A Positive Correlation between Elevated Altitude and Frequency of Mutant Alleles at the EPAS1 and HBB Loci in Chinese Indigenous Dogs

Fan, Ruoxi; Liu, Fei; Wu, Hong; Wu, Shi-Fang; Zhu, Chun-Ling; Li, Yan; Wang, Guodong; Zhang, Yaping

doi:10.1016/j.jgg.2015.02.006

Cited by 8 publications

(13 citation statements)

References 21 publications

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“…Variants at the same locus also prove adaptive in high-altitude hummingbirds in South America . Adaptive signals are noted at EPAS1 and HBB loci in domesticated dogs at altitude (Gou et al, 2014;Wang et al, 2014;Fan et al, 2015), and yak share an adaptive selection signal with Tibetans at the ADAM17 locus (Qiu et al, 2012).…”

Section: Replicated Genetic Signals Of Adaptation In Other Populationmentioning

confidence: 95%

Altitude Adaptation: A Glimpse Through Various Lenses

Simonson

2015

High Altitude Medicine & Biology

137

141

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Simonson, Tatum S. Altitude adaptation: A glimpse through various lenses. High Alt Med Biol 16:125-137, 2015.-Recent availability of genome-wide data from highland populations has enabled the identification of adaptive genomic signals. Some of the genomic signals reported thus far among Tibetan, Andean, and Ethiopian are the same, while others appear unique to each population. These genomic findings parallel observations conveyed by decades of physiological research: different continental populations, resident at high altitude for hundreds of generations, exhibit a distinct composite of traits at altitude. The most commonly reported signatures of selection emanate from genomic segments containing hypoxia-inducible factor (HIF) pathway genes. Corroborative evidence for adaptive significance stems from associations between putatively adaptive gene copies and sea-level ranges of hemoglobin concentration in Tibetan and Amhara Ethiopians, birth weights and metabolic factors in Andeans and Tibetans, maternal uterine artery diameter in Andeans, and protection from chronic mountain sickness in Andean males at altitude. While limited reports provide mechanistic insights thus far, efforts to identify and link precise genetic variants to molecular, physiological, and developmental functions are underway, and progress on the genomics front continues to provide unprecedented movement towards these goals. This combination of multiple perspectives is necessary to maximize our understanding of orchestrated biological and evolutionary processes in native highland populations, which will advance our understanding of both adaptive and non-adaptive responses to hypoxia.

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Section: Replicated Genetic Signals Of Adaptation In Other Populationmentioning

confidence: 95%

Altitude Adaptation: A Glimpse Through Various Lenses

Simonson

2015

High Altitude Medicine & Biology

137

141

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“…Whole-genome resequencing analyses have been carried out to investigate the genetic basis of the hypoxia adaptation in many domestic animals, such as yak ( Qiu et al, 2012 ), Tibetan pig ( Ai et al, 2014 ), dog ( Li et al, 2014 ), and birds ( Cai et al, 2013 ). Various candidate genes have been identified for high-altitude adaptation, including EPAS1 (endothelial PAS domain protein 1) and HBB (hemoglobin beta) ( Gou et al, 2014 ; Fan et al, 2015 ; Song et al, 2016 ). In prior studies, both EPAS1 and HBB revealed six non-synonymous mutations potentially affecting the gene function and influencing high-altitude hypoxic adaptation in dogs ( Fan et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

“…Various candidate genes have been identified for high-altitude adaptation, including EPAS1 (endothelial PAS domain protein 1) and HBB (hemoglobin beta) ( Gou et al, 2014 ; Fan et al, 2015 ; Song et al, 2016 ). In prior studies, both EPAS1 and HBB revealed six non-synonymous mutations potentially affecting the gene function and influencing high-altitude hypoxic adaptation in dogs ( Fan et al, 2015 ). These studies proved that the domestic animals are a useful animal model to explore high-altitude adaptation.…”

