Genetic adaptation to high altitude in the Ethiopian highlands

Scheinfeldt, Laura B.; Soi, Sameer; Thompson, S. R.; Ranciaro, Alessia; Woldemeskel, Dawit; Beggs, William; Lambert, Charla; Jarvis, Joseph P.; Abate, Dawit; Belay, Gurja; Tishkoff, Sarah A.

doi:10.1186/gb-2012-13-1-r1

Cited by 355 publications

(222 citation statements)

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“…Gene variants associated with adaptation in this population include ARNT (encoding HIF-1β) and EDNRB. 112 Finally, in addition to studies conducted in humans residing at high altitude, recent work has also examined the genetics associated with development of HPH in cattle. Comparison between cattle that developed PH at altitude and those that did not revealed variants in EPAS1 that likely confer gain of function and were associated with HPH susceptibility.…”

Section: Mechanisms Of Hph: Lessons From High-altitude Genomicsmentioning

confidence: 99%

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

2016

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Pulmonary blood vessel structure and tone are maintained by a complex interplay between endogenous vasoactive factors and oxygen-sensing intermediaries. Under physiological conditions, these signaling networks function as an adaptive interface between the pulmonary circulation and environmental or acquired perturbations to preserve oxygenation and maintain systemic delivery of oxygen-rich hemoglobin. Chronic exposure to hypoxia, however, triggers a range of pathogenetic mechanisms that include hypoxia-inducible factor 1α (HIF-1α)-dependent upregulation of the vasoconstrictor peptide endothelin 1 in pulmonary endothelial cells. In pulmonary arterial smooth muscle cells, chronic hypoxia induces HIF-1α-mediated upregulation of canonical transient receptor potential proteins, as well as increased Rho kinase-Ca 2+ signaling and pulmonary arteriole synthesis of the profibrotic hormone aldosterone. Collectively, these mechanisms contribute to a contractile or hypertrophic pulmonary vascular phenotype. Genetically inherited disorders in hemoglobin structure are also an important etiology of abnormal pulmonary vasoreactivity. In sickle cell anemia, for example, consumption of the vasodilator and antimitogenic molecule nitric oxide by cell-free hemoglobin is an important mechanism underpinning pulmonary hypertension. Contemporary genomic and transcriptomic analytic methods have also allowed for the discovery of novel risk factors relevant to sickle cell disease, including GALNT13 gene variants. In this report, we review cutting-edge observations characterizing these and other pathobiological mechanisms that contribute to pulmonary vascular and right ventricular vulnerability.Keywords: hypoxia, pulmonary hypertension, genetics. In the autumn of 2015 at the Lost Valley Ranch in Sedalia, Colorado, the 34th Grover Conference, on pulmonary circulation in the "omics" era, convened for a 4-day symposium to discuss contemporary scientific concepts in the genetics, genomics, proteomics, and epigenetics of pulmonary vascular diseases. This biannual meeting, sponsored by the American Thoracic Society and co-led this year by Drs. C. Gregory Elliot, Wendy K. Chung, D. Hunter Best, and Eric D. Austin, commemorates the perpetual and transformative scientific contributions of Dr. Robert Grover 1 to the fields of high-altitude medicine and pulmonary vascular disease. This review is part of an ongoing Pulmonary Circulation thematic series that aims to provide a synopsis of key concepts presented at this year's Grover Conference.Here, we summarize the discussions that constituted a section of the conference emphasizing novel genetic and molecular mechanisms underpinning "pulmonary vascular and ventricular dysfunction in the susceptible patient." To accomplish this, three concepts are reviewed in detail: the functional relevance of chronic hypoxia (CH), discovered through genomic analyses; novel molecular mechanisms and phenotypic signatures of pulmonary vascular disease in sickle cell disease; and hormonal regulation of vascular f...

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Section: Mechanisms Of Hph: Lessons From High-altitude Genomicsmentioning

confidence: 99%

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

2016

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“…Such empirical studies also highlight the current deficiencies of such methods, as some of the best signals in these studies are not shared across populations with broadly similar environments and instead indicate that adaptation has occurred through independent mutations in the same gene or pathway. For example, high-altitude adaptation seems to have a different genetic basis in highland Ethiopian and Andean populations (Bigham et al 2010;Scheinfeldt et al 2012). Methods based on environmental correlations will fail to detect such cases, unless the data are split into the appropriate geographic subsets (e.g., Hancock et al 2011c) on an appropriate geographic scale (Ralph and Coop 2010).…”

