Genetic variation in hypoxia-inducible factor 1α and its possible association with high altitude adaptation in Sherpas

Suzuki, Kohei; Kizaki, Takako; Hitomi, Yoshiaki; Nukita, M; Kimoto, Kiyoko; Miyazawa, Nobuko; Kobayashi, Kanae; Ohnuki, Yasushi; Ohno, Hideki

doi:10.1016/s0306-9877(03)00178-6

Cited by 47 publications

(26 citation statements)

References 29 publications

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“…Alternatively, increased NADH/NAD + ratios could impede the tricarboxylic acid cycle, increasing succinate or fumarate levels which could strabilize hypoxia-inducible factors 1 and 2 (HIF-1, HIF-2) and increase adaptation to hypoxia (44). The genes of the HIF-1 and -2 pathways have been found to be altered in Tibetan and Andean populations (45)(46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans

Ji¹,

Sharpley

Derbeneva

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

123

107

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The distinction between mild pathogenic mtDNA mutations and population polymorphisms can be ambiguous because both are homoplasmic, alter conserved functions, and correlate with disease. One possible explanation for this ambiguity is that the same variant may have different consequences in different contexts. The NADH dehydrogenase subunit 1 (ND1) nucleotide 3394 T > C (Y30H) variant is such a case. This variant has been associated with Leber hereditary optic neuropathy and it reduces complex I activity and cellular respiration between 7% and 28% on the Asian B4c and F1 haplogroup backgrounds. However, complex I activity between B4c and F1 mtDNAs, which harbor the common 3394T allele, can also differ by 30%. In Asia, the 3394C variant is most commonly associated with the M9 haplogroup, which is rare at low elevations but increases in frequency with elevation to an average of 25% of the Tibetan mtDNAs (odds ratio = 23.7). In high-altitude Tibetan and Indian populations, the 3394C variant occurs on five different macrohaplogroup M haplogroup backgrounds and is enriched on the M9 background in Tibet and the C4a4 background on the Indian Deccan Plateau (odds ratio = 21.9). When present on the M9 background, the 3394C variant is associated with a complex I activity that is equal to or higher than that of the 3394T variant on the B4c and F1 backgrounds. Hence, the 3394C variant can either be deleterious or beneficial depending on its haplogroup and environmental context. Thus, this mtDNA variant fulfills the criteria for a common variant that predisposes to a "complex" disease.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans

Ji¹,

Sharpley

Derbeneva

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

123

107

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“…An investigation of polymorphisms in the HIF1A gene of Tibetans (Sherpas) found a dinucleotide repeat in 20 Tibetans that was not found in 30 Japanese lowlander controls (59). However, no phenotypic data were reported.…”

Section: Are These Functional Adaptations Heritable?mentioning

confidence: 99%

Two routes to functional adaptation: Tibetan and Andean high-altitude natives

Beall

2007

Proc. Natl. Acad. Sci. U.S.A.

600

532

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Populations native to the Tibetan and Andean Plateaus are descended from colonizers who arrived perhaps 25,000 and 11,000 years ago, respectively. Both have been exposed to the opportunity for natural selection for traits that offset the unavoidable environmental stress of severe lifelong high-altitude hypoxia. This paper presents evidence that Tibetan and Andean high-altitude natives have adapted differently, as indicated by large quantitative differences in numerous physiological traits comprising the oxygen delivery process. These findings suggest the hypothesis that evolutionary processes have tinkered differently on the two founding populations and their descendents, with the result that the two followed different routes to the same functional outcome of successful oxygen delivery, longterm persistence and high function. Assessed on the basis of basal and maximal oxygen consumption, both populations avail themselves of essentially the full range of oxygen-using metabolism as populations at sea level, in contrast with the curtailed range available to visitors at high altitudes. Efforts to identify the genetic bases of these traits have included quantitative genetics, genetic admixture, and candidate gene approaches. These reveal generally more genetic variance in the Tibetan population and more potential for natural selection. There is evidence that natural selection is ongoing in the Tibetan population, where women estimated to have genotypes for high oxygen saturation of hemoglobin (and less physiological stress) have higher offspring survival. Identifying the genetic bases of these traits is crucial to discovering the steps along the Tibetan and Andean routes to functional adaptation.hypoxia ͉ natural selection ͉ human

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“…The study found no association, although it did acknowledge that it had low statistical power owing to the small sample size of 49 cases and 54 controls [ 111 ]. Another study reported a new sequence in the HIF1A gene among Sherpas as compared with Japanese and also reported other allele frequency differences at that locus [ 112 ]. In contrast, the HIF1A sequence of Andean highlanders did not differ from that of low-altitude controls [ 113 ].…”

Section: Genome-wide Signals Have Different Strengths To Detect Selecmentioning

confidence: 87%

Human Evolution at High Altitude

Beall

2013

High Altitude

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This chapter reviews evidence that natural selection is acting or has acted on indigenous high-altitude populations of the Andean, Tibetan and East African plateaus and resulted in distinctive biological characteristics conferring vigor and health. It describes the results of classic era and genomic era approaches to detecting natural selection. Genomic era evidence of natural selection on high-altitude populations is accumulating rapidly and broadly supports that from the classic era. An important remaining step is to associate phenotypic with genomic variation and to associate them with survival and reproduction, the demographic currency of natural selection.

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Genetic variation in hypoxia-inducible factor 1α and its possible association with high altitude adaptation in Sherpas

Cited by 47 publications

References 29 publications

Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans

Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans

Two routes to functional adaptation: Tibetan and Andean high-altitude natives

Human Evolution at High Altitude

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