Zhaohui Yang

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.

Genetic evidence of Paleolithic colonization and Neolithic expansion of modern humans on the Tibetan Plateau

Tibetans live on the highest plateau in the world, their current population size is approximately 5 million, and most of them live at an altitude exceeding 3,500 m. Therefore, the Tibetan Plateau is a remarkable area for cultural and biological studies of human population history. However, the chronological profile of the Tibetan Plateaus colonization remains an unsolved question of human prehistory. To reconstruct the prehistoric colonization and demographic history of modern humans on the Tibetan Plateau, we systematically sampled 6,109 Tibetan individuals from 41 geographic populations across the entire region of the Tibetan Plateau and analyzed the phylogeographic patterns of both paternal (n = 2,354) and maternal (n = 6,109) lineages as well as genome-wide single nucleotide polymorphism markers (n = 50) in Tibetan populations. We found that there have been two distinct, major prehistoric migrations of modern humans into the Tibetan Plateau. The first migration was marked by ancient Tibetan genetic signatures dated to approximately 30,000 years ago, indicating that the initial peopling of the Tibetan Plateau by modern humans occurred during the Upper Paleolithic rather than Neolithic. We also found evidences for relatively young (only 7-10 thousand years old) shared Y chromosome and mitochondrial DNA haplotypes between Tibetans and Han Chinese, suggesting a second wave of migration during the early Neolithic. Collectively, the genetic data indicate that Tibetans have been adapted to a high altitude environment since initial colonization of the Tibetan Plateau in the early Upper Paleolithic, before the last glacial maximum, followed by a rapid population expansion that coincided with the establishment of farming and yak pastoralism on the Plateau in the early Neolithic.

Identification of a Tibetan-specific mutation in the hypoxic gene EGLN1 and its contribution to high-altitude adaptation

Tibetans are well adapted to high-altitude hypoxic conditions, and in recent genome-wide scans, many candidate genes have been reported involved in the physiological response to hypoxic conditions. However, the limited sequence variations analyzed in previous studies would not be sufficient to identify causal mutations. Here we conducted resequencing of the entire genomic region (59.4 kb) of the hypoxic gene EGLN1 (one of the top candidates from the genome-wide scans) in Tibetans and identified 185 sequence variations, including 13 novel variations (12 substitutions and 1 insertion or deletion). There is a nonsynonymous mutation (rs186996510, D4E) showing surprisingly deep divergence between Tibetans and lowlander populations (Fst = 0.709 between Tibetans and Han Chinese). It is highly prevalent in Tibetans (70.9% on average) but extremely rare in Han Chinese, Japanese, Europeans, and Africans (0.56-2.27%), suggesting that it might be the causal mutation of EGLN1 contributing to high-altitude hypoxic adaptation. Neutrality test confirmed the signal of Darwinian positive selection on EGLN1 in Tibetans. Haplotype network analysis revealed a Tibetan-specific haplotype, which is absent in other world populations. The estimated selective intensity (0.029 for the C allele of rs186996510) puts EGLN1 among the known genes that have undergone the strongest selection in human populations, and the onset of selection was estimated to have started at the early Neolithic (∼8,400 years ago). Finally, we detected a significant association between rs186996510 and hemoglobin levels in Tibetans, suggesting that EGLN1 contributes to the adaptively low hemoglobin level of Tibetans compared with acclimatized lowlanders at high altitude.

A Genetic Mechanism for Convergent Skin Lightening During Recent Human Evolution

Skin lightening among Eurasians is thought to have been a convergence occurring independently in Europe and East Asia as an adaptation to high latitude environments. Among Europeans, several genes responsible for such lightening have been found, but the information available for East Asians is much more limited. Here, a genome-wide comparison between dark-skinned Africans and Austro-Asiatic speaking aborigines and light-skinned northern Han Chinese identified the pigmentation gene OCA2, showing unusually deep allelic divergence between these groups. An amino acid substitution (His615Arg) of OCA2 prevalent in most East Asian populations—but absent in Africans and Europeans—was significantly associated with skin lightening among northern Han Chinese. Further transgenic and targeted gene modification analyses of zebrafish and mouse both exhibited the phenotypic effect of the OCA2 variant manifesting decreased melanin production. These results indicate that OCA2 plays an important role in the convergent skin lightening of East Asians during recent human evolution.

