Yaqun Guan

A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence

Tibetan high-altitude adaptation (HAA) has been studied extensively, and many candidate genes have been reported. Subsequent efforts targeting HAA functional variants, however, have not been that successful (e.g., no functional variant has been suggested for the top candidate HAA gene, EPAS1). With WinXPCNVer, a method developed in this study, we detected in microarray data a Tibetan-enriched deletion (TED) carried by 90% of Tibetans; 50% were homozygous for the deletion, whereas only 3% carried the TED and 0% carried the homozygous deletion in 2,792 worldwide samples (p < 10(-15)). We employed long PCR and Sanger sequencing technologies to determine the exact copy number and breakpoints of the TED in 70 additional Tibetan and 182 diverse samples. The TED had identical boundaries (chr2: 46,694,276-46,697,683; hg19) and was 80 kb downstream of EPAS1. Notably, the TED was in strong linkage disequilibrium (LD; r(2) = 0.8) with EPAS1 variants associated with reduced blood concentrations of hemoglobin. It was also in complete LD with the 5-SNP motif, which was suspected to be introgressed from Denisovans, but the deletion itself was absent from the Denisovan sequence. Correspondingly, we detected that footprints of positive selection for the TED occurred 12,803 (95% confidence interval = 12,075-14,725) years ago. We further whole-genome deep sequenced (>60×) seven Tibetans and verified the TED but failed to identify any other copy-number variations with comparable patterns, giving this TED top priority for further study. We speculate that the specific patterns of the TED resulted from its own functionality in HAA of Tibetans or LD with a functional variant of EPAS1.

Characteristics of dental morphology in the Xinjiang Uyghurs and correlation with the EDARV370A variant

Teeth are one of the most important materials for anthropological studies because they are likely to be preserved in ancient remains. While the frequencies of dental characteristics can provide clues to the phylogeny of populations, genetic studies at the individual level can further reveal the biological mechanisms and evolutionary context of dental characteristics. In this study, by analyzing 38 dental characteristics of 242 Xinjiang Uyghur individuals, we found that (i) the dental characteristics of the Uyghurs showed evidence of admixture between European and East Asian populations. The admixture proportions were in line with those previously reported in population genetic studies; (ii) the Xinjiang Uyghur dental characteristics formed three clusters in pairwise correlation analysis. One of the main clusters consisted of characteristics including incisor shoveling, double shoveling and mesial ridge; and (iii) all the characteristics in this cluster were significantly correlated with the genetic variant EDARV370A. The extracted composite phenotypic factor was also significantly associated with EDARV370A, which explained 18% of the total phenotypic variance. This indicated a pleiotropic effect, i.e., the same genetic factor affects a number of dental characteristics at the same time. Our results confirmed that EDARV370A, a genetic variant that first originated in East Asia about 30000 years ago, played an important role in incisor shoveling in East Asia. This finding suggested that incisor shoveling in modern humans in East Asia is likely to have appeared after the late Pleistocene.

Genetic History of Xinjiang’s Uyghurs Suggests Bronze Age Multiple-Way Contacts in Eurasia

The Uyghur people residing in Xinjiang, a territory located in the far west of China and crossed by the Silk Road, are a key ethnic group for understanding the history of human dispersion in Eurasia. Here we assessed the genetic structure and ancestry of 951 Xinjiangs Uyghurs (XJU) representing 14 geographical subpopulations. We observed a southwest and northeast differentiation within XJU, which was likely shaped jointly by the Tianshan Mountains, which traverses from east to west as a natural barrier, and gene flow from both east and west directions. In XJU, we identified four major ancestral components that were potentially derived from two earlier admixed groups: one from the West, harboring European (25-37%) and South Asian ancestries (12-20%), and the other from the East, with Siberian (15-17%) and East Asian (29-47%) ancestries. By using a newly developed method, MultiWaver, the complex admixture history of XJU was modeled as a two-wave admixture. An ancient wave was dated back to ∼3,750 years ago (ya), which is much earlier than that estimated by previous studies, but fits within the range of dating of mummies that exhibited European features that were discovered in the Tarim basin, which is situated in southern Xinjiang (4,000-2,000 ya); a more recent wave occurred around 750 ya, which is in agreement with the estimate from a recent study using other methods. We unveiled a more complex scenario of ancestral origins and admixture history in XJU than previously reported, which further suggests Bronze Age massive migrations in Eurasia and East-West contacts across the Silk Road.

