About
325
Publications
101,718
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
11,538
Citations
Introduction
1.Primate comparative genomics and genetic mechanism of origin of humans.
2. Genetic variations in human populations for reconstructing prehistory of modern humans and for understanding the role of natural selection in shaping up human genetic makeup.
Additional affiliations
September 2001 - present
April 2001 - August 2005
August 1997 - April 2001
Education
September 1991 - July 1996
September 1985 - July 1989
Publications
Publications (325)
Compared with lowlander migrants, native Tibetans have a higher reproductive success at high altitude though the underlying mechanism remains unclear. Here, we compared the transcriptome and histology of full-term placentas between native Tibetans and Han migrants. We found that the placental trophoblast shows the largest expression divergence betw...
Compared with lowlander migrants, native Tibetans have a higher reproductive success at high altitude though the underlying mechanism remains unclear. Here, we compared the transcriptome and histology of full-term placentas between native Tibetans and Han migrants. We found that the placental trophoblast shows the largest expression divergence betw...
Compared with lowlander migrants, native Tibetans have a higher reproductive success at high altitude though the underlying mechanism remains unclear. Here, we compared the transcriptome and histology of full-term placentas between native Tibetans and Han migrants. We found that the placental trophoblast shows the largest expression divergence betw...
The crab-eating macaques (Macaca fascicularis) and rhesus macaques (M. mulatta) are widely studied nonhuman primates in biomedical and evolutionary research. Despite their significance, the current understanding of the complex genomic structure in macaques and the differences between species requires substantial improvement. Here, we present a comp...
The evolution of light skin pigmentation among Eurasians is considered an adaptation to the high-latitude environments. East Asians are ideal populations for studying skin color evolution because of the complex environment of East Asia. Here, we report a strong selection signal for the pigmentation gene PAH in light-skinned Han Chinese individuals....
Compared with lowlander migrants, native Tibetans have a higher reproductive success at high altitude though the underlying mechanism remains unclear. Here, we compared the transcriptome and histology of full-term placentas between native Tibetans and Han migrants. We found that the placental trophoblast shows the largest expression divergence betw...
Human-specific duplicated genes contributed to phenotypic innovations during the origin of our own species, such as an enlarged brain and highly developed cognitive abilities. While prior studies on transgenic mice carrying the human-specific SRGAP2C gene have shown enhanced brain connectivity, the relevance to humans remains unclear due to the sig...
Background
Domestication and introduction of dairy animals facilitated the permanent human occupation of the Tibetan Plateau. Yet the history of dairy pastoralism in the Tibetan Plateau remains poorly understood. Little is known how Tibetans adapted to milk and dairy products.
Results
We integrated archeological evidence and genetic analysis to sh...
The cellular and genetic mechanism underlying the human-specific features of cortex development remains unclear. We generated a cell-type resolved atlas of transcriptome and regulome of the developing macaque and mouse prefrontal cortex, and conducted evolutionary analyses with the published complementary human data. We discovered a primate-specifi...
Compared with lowlander migrants, native Tibetans have a higher reproductive success at high altitude though the underlying mechanism remains unclear. Here, we compared the transcriptome and histology of full-term placentas between native Tibetans and Han migrants. We found that the placental trophoblast shows the largest expression divergence betw...
During the origin of great apes about 14 million years ago, a series of phenotypic innovations emerged, such as the increased body size, the enlarged brain volume, the improved cognitive skill and the diversified diet. Yet, the genomic basis of these evolutionary changes remains unclear. Utilizing the high-quality genome assemblies of great apes (i...
Tibetans are the ideal population to study genetic adaptation in extreme environments. Here, we performed systematic phenotyping of 11,880 highlanders, covering 133 quantitative traits of 13 organ systems. We provided a comprehensive phenotypic atlas by comparing altitude adaptation and altitude acclimatization. We found the differences between ada...
The adaptation of Tibetans to high-altitude environments has been studied extensively. However, the direct assessment of evolutionary adaptation, i.e., the reproductive fitness of Tibetans and its genetic basis, remains elusive. Here, we conduct systematic phenotyping and genome-wide association analysis of 2,252 mother-newborn pairs of indigenous...
Although continual expansion of the brain during primate evolution accounts for our enhanced cognitive capabilities, the drivers of brain evolution have scarcely been explored in these ancestral nodes. Here we performed large-scale comparative genomic, transcriptomic and epigenomic analyses to investigate the evolutionary alterations acquired by br...