Section: Introductionmentioning

confidence: 99%

Sequence Characterization of DSG3 Gene to Know Its Role in High-Altitude Hypoxia Adaptation in the Chinese Cashmere Goat

et al. 2018

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The Tibetan cashmere goat is one of the main goat breeds used by people living in the plateau. It exhibits the distinct phenotypic characteristics observed in lowland goats, allowing them to adapt to the challenging conditions at high altitudes. It provides an ideal model for understanding the genetic mechanisms underlying high-altitude adaptation and hypoxia-related diseases. Our previous exome sequencing of five Chinese cashmere breeds revealed a candidate gene, DSG3 (Desmoglein 3), responsible for the high-altitude adaptation of the Tibetan goat. However, the whole DSG3 gene (44 kbp) consisting of 16 exons in the goat genome was not entirely covered by the exome sequencing. In this study, we resequenced all the 16 exons of the DSG3 gene in ten Chinese native goat populations. Twenty-seven SNP variants were found between the lowland and highland goat populations. The genetic distance (FST) of significant SNPs between the lowland and highland populations ranged from 0.42 to 0.58. By using correlation coefficient analysis, linkage disequilibrium, and haplotype network construction, we found three non-synonymous SNPs (R597E, T595I, and G572S) in exon 5 and two synonymous SNPs in exons 8 and 16 in DSG3. These mutations significantly segregated high- and low-altitude goats in two clusters, indicating the contribution of DSG3 to the high-altitude hypoxia adaptation in the Tibetan goat.

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“…It was recently reported that indigenous Chinese dogs, including breeds such as the Tibetan Mastiff, carry coding variation in HBB as well as in EPAS1 (which encodes HIF-2alpha, a transcription factor that regulates levels of red blood cells according to oxygen levels; this gene was previously shown to be under evolutionary selection for adaptation to high-altitude in humans [ 30 – 32 ]) [ 33 ]. Notably, that variation is strongly implicated to be under selection because their allele frequencies are directly correlated with altitude [ 34 ]. We thus evaluated Vaysse et al’s previously published dataset of genotypes and statistical analysis of evolutionary selection from 509 dogs belonging to 46 breeds [ 4 ].…”

Section: Resultsmentioning

confidence: 99%

Comparative genomics of canine hemoglobin genes reveals primacy of beta subunit delta in adult carnivores

et al. 2017

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BackgroundThe main function of hemoglobin (Hb) is to transport oxygen in the circulation. It is among the most highly studied proteins due to its roles in physiology and disease, and most of our understanding derives from comparative research. There is great diversity in Hb gene evolution in placental mammals, mostly in the repertoire and regulation of the β-globin subunits. Dogs are an ideal model in which to study Hb genes because: 1) they are members of Laurasiatheria, our closest relatives outside of Euarchontoglires (including primates, rodents and rabbits), 2) dog breeds are isolated populations with their own Hb-associated genetics and diseases, and 3) their high level of health care allows for development of biomedical investigation and translation.ResultsWe established that dogs have a complement of five α and five β-globin genes, all of which can be detected as spliced mRNA in adults. Strikingly, HBD, the allegedly-unnecessary adult β-globin protein in humans, is the primary adult β-globin in dogs and other carnivores; moreover, dogs have two active copies of the HBD gene. In contrast, the dominant adult β-globin of humans, HBB, has high sequence divergence and is expressed at markedly lower levels in dogs. We also showed that canine HBD and HBB genes are complex chimeras that resulted from multiple gene conversion events between them. Lastly, we showed that the strongest signal of evolutionary selection in a high-altitude breed, the Bernese Mountain Dog, lies in a haplotype block that spans the β-globin locus.ConclusionsWe report the first molecular genetic characterization of Hb genes in dogs. We found important distinctions between adult β-globin expression in carnivores compared to other members of Laurasiatheria. Our findings are also likely to raise new questions about the significance of human HBD. The comparative genomics of dog hemoglobin genes sets the stage for diverse research and translation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3513-0) contains supplementary material, which is available to authorized users.

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A Positive Correlation between Elevated Altitude and Frequency of Mutant Alleles at the EPAS1 and HBB Loci in Chinese Indigenous Dogs

Cited by 8 publications

References 21 publications

Altitude Adaptation: A Glimpse Through Various Lenses

Altitude Adaptation: A Glimpse Through Various Lenses

Sequence Characterization of DSG3 Gene to Know Its Role in High-Altitude Hypoxia Adaptation in the Chinese Cashmere Goat

Comparative genomics of canine hemoglobin genes reveals primacy of beta subunit delta in adult carnivores

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