Genetic variation in HIF‐2α attenuates ventilatory sensitivity and carotid body growth in chronic hypoxia in high‐altitude deer mice
Bibliographic record
Abstract
Abstract The gene encoding HIF‐2α, Epas1 , has experienced a history of natural selection in many high‐altitude taxa, but the functional role of mutations in this gene is still poorly understood. We investigated the influence of the high‐altitude variant of Epas1 in North American deer mice ( Peromyscus maniculatus ) on the control of breathing and carotid body growth during chronic hypoxia. We created hybrids between high‐ and low‐altitude populations of deer mice to disrupt linkages between genetic loci so that the physiological effects of Epas1 alleles ( Epas1 H and Epas1 L , respectively) could be examined on an admixed genomic background. In general, chronic hypoxia (4 weeks at 12 kPa O 2 ) enhanced ventilatory chemosensitivity (assessed as the acute ventilatory response to hypoxia), increased total ventilation and arterial O 2 saturation during progressive poikilocapnic hypoxia, and increased haematocrit and blood haemoglobin content across genotypes. However, the effects of chronic hypoxia on ventilatory chemosensitivity were attenuated in mice that were homozygous for the high‐altitude Epas1 allele ( Epas1 H/H ). Carotid body growth and glomus cell hyperplasia, which was strongly induced in Epas1 L/L mice in chronic hypoxia, was not observed in Epas1 H/H mice. Epas1 genotype also modulated the effects of chronic hypoxia on metabolism and body temperature depression in hypoxia, but had no effects on haematological traits. These findings confirm the important role of HIF‐2α in modulating ventilatory sensitivity and carotid body growth in chronic hypoxia, and show that genetic variation in Epas1 is responsible for evolved changes in the control of breathing and metabolism in high‐altitude deer mice. image Key points High‐altitude natives of many species have experienced natural selection on the gene encoding HIF‐2α, Epas1 , including high‐altitude populations of deer mice. HIF‐2α regulates ventilation and carotid body growth in hypoxia, and so the genetic variants in Epas1 in high‐altitude natives may underlie evolved changes in control of breathing. Deer mice from controlled crosses between high‐ and low‐altitude populations were used to examine the effects of Epas1 genotype on an admixed genomic background. The high‐altitude variant was associated with reduced ventilatory chemosensitivity and carotid body growth in chronic hypoxia, but had no effects on haematology. The results help us better understand the genetic basis for the unique physiological phenotype of high‐altitude natives.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".