Unlabelled:
Blood oxygen saturation (SpO2) is a key indicator of oxygen availability in the body. It is known that a low SpO2 at high altitude is associated with morbidity and mortality risks due to physiological hypoxemia. Previously, it was proposed that the lowlander immigrants living at high altitude should have a lower SpO2 level compared to...
Compared with lowlander migrants, native Tibetans have a higher reproductive success at high altitude though the underlying mechanism remains unclear. Here, we compared the transcriptome and histology of full-term placentas between native Tibetans and Han migrants. We found that the placental trophoblast shows the largest expression divergence betw...
Background
Tibetans are genetically adapted to high-altitude environments. Though many studies have been conducted, the genetic basis of the adaptation remains elusive due to the poor reproducibility for detecting selective signatures in the Tibetan genomes.
Results
Here, we present whole-genome sequencing (WGS) data of 1001 indigenous Tibetans, c...
During the origin of great apes about 14 million years ago, a series of phenotypic innovations emerged, such as the increased body size, the enlarged brain volume, the improved cognitive skill and the diversified diet. Yet, the genomic basis of these evolutionary changes remains unclear. Utilizing the high-quality genome assemblies of great apes (i...
Systems genetics holds the promise to decipher complex traits by interpreting their associated SNPs through gene regulatory networks derived from comprehensive multi-omics data of cell types, tissues, and organs. Here, we propose SpecVar to integrate paired chromatin accessibility and gene expression data into context-specific regulatory network at...
Strong ultraviolet (UV) radiation at high altitude imposes a serious selective pressure, which may induce skin pigmentation adaptation of indigenous populations. We conducted skin pigmentation phenotyping and genome-wide analysis of Tibetans in order to understand the underlying mechanism of adaptation to UV radiation. We observe that Tibetans have...
Southern East Asia is the dispersal center regarding the prehistoric settlement and migrations of modern humans in Asia-Pacific regions. However, the settlement pattern and population structure of paleolithic humans in this region remain elusive, and ancient DNA can provide direct information. Here, we sequenced the genome of a Late Pleistocene hom...
Unlabelled:
Birth weight (BW) is a key determinant of infant mortality. Previous studies have reported seasonal fluctuation of BW. However, the responsible environmental factors remain disputable. High-altitude environment provides a great opportunity to test the current hypotheses due to its distinctive climate conditions. We collected BW data of...
Southeast Asian aborigines, the hunter-gatherer populations living in the tropical rainforests, exhibit distinct morphological phenotypes including short stature, dark skin, curly hair and wide and snub nose. The underlying genetic architecture and evolutionary mechanism of these phenotypes remain a long-term mystery. Here we conducted whole genome...
Elucidating the regulatory mechanisms of human brain evolution is essential to understanding human cognition and mental disorders. We generated multi-omics profiles and constructed a high-resolution map of 3D genome architecture of rhesus macaque during corticogenesis. By comparing the 3D genomes of human, macaque, and mouse brains, we identified m...
Significance
We undertook an ancient genomic DNA investigation of large animal remains dated ∼5,200 y B.P. from the Tibetan Plateau. We provide compelling evidence that the present-day low-latitude tropical inhabitants Bos gaurus and Dicerorhinus sumatrensis once roamed as far north as the margin of the northeastern Tibetan Plateau (NETP) during th...
High-altitude adaptation of Tibetans represents a remarkable case of natural selection during recent human evolution. Previous genome-wide scans found many non-coding variants under selection, suggesting a pressing need to understand the functional role of non-coding regulatory elements (REs). Here, we generate time courses of paired ATAC-seq and R...
Hanging Coffin is a unique and ancient burial custom which had been practiced in southern China, Southeast Asia and near Oceania regions for more than 3,000 years. Here, we conducted mitochondrial whole genome analyses of 41 human remains sampled from 13 Hanging Coffin sites in southern China and northern Thailand, which were dated between ∼2,500 t...
Structural variants (SVs) may play important roles in human adaptation to extreme environments such as high altitude but have been under-investigated. Here, combining long-read sequencing with multiple scaffolding techniques, we assembled a high-quality Tibetan genome (ZF1), with a contig N50 length of 24.57 mega-base pairs (Mb) and a scaffold N50...
CRISPR-Cas9 is a widely-used genome editing tool, but its off-target effect and on-target complex mutations remain a concern, especially in view of future clinical applications. Non-human primates (NHPs) share close genetic and physiological similarities with humans, making them an ideal preclinical model for developing Cas9-based therapies. Howeve...
