藏族的高原适应——西藏藏族生物人类学研究回顾

藏族生活在具有世界屋脊之称的青藏高原, 特殊的生态环境和特殊的文化背景造就了藏族特殊的适应高原缺氧机制, 引起了国内外学者的广泛关注和浓厚的研究兴趣。本文根据国内外数据库的文献并结合我们的研究工作, 从高原适应的角度回顾了30多年藏族人类学研究。回顾显示, 藏族由于长期生活在高原缺氧的环境中, 不仅形态和机能发生了适应性变化, 而且体成分也表现出相应的变化, 体现了形态、机能和体成分的统一。这些变化是长期进化形成的, 与安第斯山人等有明显不同, 就是在同一高原生活的西藏、青海、四川、甘肃和云南的藏族乃至尼泊尔和印度藏族的体质也表现出地域差异, 这些差异的产生是多种因素所致, 两个关键性的基因是导致两大高原人口高原适应机制不同的最主要的原因。     

A preliminary study of copy number variation in tibetans

Genetic features of Tibetans have been broadly investigated, but the properties of copy number variation (CNV) have not been well examined. To get a preliminary view of CNV in Tibetans, we scanned 29 Tibetan genomes with the Illumina Human-1 M high-resolution genotyping microarray and identified 139 putative copy number variable regions (CNVRs), consisting of 70 deletions, 61 duplications, and 8 multi-allelic loci. Thirty-four of the 139 CNVRs showed differential allele frequencies versus other East-Asian populations, with P values <0.0001. These results indicated a distinct pattern of CNVR allele frequency distribution in Tibetans. The Tibetan CNVRs are enriched for genes in the disease class of human reproduction (such as genes from the DAZ, BPY2, CDY, and HLA-DQ and -DR gene clusters) and biological process categories of "response to DNA damage stimulus" and "DNA repair" (such as RAD51, RAD52, and MRE11A). These genes are related to the adaptive traits of high infant birth weight and darker skin tone of Tibetans, and may be attributed to recent local adaptation. Our results provide a different view of genetic diversity in Tibetans and new insights into their high-altitude adaptation.     

Differences in mtDNA whole sequence between Tibetan and Han populations suggesting adaptive selection to high altitude

We performed a mitochondrial whole-genome comparison study in 40 Tibetan and 50 Han Chinese. All subjects could be classified into 13 haplogroups pertained to the Macrohaplogroup M and N that pitched different quadrants by principal component analysis. We observed a difference in the M9 haplogroup and identified 18 significant variants by comparing whole sequences between Tibetan and Han populations. Variants in ND2, COX2, tRNA alanine and 12S rRNA were predicted to confer increased protein stability in Tibetans. We compared the base substitutions of nonsynonymous (NS) versus synonymous (S) of 13 protein-encoding genes and found the NS/S values of the ATP6, ATP8, and Cyt b genes were larger (>1) in Tibetans than that in Han population. Our findings provide clues for the existence of adaptive selection for the ATP6, ATP8, Cyt b, ND2, COX2, tRNA alanine and 12S rRNA genes in Tibetans which likely contributed to adaptation to their specific geographic environment, such as high altitude.     

Genomic Analysis of Natural Selection and Phenotypic Variation in High-Altitude Mongolians

Deedu (DU) Mongolians, who migrated from the Mongolian steppes to the Qinghai-Tibetan Plateau approximately 500 years ago, are challenged by environmental conditions similar to native Tibetan highlanders. Identification of adaptive genetic factors in this population could provide insight into coordinated physiological responses to this environment. Here we examine genomic and phenotypic variation in this unique population and present the first complete analysis of a Mongolian whole-genome sequence. High-density SNP array data demonstrate that DU Mongolians share genetic ancestry with other Mongolian as well as Tibetan populations, specifically in genomic regions related with adaptation to high altitude. Several selection candidate genes identified in DU Mongolians are shared with other Asian groups (e.g., EDAR), neighboring Tibetan populations (including high-altitude candidates EPAS1, PKLR, and CYP2E1), as well as genes previously hypothesized to be associated with metabolic adaptation (e.g., PPARG). Hemoglobin concentration, a trait associated with high-altitude adaptation in Tibetans, is at an intermediate level in DU Mongolians compared to Tibetans and Han Chinese at comparable altitude. Whole-genome sequence from a DU Mongolian (Tianjiao1) shows that about 2% of the genomic variants, including more than 300 protein-coding changes, are specific to this individual. Our analyses of DU Mongolians and the first Mongolian genome provide valuable insight into genetic adaptation to extreme environments.     

