◽  
Altitude Adaptation

Understanding how species adapt to extreme environments is an extension of the main goals of evolutionary biology. While alpine plants are an ideal system for investigating the genetic basis of high-altitude adaptation, genomic resources in these species are still limited. In the present study, we generated reference-level transcriptomic data of five Saussurea species through high-throughput sequencing and de novo assembly. Three of them are located in the highland of the Qinghai-Tibet Plateau (QTP), and the other two are close relatives distributed in the lowland. A series of comparative and evolutionary genomics analyses were conducted to explore the genetic signatures of adaptive evolution to high-altitude environments. Estimation of divergence time using single-copy orthologs revealed that Saussurea species diversified during the Miocene, a period with extensive tectonic movement and climatic fluctuation on the QTP. We characterized gene families specific to the alpine species, including genes involved in oxidoreductase activity, pectin catabolic process, lipid transport, and polysaccharide metabolic process, which may play important roles in defense of hypoxia and freezing temperatures of the QTP. Furthermore, in a phylogenetic context with the branch model, we identified hundreds of genes with signatures of positive selection. These genes are involved in DNA repair, membrane transport, response to UV-B and hypoxia, and reproductive processes, as well as some metabolic processes associated with nutrient intake, potentially responsible for Saussurea adaptation to the harsh environments of high altitude. Overall, our study provides valuable genomic resources for alpine species and gained helpful insights into the genomic basis of plants adapting to extreme environments.

A Novel PHD2 Mutation Associated with Tibetan Genetic Adaptation to High Altitude Hypoxia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2602-2602 ◽  
Author(s):  
Felipe R Lorenzo V ◽  
Tatum S Simonson ◽  
Yingzhong Yang ◽  
Rili Ge ◽  
Josef T. Prchal
Keyword(s):  
High Altitude ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
The Body ◽  
Negative Regulator ◽  
Missense Mutations ◽  
Genome Wide ◽  
Hypoxic Environment ◽  
Exon 1 ◽  
Altitude Adaptation

Abstract Abstract 2602 The ability of the body to maintain oxygen hemostasis is essential for its survival. The body is required to adapt to the physiologic constraints imposed by a hypoxic environment in order to ensure optimal physiological functions. The study of indigenous high-altitude residents provides an opportunity to identify genes that may have play a role in hypoxia adaptation, and recent studies indicate that Tibetans have genetically adapted to the extremely hypoxic environment at high altitude. Interestingly, Tibetan adaption includes protection from polycythemia. We recently reported genome-wide scans of selection (Affymetrix Human SNP chips v6.0) for Tibetans (Simonson, Science July, 2010). At least 10 chromosomal regions were identified as likely targets for high-altitude adaptation, and two of these regions, EGLN1 (PHD2) and PPARA, were associated with protection against high-altitude polycythemia which is unique to this indigenous highland population. PHD2 is a negative regulator of the alpha subunits of HIF-1 and HIF-2 transcription factors regulating many essential functions including erythropoiesis, iron metabolism, development, in addition to other functions. A gain of function mutation of the alpha subunit of HIF-2 is associated with congenital polycythemia. We sequenced the exons of PPARA and PHD2 by direct sequencing and found two missense mutations in exon 1 of the PHD2 gene: the first is located within codon 4, and changes Aspartate to Glutamate (Asp4Glu) and the second is an unvalidated SNP (rs12097901) at codon 127 that changes Cysteine to Serine (Cy127Ser). The samples with high Hb show a heterozygous change, while the subject with normal Hb exhibited a homozygous change in both codons of the PHD2 gene. The association of these two missense PHD2 mutations to hemoglobin level is now being evaluated by studies of a larger population of Tibetan natives and the functional effects on levels and activities of HIF-1 and HIF-2 genes evaluated by transfection of these mutated PHD2 cDNA constructs in reporter cells. Table 1. List of samples and controls screened for mutation in PHD2. Sample Race Sex Hb PHD2 Mutation Asp4Glu Cys127Ser T03 Tibetan F 194 Hetero Hetero T43 Tibetan M 194 Hetero Hetero T48 Tibetan M 101 Hetero Homo T53 Tibetan M 159 Homo Homo Control Caucasian M ? WT WT Control Caucasian F ? WT WT Disclosure: No relevant conflicts of interest to declare.