A metagenomic approach to dissect the genetic composition of enterotypes in Han Chinese and two Muslim groups

Distinct enterotypes have been observed in the human gut but little is known about the genetic basis of the microbiome. Moreover, it is not clear how many genetic differences exist between enterotypes within or between populations. In this study, both the 16S rRNA gene and the metagenomes of the gut microbiota were sequenced from 48 Han Chinese, 48 Kazaks, and 96 Uyghurs, and taxonomies were assigned after de novo assembly. Single nucleotide polymorphisms were also identified by referring to data from the Human Microbiome Project. Systematic analysis of the gut communities in terms of their abundance and genetic composition was also performed, together with a genome-wide association study of the host genomes. The gut microbiota of 192 subjects was clearly classified into two enterotypes (Bacteroides and Prevotella). Interestingly, both enterotypes showed a clear genetic differentiation in terms of their functional catalogue of genes, especially for genes involved in amino acid and carbohydrate metabolism. In addition, several differentiated genera and genes were found among the three populations. Notably, one human variant (rs878394) was identified that showed significant association with the abundance of Prevotella, which is linked to LYPLAL1, a gene associated with body fat distribution, the waist-hip ratio and insulin sensitivity. Taken together, considerable differentiation was observed in gut microbes between enterotypes and among populations that was reflected in both the taxonomic composition and the genetic makeup of their functional genes, which could have been influenced by a variety of factors, such as diet and host genetic variation.

Regulation of PPARγ and CIDEC expression by adenovirus 36 in adipocyte differentiation

This study is to investigate the role of adenovirus 36 (Ad36) in regulating expression of peroxisome proliferator-activated receptor γ (PPARγ) and cell death-inducing DFFA-like effector c (CIDEC) in Ad36-induced adipocyte differentiation. Human adipose-derived mesenchymal stem cells (hAMSCs) were isolated and cultured, and then infected with Ad36. Ad36-induced adipocytes were identified using quantitative real-time PCR and Oil red O staining. The expression levels of PPARγ and CIDEC in Ad36-induced adipocytes were determined by quantitative real-time PCR and Western blot analysis. Glucose uptake and intracellular triglyceride content were also determined in these induced cells. Our results from the Oil red O staining showed that Ad36 induced the differentiation of hAMSCs into human adipocytes in vitro. Moreover, the medium glucose concentration was significantly decreased, while the intracellular triglyceride content was significantly increased, in the Ad36-induced adipocytes, compared with the control group. Furthermore, our results showed that, the mRNA and protein expression levels of PPARγ and CIDEC were significantly upregulated in Ad36-induced adipocytes, in a time-dependent manner. On the other hand, compared with the control group, the CIDEC expression was downregulated when the Ad36-induced adipocytes were treated with the PPARγ inhibitor, GW9662. Ad36 could upregulate the expression level of CIDEC through increasing PPARγ expression during the adipocyte differentiation process.

Genome-wide association studies and CRISPR/Cas9-mediated gene editing identify regulatory variants influencing eyebrow thickness in humans

Hair plays an important role in primates and is clearly subject to adaptive selection. While humans have lost most facial hair, eyebrows are a notable exception. Eyebrow thickness is heritable and widely believed to be subject to sexual selection. Nevertheless, few genomic studies have explored its genetic basis. Here, we performed a genome-wide scan for eyebrow thickness in 2961 Han Chinese. We identified two new loci of genome-wide significance, at 3q26.33 near SOX2 (rs1345417: P = 6.51×10−10) and at 5q13.2 near FOXD1 (rs12651896: P = 1.73×10−8). We further replicated our findings in the Uyghurs, a population from China characterized by East Asian-European admixture (N = 721), the CANDELA cohort from five Latin American countries (N = 2301), and the Rotterdam Study cohort of Dutch Europeans (N = 4411). A meta-analysis combining the full GWAS results from the three cohorts of full or partial Asian descent (Han Chinese, Uyghur and Latin Americans, N = 5983) highlighted a third signal of genome-wide significance at 2q12.3 (rs1866188: P = 5.81×10−11) near EDAR. We performed fine-mapping and prioritized four variants for further experimental verification. CRISPR/Cas9-mediated gene editing provided evidence that rs1345417 and rs12651896 affect the transcriptional activity of the nearby SOX2 and FOXD1 genes, which are both involved in hair development. Finally, suitable statistical analyses revealed that none of the associated variants showed clear signals of selection in any of the populations tested. Contrary to popular speculation, we found no evidence that eyebrow thickness is subject to strong selective pressure.