Identifying Signatures of Natural Selection in Tibetan and Andean Populations Using Dense Genome Scan Data

High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary to confirm the role of selection-nominated candidate genes and gene regions in adaptation to altitude.     

卫藏藏族与康巴藏族的Heath-Carter法体型

运用Heath-Carter人体测量法,对云南省迪庆400例康巴藏族成人和西藏林芝507例卫藏藏族成人进行了体型研究。卫藏藏族男性(5.0-6.2-1.1)和康巴藏族男性(4.4-5.1-1.6)均为偏内胚层的中胚层体型。卫藏藏族女性(5.7-6.1-0.8)和康巴藏族女性(5.6-5.7-1.1)均为内胚层-中胚层均衡型体型。总体上看,卫藏藏族和康巴藏族体型具有一致性,也存在差异。卫藏藏族男、女性和康巴藏族男、女性都属于身体线性度低,骨骼、肌肉发达,体脂丰满的体型。卫藏藏族男性、女性比康巴藏族男性、女性的脂肪更多一些,肌肉、骨骼更发达一些,体态更丰满一些。本文从藏族族源的形成以及生活环境的视角,探讨了同为藏族的卫藏与康巴藏族之间体型的异同,和同为生活在高海拔族群间体型差异产生的原因。研究结果提示藏族具有中国北方民族的体型特征。藏族的多脂肪,骨骼肌肉发达,身体粗壮的体型特征也是对高原环境的适应。     

Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas

Modern humans have occupied almost all possible environments globally since exiting Africa about 100,000 years ago. Both behavioral and biological adaptations have contributed to their success in surviving the rigors of climatic extremes, including cold, strong ultraviolet radiation, and high altitude. Among these environmental stresses, high-altitude hypoxia is the only condition in which traditional technology is incapable of mediating its effects. Inhabiting at >3,000-m high plateau, the Tibetan population provides a widely studied example of high-altitude adaptation. Yet, the genetic mechanisms underpinning long-term survival in this environmental extreme remain unknown. We performed an analysis of genome-wide sequence variations in Tibetans. In combination with the reported data, we identified strong signals of selective sweep in two hypoxia-related genes, EPAS1 and EGLN1. For these two genes, Tibetans show unusually high divergence from the non-Tibetan lowlanders (Han Chinese and Japanese) and possess high frequencies of many linked sequence variations as reflected by the Tibetan-specific haplotypes. Further analysis in seven Tibetan populations (1,334 individuals) indicates the prevalence of selective sweep across the Himalayan region. The observed indicators of natural selection on EPAS1 and EGLN1 suggest that during the long-term occupation of high-altitude areas, the functional sequence variations for acquiring biological adaptation to high-altitude hypoxia have been enriched in Tibetan populations.     

Population history and genomic signatures for high-altitude adaptation in Tibetan pigs

Background

The Tibetan pig is one of domestic animals indigenous to the Qinghai-Tibet Plateau. Several geographically isolated pig populations are distributed throughout the Plateau. It remained an open question if these populations have experienced different demographic histories and have evolved independent adaptive loci for the harsh environment of the Plateau. To address these questions, we herein investigated ~ 40,000 genetic variants across the pig genome in a broad panel of 678 individuals from 5 Tibetan geographic populations and 34 lowland breeds.