Section: Discussionmentioning

confidence: 99%

Robust Identification of Local Adaptation from Allele Frequencies

2013

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Comparing allele frequencies among populations that differ in environment has long been a tool for detecting loci involved in local adaptation. However, such analyses are complicated by an imperfect knowledge of population allele frequencies and neutral correlations of allele frequencies among populations due to shared population history and gene flow. Here we develop a set of methods to robustly test for unusual allele frequency patterns and correlations between environmental variables and allele frequencies while accounting for these complications based on a Bayesian model previously implemented in the software Bayenv. Using this model, we calculate a set of "standardized allele frequencies" that allows investigators to apply tests of their choice to multiple populations while accounting for sampling and covariance due to population history. We illustrate this first by showing that these standardized frequencies can be used to detect nonparametric correlations with environmental variables; these correlations are also less prone to spurious results due to outlier populations. We then demonstrate how these standardized allele frequencies can be used to construct a test to detect SNPs that deviate strongly from neutral population structure. This test is conceptually related to F ST and is shown to be more powerful, as we account for population history. We also extend the model to next-generation sequencing of population poolsa cost-efficient way to estimate population allele frequencies, but one that introduces an additional level of sampling noise. The utility of these methods is demonstrated in simulations and by reanalyzing human SNP data from the Human Genome Diversity Panel populations and pooled next-generation sequencing data from Atlantic herring. An implementation of our method is available from http://gcbias.org.T HE phenotypes of individuals within a species often vary clinally along environmental gradients (Huxley 1939). Such phenotypic clines have long been central to adaptive arguments in evolutionary biology (Mayr 1942), with diverse examples including latitudinal clines in skin pigmentation in humans (Jablonski 2004), body size and temperature tolerance in Drosophila (Hoffmann and Weeks 2007), and flowering time in plants ( Stinchcombe et al. 2004). Unsurprisingly, comparisons of allele frequencies between populations that differ in environment were among the earliest population genetic tests for selection (Cavalli-Sforza 1966;Lewontin and Krakauer 1973;Endler 1986) and have continued to be central to population genetics to this day (e.g., Coop et al. 2009;Akey et al. 2010).The falling cost of sequencing and genotyping means that such comparisons can now be made on a genome-wide scale, allowing us to start to understand the genetic basis of local adaptation across a broad range of organisms. However, such studies need to acknowledge the sampling issues inherent in population genetic studies of natural populations. In assessing correlations between allele frequencies and environmental vari...

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“…Candidate genes include basic HLH family member e41 (BHLHE41 also known as DEC2 or SHARP1), mitochondrial calcium uptake 1 (MICU, also known as CBARA1), vav 3 guanine nucleotide exchange factor (VAV3), arylhydrocarbon receptor nuclear translocator 2 (ARNT2), and thyroid hormone receptor b (THRB) as well as a generich region on chromosome 19 containing several genes that are involved in vascular physiology (CXCL17 and PAFAH1B3) or have been linked to hypoxia (LIPE) (Scheinfeldt et al 2012;Huerta-Sanchez et al 2013;Udpa et al 2014). Two genes in particular, ARNT2 and THRB, show suggestive relationships with hemoglobin concentration; for example, Ethiopian Amhara with two copies of the THRB rs826216 C allele display hemoglobin levels that are higher than those in individuals with two copies of the T allele (Scheinfeldt et al 2012). Recent research also has identified HIF pathway candidate genes showing signatures of natural selection in other human populations, including Sherpa, Indians, and Mongolians (Aggarwal et al 2010;Hanaoka et al 2012;Kang et al 2013;Xing et al 2013;Jeong et al 2014).…”

Section: Andean and Ethiopian Adaptation To High Altitude And Geneticmentioning

confidence: 99%

Human high-altitude adaptation: forward genetics meets the HIF pathway

2014

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Humans have adapted to the chronic hypoxia of high altitude in several locations, and recent genome-wide studies have indicated a genetic basis. In some populations, genetic signatures have been identified in the hypoxia-inducible factor (HIF) pathway, which orchestrates the transcriptional response to hypoxia. In Tibetans, they have been found in the HIF2A (EPAS1) gene, which encodes for HIF-2α, and the prolyl hydroxylase domain protein 2 (PHD2, also known as EGLN1) gene, which encodes for one of its key regulators, PHD2. High-altitude adaptation may be due to multiple genes that act in concert with one another. Unraveling their mechanism of action can offer new therapeutic approaches toward treating common human diseases characterized by chronic hypoxia.

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Genetic adaptation to high altitude in the Ethiopian highlands

Cited by 355 publications

References 40 publications

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

Robust Identification of Local Adaptation from Allele Frequencies

Human high-altitude adaptation: forward genetics meets the HIF pathway

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