Native highland and lowland populations differ in .GAMMA.-globin gene promoter polymorphisms related to altered fetal hemoglobin levels and delayed fetal to adult globin switch after birth

Rottgardt, Inken; Rothhammer, Francisco; Dittmar, Manuela

doi:10.1537/ase.090402

Cited by 11 publications

(10 citation statements)

References 42 publications

(48 reference statements)

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“…The encoded protein hydroxylates the product of EPAS1, a gene shown to harbor variants responsible for human adaptation to high altitude in Tibet (Yi et al 2013). We also find members of the ß-globin cluster (HBE1-HBG2) that are involved in oxygen transport and have strong associations to hemoglobin levels and ß-thalassemia (Danjou et al 2015), and for which there is also evidence for recent positive selection in Andean (HBE1, HBG2) or Tibetan (HBG2) populations (Bigham et al 2010;Rottgardt et al 2010;Yi et al 2010). It is plausible that these genes have been under LTBS and undergone a shift in selective pressures in high-altitude…”

Section: Properties Of Candidate Genesmentioning

confidence: 68%

Signatures of long-term balancing selection in human genomes

Bitarello

Filippo

Teixeira

et al. 2017

Preprint

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Balancing selection maintains advantageous diversity in populations through various mechanisms. While extensively explored from a theoretical perspective, an empirical understanding of its prevalence and targets lags behind our knowledge of positive selection. Here we describe the Non-Central Deviation (NCD), a simple yet powerful statistic to detect long-term balancing selection (LTBS) that quantifies how close frequencies are to expectations under LTBS, and provides the basis for a neutrality test. NCD can be applied to a single locus or genomic data, and can be implemented considering only polymorphisms (NCD1) or also considering fixed differences with respect to an outgroup (NCD2) species. Incorporating fixed differences improves power, and NCD2 has higher power to detect LTBS in humans under different frequencies of the balanced allele(s) than other available methods. Applied to genome-wide data from African and European human populations, in both cases using chimpanzee as an outgroup, NCD2 shows that, albeit not prevalent, LTBS affects a sizable portion of the genome: about 0.6% of analyzed genomic windows and 0.8% of analyzed positions. Significant windows (p < 0.0001) contain 1.6% of SNPs in the genome, which disproportionally fall within exons and change protein sequence, but are not enriched in putatively regulatory sites. These windows overlap about 8% of the protein-coding genes, and these have larger number of transcripts than expected by chance even after controlling for gene length. Our catalog includes known targets of LTBS but a majority of them (90%) are novel. As expected, immune-related genes are among those with the strongest signatures, although most candidates are involved in other biological functions, suggesting that LTBS potentially influences diverse human phenotypes.

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Section: Properties Of Candidate Genesmentioning

confidence: 68%

Signatures of long-term balancing selection in human genomes

Bitarello

Filippo

Teixeira

et al. 2017

Preprint

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“…Further, promoter variants of the HBG2 locus have been reported in native Chilean Andes highlanders, causing delayed transition from HbF to adult hemoglobin 15 ; however, we are not aware of any previous studies of dysregulated expression of HbF in Tibetans. As there are reports of increased HbF in individuals exposed to hypoxia 16 , we also quantitated HbF in 29 additional Tibetan subjects living at 4320 m, 25 Aymara and 5 Caucasian Andean residents and all of them had normal HbF.…”

Section: Resultsmentioning

confidence: 89%

High altitude genetic adaptation in Tibetans: No role of increased hemoglobin–oxygen affinity

Tashi

Tian

Koul

et al. 2014

Blood Cells, Molecules, and Diseases

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High altitude exerts selective evolutionary pressure primarily due to its hypoxic environment, resulting in multiple adaptive responses. High hemoglobin-oxygen affinity is postulated to be one such adaptive change, which has been reported in Sherpas of the Himalayas. Tibetans have lived on the Qinghai-Tibetan plateau for thousands of years and have developed unique phenotypes, such as protection from polycythemia which has been linked to PDH2 mutation, resulting in downregulation of HIF pathway. In order to see if Tibetans also developed high hemoglobin-oxygen affinity as a part of their genetic adaptation, we conducted this study assessing hemoglobin-oxygen affinity and their fetal hemoglobin levels in Tibetan subjects from 3 different altitudes. We found normal hemoglobin-oxygen affinity in all subjects, fetal hemoglobin levels were normal in all except one and no hemoglobin variants in any of the subjects. We conclude that increased hemoglobin-oxygen affinity or increased fetal hemoglobin are not adaptive phenotypes of the Tibetan highlanders.

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“…Elevated HbF levels, due to increased Gγ globin expression, have been associated with a C→T substitution at position−158 [ 40 ]. Both the AGCA deletion, which is common in Europeans and Africans [ 41 ] and the HBG2 −158 T allele, are associated with a delayed fetal to adult globin switch after birth [ 42 ]. In order to investigate whether polymorphisms associated with altered fetal γ-globin expression differ in their frequencies between Aymara and non Aymara individuals, recently Rottgardt el al.…”

Section: Discussionmentioning

confidence: 99%

Neonatal Variables, Altitude of Residence and Aymara Ancestry in Northern Chile

et al. 2015

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Studies performed in the Andean plateau, one of the highest inhabited areas in the world, have reported that reduced availability of oxygen is associated to fetal growth retardation and lower birth weight, which are established predictors of morbidity and mortality during the first year of life. To test this hypothesis, perinatal variables of neonates born at the Juan Noé Hospital of Arica, Chile, were analyzed in relation to altitude of residence and Aymara ancestry of their mothers. The study population comprised the offspring of 5,295 mothers born between February 2004 and August 2010. Information included birth weight, height, head circumference, gestational age, altitude of residence and socioeconomic status, and was obtained from medical records. Mother´s ancestry was assessed based on surnames which were linked to percentages of Aymara admixture estimates relying on 40 selected ancestry informative markers. After correcting for the effect of multicollinearity among predictor variables, neonates born to mothers with an increased component of Aymara ancestry showed significantly higher birth weight and height at sea level, a marginally significant (p-value 0.06) decrease of birth weight and a significant decrease of height with altitude in comparison with the offspring of mothers with low Aymara ancestry. Since observed tendencies are suggestive of a possible genetic adaptation to hypoxia of the Chilean Aymara, we discuss briefly preliminary evidence related to fetal oxygen transport, particularly polymorphisms in the promoters of the HBG1 and HBG2 genes that are modulators of HbF synthesis, obtained in this ethnic group.

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Native highland and lowland populations differ in .GAMMA.-globin gene promoter polymorphisms related to altered fetal hemoglobin levels and delayed fetal to adult globin switch after birth

Cited by 11 publications

References 42 publications

Signatures of long-term balancing selection in human genomes

Signatures of long-term balancing selection in human genomes

High altitude genetic adaptation in Tibetans: No role of increased hemoglobin–oxygen affinity

Neonatal Variables, Altitude of Residence and Aymara Ancestry in Northern Chile

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