We present a high-quality de novo genome assembly (rheMacS) of the Chinese rhesus macaque (Macaca mulatta) using long-read sequencing and multiplatform scaffolding approaches. Compared to the current Indian rhesus macaque reference genome (rheMac8), rheMacS increases sequence contiguity 75-fold, closing 21,940 of the remaining assembly gaps (60.8 M...
Human genetic adaptation to high altitudes (>2500 m) has been extensively studied over the last few years, but few functional adaptive genetic variants have been identified, largely owing to the lack of deep-genome sequencing data available to previous studies. Here, we build a list of putative adaptive variants, including 63 missense, 7 loss-of-fu...
We present a method that jointly analyzes the polymorphism and divergence sites in genomic sequences of multiple species to identify the genes under natural selection and pinpoint the occurrence time of selection to a specific lineage of the species phylogeny. This method integrates population genetics models using a Bayesian Poisson random field f...
Rhesus macaque (Macaca mulatta) is a widely-studied nonhuman primate. Here we present a high-quality de novo genome assembly of the Chinese rhesus macaque (rheMacS) using long-read sequencing and multiplatform scaffolding approaches. Compared to the current Indian rhesus macaque reference genome (rheMac8), the rheMacS genome assembly improves seque...
Why humans have large brains with higher cognitive abilities is a question long asked by scientists. However, much remains unknown, especially the underlying genetic mechanisms. With the use of a transgenic monkey model, we showed that human-specific sequence changes of a key brain development gene (primary microcephaly1, MCPH1) could result in det...
Brain size and cognitive skills are the most dramatically changed traits in humans during evolution and yet the genetic mechanisms underlying these human-specific changes remain elusive. Here, we successfully generated 11 transgenic rhesus monkeys (8 first-generation and 3 second-generation) carrying human copies of MCPH1 , an important gene for br...
Yak is one of the largest native mammalian species at the Himalayas, the highest plateau area in the world with an average elevation of >4,000 m above the sea level. Yak is well adapted to high altitude environment with a set of physiological features for a more efficient blood flow for oxygen delivery under hypobaric hypoxia. Yet, the genetic mech...
We present a method that jointly analyzes the polymorphism and divergence sites in genomic sequences of multiple species to identify the genes under positive or negative selection and pinpoints the occurrence time of selection to a specific lineage of the species phylogeny. This method integrates population genetics models using the Bayesian Poisso...
Human skin color diversity is considered an adaptation to environmental conditions such as UV radiation. Investigations into the genetic bases of such adaptation have identified a group of pigmentation genes contributing to skin color diversity in African and non-African populations. Here we present a population analysis of the pigmentation gene KI...
CRISPR-Cas9 is a widely-used genome editing tool, but its off-target effect remains a concern, especially in view of future clinical applications. Non-human primates (NHPs) share close genetic and physiological similarities with humans, making them an ideal preclinical model for developing Cas9-based therapies. However, no comprehensive in vivo off...
Schizophrenia (SCZ) is a complex mental disorder with high heritability. Genetic studies (especially recent genome-wide association studies) have identified many risk genes for schizophrenia. However, the physical interactions among the proteins encoded by schizophrenia risk genes remain elusive and it is not known whether the identified risk genes...
Nitric oxide (NO) is an important molecule for vasomotor tone, and elevated NO signaling was previously hypothesized as a unique and adaptive physiological change in highland Tibetans. However, there has been lack of NO data from Tibetans living at low altitude and lowlander immigrants living at high altitude, which is crucial to test this hypothes...
The von Economo neurons (VENs) are specialized large bipolar projection neurons with restricted distribution in the human brain, and they are far more abundant in humans than in non-human primates. However, VEN functions remain elusive due to the difficulty of isolating VENs and dissecting their connections in the brain. Here, we combined laser-cap...
Background
Currently, there is limited knowledge about the genetics underlying pigmentary traits in East Asian populations. Here, we report the results of the first genome-wide association study of pigmentary traits (skin and iris color) in individuals of East Asian ancestry.
Methods
We obtained quantitative skin pigmentation measures (M-index) in...
Genome-wide significant and suggestive signals observed in the genome-wide association study of skin pigmentation (M-index) and iris color (L*, a*, b* and delta values)
All the regions indicated in the file have more than one genome-wide significant or suggestive marker with good imputation scores (info score >0.8).
Regional plots for suggestive regions (p-value <10−5) identified in the GWAs of iris color (L* values)
All these regions harbour multiple markers showing suggestive significance and good imputation.
