By impairing both function and survival, the severe reduction in oxygen availability associated with high-altitude environments is likely to act as an agent of natural selection. We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2α, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. Second, in a separate cohort of Tibetans residing at 4,200 m, we identified 31 EPAS1 SNPs in high linkage disequilibrium that correlated significantly with hemoglobin concentration. The sex-adjusted hemoglobin concentration was, on average, 0.8 g/dL lower in the major allele homozygotes compared with the heterozygotes. These findings were replicated in a third cohort of Tibetans residing at 4,300 m. The alleles associating with lower hemoglobin concentrations were correlated with the signal from the GWADS study and were observed at greatly elevated frequencies in the Tibetan cohorts compared with the Han. High hemoglobin concentrations are a cardinal feature of chronic mountain sickness offering one plausible mechanism for selection. Alternatively, as EPAS1 is pleiotropic in its effects, selection may have operated on some other aspect of the phenotype. Whichever of these explanations is correct, the evidence for genetic selection at the EPAS1 locus from the GWADS study is supported by the replicated studies associating function with the allelic variants.chronic mountain sickness | high altitude | human genome variation | hypoxia | hypoxia-inducible factor

To assess factors influencing the success of whole genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases across a broad spectrum of disorders in whom prior screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritisation. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease causing variants in 21% of cases, rising to 34% (23/68) for Mendelian disorders and 57% (8/14) in trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, though only four were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis, but also highlight many outstanding challenges.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use

BackgroundThe von Hippel–Lindau tumour suppressor protein–hypoxia-inducible factor (VHL–HIF) pathway has attracted widespread medical interest as a transcriptional system controlling cellular responses to hypoxia, yet insights into its role in systemic human physiology remain limited. Chuvash polycythaemia has recently been defined as a new form of VHL-associated disease, distinct from the classical VHL-associated inherited cancer syndrome, in which germline homozygosity for a hypomorphic VHL allele causes a generalised abnormality in VHL–HIF signalling. Affected individuals thus provide a unique opportunity to explore the integrative physiology of this signalling pathway. This study investigated patients with Chuvash polycythaemia in order to analyse the role of the VHL–HIF pathway in systemic human cardiopulmonary physiology.Methods and FindingsTwelve participants, three with Chuvash polycythaemia and nine controls, were studied at baseline and during hypoxia. Participants breathed through a mouthpiece, and pulmonary ventilation was measured while pulmonary vascular tone was assessed echocardiographically. Individuals with Chuvash polycythaemia were found to have striking abnormalities in respiratory and pulmonary vascular regulation. Basal ventilation and pulmonary vascular tone were elevated, and ventilatory, pulmonary vasoconstrictive, and heart rate responses to acute hypoxia were greatly increased.ConclusionsThe features observed in this small group of patients with Chuvash polycythaemia are highly characteristic of those associated with acclimatisation to the hypoxia of high altitude. More generally, the phenotype associated with Chuvash polycythaemia demonstrates that VHL plays a major role in the underlying calibration and homeostasis of the respiratory and cardiovascular systems, most likely through its central role in the regulation of HIF.

Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from the liver, it inhibits the iron exporter ferroportin in the gut and spleen, the sites of iron absorption and recycling respectively. Recently, we demonstrated that ferroportin is also found in cardiomyocytes, and that its cardiac-specific deletion leads to fatal cardiac iron overload. Hepcidin is also expressed in cardiomyocytes, where its function remains unknown. To define the function of cardiomyocyte hepcidin, we generated mice with cardiomyocyte-specific deletion of hepcidin, or knock-in of hepcidin-resistant ferroportin. We find that while both models maintain normal systemic iron homeostasis, they nonetheless develop fatal contractile and metabolic dysfunction as a consequence of cardiomyocyte iron deficiency. These findings are the first demonstration of a cell-autonomous role for hepcidin in iron homeostasis. They raise the possibility that such function may also be important in other tissues that express both hepcidin and ferroportin, such as the kidney and the brain.DOI: http://dx.doi.org/10.7554/eLife.19804.001

The Tibetan and Andean Plateaus and Ethiopian highlands are the largest regions to have long-term high-altitude residents. Such populations are exposed to lower barometric pressures and hence atmospheric partial pressures of oxygen. Such “hypobaric hypoxia” may limit physical functional capacity, reproductive health, and even survival. As such, selection of genetic variants advantageous to hypoxic adaptation is likely to have occurred. Identifying signatures of such selection is likely to help understanding of hypoxic adaptive processes. Here, we seek evidence of such positive selection using five Ethiopian populations, three of which are from high-altitude areas in Ethiopia. As these populations may have been recipients of Eurasian gene flow, we correct for this admixture. Using single-nucleotide polymorphism genotype data from multiple populations, we find the strongest signal of selection in BHLHE41 (also known as DEC2 or SHARP1). Remarkably, a major role of this gene is regulation of the same hypoxia response pathway on which selection has most strikingly been observed in both Tibetan and Andean populations. Because it is also an important player in the circadian rhythm pathway, BHLHE41 might also provide insights into the mechanisms underlying the recognized impacts of hypoxia on the circadian clock. These results support the view that Ethiopian, Andean, and Tibetan populations living at high altitude have adapted to hypoxia differently, with convergent evolution affecting different genes from the same pathway.