Results

Using a series of population genetic analyses, we show that Tibetan pig populations have marked genetic differentiations. Tibetan pigs appear to be 3 independent populations corresponding to the Tibetan, Gansu and Sichuan & Yunnan locations. Each population is more genetically similar to its geographic neighbors than to any of the other Tibetan populations. By applying a locus-specific branch length test, we identified both population-specific and -shared candidate genes under selection in Tibetan pigs. These genes, such as PLA2G12A, RGCC, C9ORF3, GRIN2B, GRID1 and EPAS1, are involved in high-altitude physiology including angiogenesis, pulmonary hypertension, oxygen intake, defense response and erythropoiesis. A majority of these genes have not been implicated in previous studies of highlanders and high-altitude animals.

Conclusion

Tibetan pig populations have experienced substantial genetic differentiation. Historically, Tibetan pigs likely had admixture with neighboring lowland breeds. During the long history of colonization in the Plateau, Tibetan pigs have developed a complex biological adaptation mechanism that could be different from that of Tibetans and other animals. Different Tibetan pig populations appear to have both distinct and convergent adaptive loci for the harsh environment of the Plateau.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-834) contains supplementary material, which is available to authorized users.     

Ventilation and hypoxic ventilatory response of Tibetan and Aymara high altitude natives

Newcomers acclimatizing to high altitude and adult male Tibetan high altitude natives have increased ventilation relative to sea level natives at sea level. However, Andean and Rocky Mountain high altitude natives have an intermediate level of ventilation lower than that of newcomers and Tibetan high altitude natives although generally higher than that of sea level natives at sea level. Because the reason for the relative hypoventilation of some high altitude native populations was unknown, a study was designed to describe ventilation from adolescence through old age in samples of Tibetan and Andean high altitude natives and to estimate the relative genetic and environmental influences. This paper compares resting ventilation and hypoxic ventilatory response (HVR) of 320 Tibetans 9–82 years of age and 542 Bolivian Aymara 13–94 years of age, native residents at 3,800–4,065 m. Tibetan resting ventilation was roughly 1.5 times higher and Tibetan HVR was roughly double that of Aymara. Greater duration of hypoxia (older age) was not an important source of variation in resting ventilation or HVR in either sample. That is, contrary to previous studies, neither sample acquired hypoventilation in the age ranges under study. Within populations, greater severity of hypoxia (lower percent of oxygen saturation of arterial hemoglobin) was associated with slightly higher resting ventilation among Tibetans and lower resting ventilation and HVR among Aymara women, although the associations accounted for just 2–7% of the variation. Between populations, the Tibetan sample was more hypoxic and had higher resting ventilation and HVR. Other systematic environmental contrasts did not appear to elevate Tibetan or depress Aymara ventilation. There was more intrapopulation genetic variation in these traits in the Tibetan than the Aymara sample. Thirty-five percent of the Tibetan, but none of the Aymara, resting ventilation variance was due to genetic differences among individuals. Thirty-one percent of the Tibetan HVR, but just 21% of the Aymara, HVR variance was due to genetic differences among individuals. Thus there is greater potential for evolutionary change in these traits in the Tibetans. Presently, there are two different ventilation phenotypes among high altitude natives as compared with sea level populations at sea level: lifelong sustained high resting ventilation and a moderate HVR among Tibetans in contrast with a slightly elevated resting ventilation and a low HVR among Aymara. Am J Phys Anthropol 104:427–447, 1997. © 1997 Wiley-Liss, Inc.     

中国西藏拉托唐古墓地古代居民线粒体全基因组研究

目前青藏高原高海拔地区古DNA研究匮乏。拉托唐古墓地位于青藏高原西南高海拔区域,本文对该墓地出土距今约700年的人骨进行古DNA提取,捕获了高质量线粒体全基因组数据,结合东亚线粒体基因组数据库,运用遗传统计方法开展分析。研究结果表明,距今3000年以内青藏高原西南部人群的遗传历史具有连续性,距今700年左右的拉托唐古墓地居民与距今3150-1250年的古代尼泊尔居民以及现代中国西藏居民母系遗传关系较近,且他们都具有共同的M9a1a1c1b1a单倍群。对M9a1a1c1b1a单倍群的深入研究发现,距今10930-5150年期间青藏高原可能发生了人口扩张事件。以上结果为我们了解古代青藏高原高海拔地区人群遗传历史提供了重要信息。     