Table reporting allele frequencies and effect size estimates in the East Asian sample for markers known to be associated with light skin in European populations
The table includes variants in the genes SLC24A5 and SLC45A2, which have very high frequencies in Europe and have been reported to have very strong effects on skin pigmentation in admixed g...
Distribution of delta values (e.g., difference in color coordinates between the pupillary and ciliary regions of the iris) in the East Asian sample
Regional plots for suggestive regions (p-value <10−5) identified in the GWAs of skin pigmentation
All these regions harbour multiple markers showing suggestive significance and good imputation scores (e.g., score info > 0.8).
Regional plots for suggestive regions (p-value <10−5) identified in the GWAs of iris color (delta values)
All these regions harbour multiple markers showing suggestive significance and good imputation scores (e.g., score info > 0.8).
Scatterplots of a* and b* ( Fig. 2A), a* and L* (Fig. 2B) and b* and L* (Fig. 2C) CIELab iris color coordinates in the East Asian sample
Protein-protein interaction (PPI) is informative in identifying hidden disease risk genes that tend to interact with known risk genes usually working together in the same disease module. With the use of an integrated approach combining PPI information with pathway and expression analysis as well as genome-wide association study (GWAS), we intended...
Background: The genetic relationships reported by recent studies between Sherpas and Tibetans are controversial. To gain insights into the population history and the genetic basis of high-altitude adaptation of the two groups, we analyzed genome-wide data in 111 Sherpas (Tibet and Nepal) and 177 Tibetans (Tibet and Qinghai), together with available...
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 potentiall...
The genetic adaptation of Tibetans to high altitude hypoxia likely involves a group of genes in the hypoxic pathway, as suggested by earlier studies. To test the adaptive role of the previously reported candidate gene EP300 (histone acetyltransferase p300), we conducted resequencing of a 108.9 kb gene region of EP300 in 80 unrelated Tibetans. The a...
Human evolution is marked by a continued enlargement of the brain. Previous studies on human brain evolution focused on identifying sequence divergences of brain size regulating genes between humans and nonhuman primates. However, the evolutionary pattern of the brain size regulating genes during recent human evolution is largely unknown. We conduc...
Tibetans are well adapted to the hypoxic environments at high altitude, yet the molecular mechanism of this adaptation remains elusive. We reported comprehensive genetic and functional analyses of EPAS1, a gene encoding hypoxia inducible factor 2α (HIF-2α) with the strongest signal of selection in previous genome-wide scans of Tibetans. We showed t...
Tibetans are well adapted to high-altitude environments. Among the adaptive traits in Tibetans, the relatively low hemoglobin level is considered a blunted erythropoietic response to hypoxic challenge. Previously, EPAS1 and EGLN1, the major upstream regulators in the hypoxic pathway, were reportedly involved in the hemoglobin regulation in Tibetans...
Background
Sherpas, a highlander population living in Khumbu region of Nepal, are well known for their superior climbing ability in Himalayas. However, the genetic basis of their adaptation to high‐altitude environments remains elusive.
Methods
We collected DNA samples of 582 Sherpas from Nepal and Tibetan Autonomous Region of China, and we measur...
Retroposition is an RNA-mediated mechanism to generate gene duplication, and is believed to play an important role in genome evolution and phenotypic adaptation in various species including primates. Previous studies suggested an elevated rate of recent retroposition in the rhesus macaque genome. To better understand the impact of retroposition on...
How do epigenetic modifications change across species and how do these modifications affect evolution? These are fundamental questions at the forefront of our evolutionary epigenomic understanding. Our previous work investigated human and chimpanzee brain methylomes, but it was limited by the lack of outgroup data which is critical for comparative...
The origin of Tibetans remains one of the most contentious puzzles in history, anthropology, and genetics. Analyses of deeply sequenced (30×-60×) genomes of 38 Tibetan highlanders and 39 Han Chinese lowlanders, together with available data on archaic and modern humans, allow us to comprehensively characterize the ancestral makeup of Tibetans and un...
In the past three years, RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system has been used to facilitate efficient genome editing in many model and non-model animals. However, its application in nonhuman primates is still at the early stage, though in view of the simi...
Genome-wide association studies (GWASs) have identified multiple schizophrenia (SCZ) risk variants for samples of European and East Asian descent, but most of the identified susceptibility variants are population-specific to either Europeans or East Asians. This strong genetic heterogeneity suggests that differential population histories may play a...