Genome-wide variants of Eurasian facial shape differentiation and a prospective model of DNA based face prediction

It is a long-standing question as to which genes define the characteristic facial features among different ethnic groups. In this study, we use Uyghurs, an ancient admixed population to query the genetic bases why Europeans and Han Chinese look different. Facial traits were analyzed based on high-dense 3D facial images; numerous biometric spaces were examined for divergent facial features between European and Han Chinese, ranging from inter-landmark distances to dense shape geometrics. Genome-wide association studies (GWAS) were conducted on a discovery panel of Uyghurs. Six significant loci were identified, four of which, rs1868752, rs118078182, rs60159418 at or near UBASH3B, COL23A1, PCDH7 and rs17868256 were replicated in independent cohorts of Uyghurs or Southern Han Chinese. A prospective model was also developed to predict 3D faces based on top GWAS signals and tested in hypothetic forensic scenarios.

Large-scale genome-wide scans do not support petaloid toenail as a Mendelian trait

Petaloid toenail, or accessory nail of the fifth toe, is a physical trait characterized by the presence of an additional tiny toenail on the small toe. Since it can occasionally cause disfigurement and tenderness while wearing tight shoes or walking, standard surgical matricectomy is often carried out to repair the petaloid toenail (Chi and Wang, 2004). Chinese legends recorded petaloid toenails as a trait unique to Han Chinese (Gao, 2010), but populationbased studies are largely absent. A recent study of petaloid toenail confirmed its prevalence in Han Chinese (Hao et al., 2005) and proposed a dominant Mendelian mode of inheritance. In this study, we examined the petaloid toenail trait in both Han Chinese and Uyghur populations in China, aiming to 1) obtain a more complete picture of the population prevalence of petaloid toenail; 2) find potential genes associated with petaloid toenail through genome-wide scans, thereby shedding light on the mode of inheritance of this trait. For this study, we collected 2980 Han Chinese samples and 721 Uyghur samples including 1349 males and 2352 females. The petaloid toenail phenotype was recorded as an ordered categorical variable scored as levels 0 to 2, following a previously established standard (Hao et al., 2005) (Fig. 1A and supplementary data). Apart from the three ordered categorical levels, we further derived two statistics combining the right and left foot statistics: Petaloid_E (“petaloid toenail exist”: the presence of a petaloid toenail on at least one foot), and Petaloid_D (“petaloid toenail double”: the presence of a petaloid toenail on both feet). We summarized the frequency of the petaloid toenail trait in Han Chinese and Uyghurs (Tables S1 and S2). The frequency of petaloid toenail in our Han Chinese population in the Jiangsu Province (58.97%) fits well with previous reports (Hao et al., 2005). While we confirmed the presence of the petaloid toenail trait in the Han Chinese population, we also found a substantial prevalence of this trait in Uyghurs (51.15%), suggesting that it is not unique to the Han Chinese. Furthermore, the petaloid toenail trait is not associated with the East Asian ancestral proportion in the Uyghurs (P1⁄4 0.357). Since the Uyghurs are a quite evenly admixed population with both eastern and western Eurasian ancestries (Xu and Jin, 2008), it is very likely that the frequency of the petaloid toenail in western Eurasian populations is also considerable. Future studies in western Eurasian populations shall provide unequivocal evidence. We found a significant correlation between the presence of a petaloid toenail on right and left feet in both Han Chinese (r 1⁄4 0.4684, P < 2.2e-16) and Uyghurs (r 1⁄4 0.5024, P < 2.2e-16). Nonetheless, the distribution of the trait is not symmetric. By