Tibetan
            <i>PHD2</i>
            , an allele with loss-of-function properties

Song, Daisheng; Navalsky, Bradleigh E.; Guan, Wei; Ingersoll, Cassandra; Wang, Tao; Loro, Emanuele; Eeles, Lydia; Matchett, Kyle B.; Percy, Melanie J.; Walsby-Tickle, John; McCullagh, James; Medina, Reinhold J.; Khurana, Tejvir S.; Bigham, Abigail W.; Lappin, Terence; Lee, Frank S.

doi:10.1073/pnas.1920546117

Cited by 27 publications

(33 citation statements)

References 62 publications

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“…2014 ; Song et al. 2014 , 2020 ). In vitro experiments revealed that the two mutations impair PHD2: p23 binding ( Song et al.…”

Section: Genetic Experiments Provide Insights Into Mechanism and Procmentioning

confidence: 99%

High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology

Storz

2021

Molecular Biology and Evolution

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Population genomic analyses of high-altitude humans and other vertebrates have identified numerous candidate genes for hypoxia adaptation, and the physiological pathways implicated by such analyses suggest testable hypotheses about underlying mechanisms. Studies of highland natives that integrate genomic data with experimental measures of physiological performance capacities and subordinate traits are revealing associations between genotypes (e.g., hypoxia-inducible factor [HIF] gene variants) and hypoxia-responsive phenotypes. The subsequent search for causal mechanisms is complicated by the fact that observed genotypic associations with hypoxia-induced phenotypes may reflect second-order consequences of selection-mediated changes in other (unmeasured) traits that are coupled with the focal trait via feedback regulation. Manipulative experiments to decipher circuits of feedback control and patterns of phenotypic integration can help identify causal relationships that underlie observed genotype-phenotype associations. Such experiments are critical for correct inferences about phenotypic targets of selection and mechanisms of adaptation.

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“…2014 ; Song et al. 2014 , 2020 ). In vitro experiments revealed that the two mutations impair PHD2: p23 binding ( Song et al.…”

Section: Genetic Experiments Provide Insights Into Mechanism and Procmentioning

confidence: 99%

High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology

Storz

2021

Molecular Biology and Evolution

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“…One exception is at the EGLN1 gene, whereby variants in the first exon found at high frequency in Tibetans (Asp4Glu; Cys127Ser) are reported to result in a gain of PHD2 function, which leads to increased HIF degradation under hypoxic conditions and erythroid progenitor disruption (Lorenzo et al, 2014). Other reports suggest these variants underlie a loss of PHD2 function via defective binding of co-chaperone p23 that would lead to increased HIF activity (Aggarwal et al, 2010;Song et al, 2014) and possibly ventilatory responses (Song et al, 2020).…”

Section: Shared Signatures Of Adaptation Within and Across Himalayanmentioning

confidence: 99%

Cross-Species Insights Into Genomic Adaptations to Hypoxia

et al. 2020

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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.

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“…Tibetans harbor a C127S substitution in PHD2 that, in the context of the WT protein, is without an appreciable effect in vitro . However, in the context of a D4E mutation that is adjacent to the PHD2 zinc finger, the C127S substitution results in markedly impaired interaction of PHD2 with the HSP90 cochaperone p23, leading to loss of function ( 29 , 30 ). We propose that the high-altitude deer mouse T755M Hif-2α mutation and the human Tibetan C127S PHD2 substitution represent two independent adaptive amino acid changes in the HIF pathway that occur in potentially disordered regions of the respective proteins, produce loss of function in the context of other selective amino acid changes, and promote adaptation to the chronic hypoxia of high altitude.…”

Section: Resultsmentioning

confidence: 99%

High-altitude deer mouse hypoxia-inducible factor-2α shows defective interaction with CREB-binding protein

Song

Bigham

Lee

2021

Journal of Biological Chemistry

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Numerous mammalian species have adapted to the chronic hypoxia of high altitude. Recent genomic studies have identified evidence for natural selection of genes and associated genetic changes in these species. A major gap in our knowledge is an understanding of the functional significance, if any, of these changes. Deer mice ( Peromyscus maniculatus ) live at both low and high altitudes in North America, providing an opportunity to identify functionally important genetic changes. High-altitude deer mice show evidence of natural selection on the Epas1 gene, which encodes for hypoxia-inducible factor-2α (Hif-2α), a central transcription factor of the hypoxia-inducible factor pathway. An SNP encoding for a T755M change in the Hif-2α protein is highly enriched in high-altitude deer mice, but its functional significance is unknown. Here, using coimmunoprecipitation and transcriptional activity assays, we show that the T755M mutation produces a defect in the interaction of Hif-2α with the transcriptional coactivator CREB-binding protein. This results in a loss of function because of decreased transcriptional activity. Intriguingly, the effect of this mutation depends on the amino acid context. Interchanges between methionine and threonine at the corresponding position in house mouse ( Mus musculus ) Hif-2α are without effects on CREB-binding protein binding. Furthermore, transfer of a set of deer mouse–specific Hif-2α amino acids to house mouse Hif-2α is sufficient to confer sensitivity of house mouse Hif-2α to the T755M substitution. These findings provide insight into high-altitude adaptation in deer mice and evolution at the Epas1 locus.

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Tibetan PHD2 , an allele with loss-of-function properties

Cited by 27 publications

References 62 publications

High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology

High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology

Cross-Species Insights Into Genomic Adaptations to Hypoxia

High-altitude deer mouse hypoxia-inducible factor-2α shows defective interaction with CREB-binding protein

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