scholarly journals Ancient Hybridization with an Unknown Population Facilitated High-Altitude Adaptation of Canids

2020 ◽  
Vol 37 (9) ◽  
pp. 2616-2629 ◽  
Author(s):  
Ming-Shan Wang ◽  
Sheng Wang ◽  
Yan Li ◽  
Yadvendradev Jhala ◽  
Mukesh Thakur ◽  
...  
Keyword(s):  
High Altitude ◽  
Evolutionary History ◽  
Nuclear Genome ◽  
Genetic Introgression ◽  
Data Set ◽  
Whole Genomes ◽  
Ancient Lineage ◽  
History Of ◽  
Evolutionary Trajectories ◽  
Altitude Adaptation

Abstract Genetic introgression not only provides material for adaptive evolution but also confounds our understanding of evolutionary history. This is particularly true for canids, a species complex in which genome sequencing and analysis has revealed a complex history of admixture and introgression. Here, we sequence 19 new whole genomes from high-altitude Tibetan and Himalayan wolves and dogs and combine these into a larger data set of 166 whole canid genomes. Using these data, we explore the evolutionary history and adaptation of these and other canid lineages. We find that Tibetan and Himalayan wolves are closely related to each other, and that ∼39% of their nuclear genome is derived from an as-yet-unrecognized wolf-like lineage that is deeply diverged from living Holarctic wolves and dogs. The EPAS1 haplotype, which is present at high frequencies in Tibetan dog breeds and wolves and confers an adaptive advantage to animals living at high altitudes, was probably derived from this ancient lineage. Our study underscores the complexity of canid evolution and demonstrates how admixture and introgression can shape the evolutionary trajectories of species.

The three missense mutations of EPAS1 , IL37 and EEF1D genes associated with high‐altitude adaptation in Chinese cattle

2020 ◽  
Vol 51 (6) ◽  
pp. 987-988
Author(s):  
Xiwen Guan ◽  
Quratulain Hanif ◽  
Fang Yu Li ◽  
Jianyong Liu ◽  
Kaixing Qu ◽  
...  
Keyword(s):  
High Altitude ◽  
Missense Mutations ◽  
High Altitude Adaptation ◽  
Chinese Cattle ◽  
Altitude Adaptation

scholarly journals De novo assembly of a Tibetan genome and identification of novel structural variants associated with high altitude adaptation

2019 ◽  
Author(s):  
Ouzhuluobu ◽  
Yaoxi He ◽  
Haiyi Lou ◽  
Chaoying Cui ◽  
Lian Deng ◽  
...  
Keyword(s):  
High Altitude ◽  
De Novo ◽  
Population Analysis ◽  
Extreme Environments ◽  
Structural Variants ◽  
Base Pairs ◽  
High Quality ◽  
Genome Wide ◽  
Long Read ◽  
Altitude Adaptation

AbstractStructural variants (SVs) may play important roles in human adaption to extreme environments such as high altitude but have been under-investigated. Here, combining long-read sequencing with multiple scaffolding techniques, we assembled a high-quality Tibetan genome (ZF1), with a contig N50 length of 24.57 mega-base pairs (Mb) and a scaffold N50 length of 58.80 Mb. The ZF1 assembly filled 80 remaining N-gaps (0.25 Mb in total length) in the reference human genome (GRCh38). Markedly, we detected 17,900 SVs, among which the ZF1-specific SVs are enriched in GTPase activity that is required for activation of the hypoxic pathway. Further population analysis uncovered a 163-bp intronic deletion in the MKL1 gene showing large divergence between highland Tibetans and lowland Han Chinese. This deletion is significantly associated with lower systolic pulmonary arterial pressure, one of the key adaptive physiological traits in Tibetans. Moreover, with the use of the high quality de novo assembly, we observed a much higher rate of genome-wide archaic hominid (Altai Neanderthal and Denisovan) shared non-reference sequences in ZF1 (1.32%-1.53%) compared to other East Asian genomes (0.70%-0.98%), reflecting a unique genomic composition of Tibetans. One such archaic-hominid shared sequence, a 662-bp intronic insertion in the SCUBE2 gene, is enriched and associated with better lung function (the FEV1/FVC ratio) in Tibetans. Collectively, we generated the first high-resolution Tibetan reference genome, and the identified SVs may serve as valuable resources for future evolutionary and medical studies.