三岩藏族体质特征研究

三岩是西藏自治区贡觉县与四川省白玉县交界的金沙江峡谷区, 本文对三岩藏族活体的测量数据做了统计分析, 认为三岩藏族的体质特征为高身材、中头型、中鼻; 属于蒙古人种北亚类型, 他们的体质特征不仅与中国南方、北方的其他民族有明显的差别, 而且跟藏族的其他支系也有很大的差别。三岩藏族具有独特的体质特征。     

Hope and Sorrow: Uncivil Religion,Tibetan Music Videos,and YouTube

Tibetan activists and their supporters are interpreting the lyrical and visual symbolism of contemporary Tibetan music videos from China as a call for Tibetans to return to a shared Tibetan identity, centered around religious piety and implied civil disobedience, in order to counter fears of cultural assimilation. As the popularity of some videos on social-networking sites dovetailed with the 2008 protests in Tibet, viewers employed a progressive hermeneutical strategy which demanded a sectarian political interpretation of the lyrics and imagery of the most popular videos out of Tibet. Within China, Tibetans have begun to add these videos to the growing canon of an emerging uncivil religion, which emphasizes Tibetan cultural, linguistic, and religious autonomy within China. Through comparing online and offline ethnography, this article explores the relationship between offline and online worlds and the connections between Tibetans in China and their supporters.     

A genome-wide search for signals of high-altitude adaptation in Tibetans

Genetic studies of Tibetans, an ethnic group with a long-lasting presence on the Tibetan Plateau which is known as the highest plateau in the world, may offer a unique opportunity to understand the biological adaptations of human beings to high-altitude environments. We conducted a genome-wide study of 1,000,000 genetic variants in 46 Tibetans (TBN) and 92 Han Chinese (HAN) for identifying the signals of high-altitude adaptations (HAAs) in Tibetan genomes. We discovered the most differentiated variants between TBN and HAN at chromosome 1q42.2 and 2p21. EGLN1 (or HIFPH2, MIM 606425) and EPAS1 (or HIF2A, MIM 603349), both related to hypoxia-inducible factor, were found most differentiated in the two regions, respectively. Strong positive correlations were also observed between the frequency of TBN-dominant haplotypes in the two gene regions and altitude in East Asian populations. Linkage disequilibrium and further haplotype network analyses of world-wide populations suggested the antiquity of the TBN-dominant haplotypes and long-term persistence of the natural selection. Finally, a "dominant haplotype carrier" hypothesis could describe the role of the two genes in HAA. All of our population genomic and statistical analyses indicate that EPAS1 and EGLN1 are most likely responsible for HAA of Tibetans. Interestingly, one each but not both of the two genes were also identified by three recent studies. We reanalyzed the available data and found the escaped top signal (EPAS1) could be recaptured with data quality control and our approaches. Based on this experience, we call for more attention to be paid to controlling data quality and batch effects introduced in public data integration. Our results also suggest limitations of extended haplotype homozygosity-based method due to its compromised power in case the natural selection initiated long time ago and particularly in genomic regions with recombination hotspots.     

Mitochondrial DNA analysis in Tibet: Implications for the origin of the Tibetan population and its adaptation to high altitude

Mitochondrial DNAs (mtDNAs) of 54 Tibetans residing at altitudes ranging from 3,000–4,500 m were amplified by polymerase chain reaction (PCR), examined by high-resolution restriction endonuclease analysis, and compared with those previously described in 10 other Asian and Siberian populations. This comparison revealed that more than 50% of Asian mtDNAs belong to a unique mtDNA lineage which is found only among Mongoloids, suggesting that this lineage most likely originated in Asia at an early stage of the human colonization of that continent. Within the Tibetan mtDNAs, sets of additional linked polymorphic sites defined seven minor lineages of related mtDNA haplotypes (haplogroups). The frequency and distribution of these haplogroups in modern Asian populations are supportive of previous genetic evidence that Tibetans, although located in southern Asia, share common ancestral origins with northern Mongoloid populations. This analysis of Tibetan mtDNAs also suggests that mtDNA mutations are unlikely to play a major role in the adaptation of Tibetans to high altitudes. © 1994 Wiley-Liss, Inc.     