An Updated Phylogeny of the Human Y-Chromosome Lineage O2a-M95 with Novel SNPs

Though the Y-chromosome O2a-M95 lineage is one of the major haplogroups present in eastern Asian populations, especially among Austro-Asiatic speaking populations from Southwestern China and mainland Southeast Asia, to date its phylogeny lacks structure due to only one downstream SNP marker (M88) assigned to the lineage. A recent array-capture-based Y chromosome sequencing of Asian samples has yielded a variety of novel SNPs purportedly belonging to the O2a-M95 lineage, but their phylogenetic positions have yet to be determined. In this study, we sampled 646 unrelated males from 22 Austro-Asiatic speaking populations from Cambodia, Thailand and Southwestern China, and genotyped 12 SNP makers among the sampled populations, including 10 of the newly reported markers. Among the 646 males, 343 belonged to the O2a-M95 lineage, confirming the supposed dominance of this Y chromosome lineage in Austro-Asiatic speaking populations. We further characterized the phylogeny of O2a-M95 by defining 5 sub-branches: O2a1*-M95, O2a1a-F789, O2a1b*-F1252, O2a1b1*-M88 and O2a1b1a -F761. This updated phylogeny not only improves the resolution of this lineage, but also allows for greater tracing of the prehistory of human populations in eastern Asia and the Pacific, which may yield novel insights into the patterns of language diversification and population movement in these regions.

Y-chromosome diversity suggests southern origin and Paleolithic backwave migration of Austro-Asiatic speakers from eastern Asia to the Indian subcontinent

Analyses of an Asian-specific Y-chromosome lineage (O2a1-M95)—the dominant paternal lineage in Austro-Asiatic (AA) speaking populations, who are found on both sides of the Bay of Bengal—led to two competing hypothesis of this group’s geographic origin and migratory routes. One hypothesis posits the origin of the AA speakers in India and an eastward dispersal to Southeast Asia, while the other places an origin in Southeast Asia with westward dispersal to India. Here, we collected samples of AA-speaking populations from mainland Southeast Asia (MSEA) and southern China, and genotyped 16 Y-STRs of 343 males who belong to the O2a1-M95 lineage. Combining our samples with previous data, we analyzed both the Y-chromosome and mtDNA diversities. We generated a comprehensive picture of the O2a1-M95 lineage in Asia. We demonstrated that the O2a1-M95 lineage originated in the southern East Asia among the Daic-speaking populations ~20–40 thousand years ago and then dispersed southward to Southeast Asia after the Last Glacial Maximum before moving westward to the Indian subcontinent. This migration resulted in the current distribution of this Y-chromosome lineage in the AA-speaking populations. Further analysis of mtDNA diversity showed a different pattern, supporting a previously proposed sex-biased admixture of the AA-speaking populations in India.

SULFUR IX TO XIII SPECTRAL MEASURMENTS BETWEEN 170 AND 500 Å

This paper reports laboratory measurements of the spectrum of highly ionized sulfur. The spectrum of S IX-S XIII has been observed in the wavelength range 170-500 A. A total of 54 lines have been measured. Forty-two of them have been classified as 2s 22pk -2s2pk +1 and 2s2pk -2pk +1 transitions. Twelve other lines have been ascribed to 2s-2p, 4p-5s, 5p-6s, 5d-6p, and 6p-8d transitions. These spectral lines have been identified, among which 22 are new and accurately measured. The analysis of the spectra was based on a comparison with other experimental results and calculated values.

Cross‐altitude analysis suggests a turning point at the elevation of 4,500 m for polycythemia prevalence in Tibetans

allogeneic transplantation as a successful rescue therapy for persistent, severe iatrogenic aplasia after relapse of acute myeloid leukemia. Bone Marrow Transplant. 2007;39:53–54. [4] Schneidawind D, Federmann B, Faul C, Vogel W, Kanz L, Bethge WA. Allogeneic hematopoietic cell transplantation with reduced-intensity conditioning following FLAMSA for primary refractory or relapsed acute myeloid leukemia. Ann Hematol. 2013;92:1389–1395.

X-RAY EMISSION FROM THE METASTABLE COMPONENTS OF SLOW Ar16+ BEAM ON METALLIC SURFACES

K-shell X-ray emission was observed in the neutralization process of Ar16+ interacting with beryllium and molybdenum at slow speed (less than Bohr velocity). The K-shell X-ray emission came from the metastable component of Ar16+ beam with the configuration (1s2s) produced from electron cyclotron resonance ion source. The intensity ratio of Kβ X-ray emission to Kα X-ray emission (IKβ/IKα) in the neutralization process decreased when the kinetic energy of the projectile increased. This is closely related to the flight time the projectiles spend above the surface, which is dominated by both the work function of the metal and the normal velocity component of the incident ions to the surface according to the classical over-barrier model. As the relation between IKβ/IKα and the above-flight time shows, the longer time above the surface the larger ratio due to the above-surface contribution. Furthermore, the smaller work function leads to the smaller contribution from the above surface.

Kinetic Energy Effect in the X-Ray Emission of Mo Surface Induced by Xe28+ Ions

L-shell x-ray spectra of Mo surface induced by Xe28+ were measured with a Si(Li) detector. The x-ray intensity was found increased rapidly with the kinetic energy of the incident ions. The relation of x-ray intensity with kinetic energy of the projectile is discussed. There is a turning point of the intensity to the kinetic energy, and the explanation is given.