scholarly journals The adaptive benefit of increases in hemoglobin-O2 affinity is contingent on tissue O2 diffusing capacity in high-altitude deer mice

2020 ◽  
Author(s):  
Oliver H. Wearing ◽  
Catherine M. Ivy ◽  
Natalia Gutiérrez-Pinto ◽  
Jonathan P. Velotta ◽  
Shane C. Campbell-Staton ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
High Altitude ◽  
Hypoxia Tolerance ◽  
Deer Mice ◽  
Diffusing Capacity ◽  
Adaptive Traits ◽  
General Role ◽  
Functional Interactions ◽  
Altitude Adaptation

AbstractComplex organismal traits are often the result of multiple interacting genes and sub-organismal phenotypes, but how these interactions shape the evolutionary trajectories of adaptive traits is poorly understood. We examined how functional interactions between cardiorespiratory traits contribute to adaptive increases in the capacity for aerobic thermogenesis (maximal O2 consumption, , during acute cold exposure) in high-altitude deer mice (Peromyscus maniculatus). We crossed highland and lowland deer mice to produce F2 inter-population hybrids, which expressed genetically based variation in hemoglobin (Hb) O2 affinity on a mixed genetic background. We then combined physiological experiments and mathematical modeling of the O2 transport pathway to examine links between cardiorespiratory traits and . Physiological experiments revealed that increases in Hb-O2 affinity of red blood cells improved blood oxygenation in hypoxia, but were not associated with enhancements in . Sensitivity analyses performed using mathematical modeling showed that the influence of Hb-O2 affinity on in hypoxia was contingent on the capacity for O2 diffusion in active tissues. These results suggest that increases in Hb-O2 affinity would only have adaptive value in hypoxic conditions if concurrent with or preceded by increases in tissue O2 diffusing capacity. In high-altitude deer mice, the adaptive benefit of increasing Hb-O2 affinity is contingent on the capacity to extract O2 from the blood, which helps resolve controversies about the general role of hemoglobin function in hypoxia tolerance.Significance StatementComplex organismal traits are often the result of multiple interacting genes and phenotypes, but the role of these interactions in shaping adaptive traits is poorly understood. We combined physiological experiments and modeling to examine how functional interactions between cardiorespiratory traits underlie high-altitude adaptation in deer mice. We show that adaptive increases in thermogenic capacity result from a functional interaction between blood hemoglobin and active tissues, in which the adaptive benefit of increasing hemoglobin O2 affinity is contingent on the capacity for O2 diffusion from the blood. This helps reconcile controversy about the general role of hemoglobin in hypoxia tolerance, and provides insight into physiological mechanisms of high-altitude adaptation.

scholarly journals Physiological and genetic convergence supports hypoxia resistance in high-altitude songbirds

PLoS Genetics ◽  
2020 ◽  
Vol 16 (12) ◽  
pp. e1009270
Author(s):  
Ying Xiong ◽  
Liqing Fan ◽  
Yan Hao ◽  
Yalin Cheng ◽  
Yongbin Chang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
High Altitude ◽  
Metabolic Diseases ◽  
Physiological Mechanism ◽  
Relative Activity ◽  
Hypoxia Tolerance ◽  
Missense Mutations ◽  
Low Oxygen ◽  
Energy Expenditures ◽  
Genetic Mechanisms

Skeletal muscle plays a central role in regulating glucose uptake and body metabolism; however, highland hypoxia is a severe challenge to aerobic metabolism in small endotherms. Therefore, understanding the physiological and genetic convergence of muscle hypoxia tolerance has a potential broad range of medical implications. Here we report and experimentally validate a common physiological mechanism across multiple high-altitude songbirds that improvement in insulin sensitivity contributes to glucose homeostasis, low oxygen consumption, and relative activity, and thus increases body weight. By contrast, low-altitude songbirds exhibit muscle loss, glucose intolerance, and increase energy expenditures under hypoxia. This adaptive mechanism is attributable to convergent missense mutations in the BNIP3L gene, and METTL8 gene that activates MEF2C expression in highlanders, which in turn increases hypoxia tolerance. Together, our findings from wild high-altitude songbirds suggest convergent physiological and genetic mechanisms of skeletal muscle in hypoxia resistance, which highlights the potentially medical implications of hypoxia-related metabolic diseases.

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