GCH1 plays a role in the high-altitude adaptation of Tibetans

Tibetans are well adapted to high-altitude hypoxia.Previous genome-wide scans have reported many candidate genes for this adaptation,but only a few have been studied.Here we report on a hypoxia gene (GCH1,GTP-cyclohydrolase I),involved in maintaining nitric oxide synthetase (NOS) function and normal blood pressure,that harbors many potentially adaptive variants in Tibetans.We resequenced an 80.8 kb fragment covering the entire gene region of GCH1 in 50 unrelated Tibetans.Combined with previously published data,we demonstrated many GCH1 variants showing deep divergence between highlander Tibetans and lowlander Han Chinese.Neutrality tests confirmed a signal of positive Darwinian selection on GCH1 in Tibetans.Moreover,association analysis indicated that the Tibetan version of GCH1 was significantly associated with multiple physiological traits in Tibetans,including blood nitric oxide concentration,blood oxygen saturation,and hemoglobin concentration.Taken together,we propose that GCH1 plays a role in the genetic adaptation of Tibetans to high altitude hypoxia.     

藏族的体质类型和人种学特征

藏族的体质类型和人种学特征一直受到学术界的关注。2018-2021年,我们测量了1530例卫藏、康巴和安多三个藏族人群的体质数据,统计结果发现,藏族男性、女性均为超中等身材,体质量超重,均为圆头型、高头型、中头型、中鼻型、中躯干型、宽胸型、宽肩型、宽骨盆型、中腿型,多有上眼睑皱褶,有内眦褶。对中国15个族群测量指标均数的主成分分析显示,藏族与东亚类型的汉族位点距离近于多数北亚类型族群,更近于多数南亚类型族群。藏族数据与国外资料中的东亚、南亚、北亚、北极类型数据的主成分分析结果显示,藏族与东亚类型位点最为接近。研究证实,当代藏族具有东亚蒙古人种类型的体质特征。     

Tracing the Genetic Legacy of the Tibetan Empire in the Balti

The rise and expansion of Tibetan Empire in the 7th to 9th centuries AD affected the course of history across East Eurasia, but the genetic impact of Tibetans on surrounding populations remains undefined. We sequenced 60 genomes for four populations from Pakistan and Tajikistan to explore their demographic history. We showed that the genomes of Balti people from Baltistan comprised 22.6–26% Tibetan ancestry. We inferred a single admixture event and dated it to about 39–21 generations ago, a period that postdated the conquest of Baltistan by the ancient Tibetan Empire. The analyses of mitochondrial DNA, Y, and X chromosome data indicated that both ancient Tibetan males and females were involved in the male-biased dispersal. Given the fact that the Balti people adopted Tibetan language and culture in history, our study suggested the impact of Tibetan Empire on Baltistan involved dominant cultural and minor demic diffusion.     

Secular morality, village law, and Buddhism in Tibetan societies

Contrary to assumptions frequently made about Buddhist societies and to models promoted by Tibetan elites, not all Tibetans understand their religion in an ethical way. This article demonstrates that, for a community of villagers in Ladakh, Buddhism is not a source of moral guidance nor is it regarded by them as providing authority for the exercise of political or judicial power. Comparing the findings of ethnographers elsewhere in the Tibetan region, it is apparent that many Tibetans regard the cosmos and its inhabitants as having little relevance for the moral order of their community or its political organization. It is suggested that such understandings have a profound effect on local understandings of the ambit and significance of Buddhism and on the course of its assimilation in the region.