Adaptive Evolution of Two Distinct Adaptive Haplotypes of Neanderthal Origin at the Immunoglobulin Heavy-chain Locus in East Asian and European Populations.

Immunoglobulins (Igs) have a crucial role in humoral immunity. Two recent studies have reported a high-frequency Neanderthal-introgressed haplotype throughout Eurasia and a high-frequency Neanderthal-introgressed haplotype specific to southern East Asia at the immunoglobulin heavy-chain (IGH) gene locus on chromosome 14q32.33. Surprisingly, we found the previously reported high-frequency Neanderthal-introgressed haplotype does not exist throughout Eurasia. Instead, our study identified two distinct high-frequency haplotypes of putative Neanderthal origin in East Asia and Europe, although they shared introgressed alleles. Notably, the alleles of putative Neanderthal origin reduced the expression of IGHG1 and increased the expression of IGHG2 and IGHG3 in various tissues. These putatively introgressed alleles also affected the production of IgG1 upon antigen stimulation and increased the risk of systemic lupus erythematosus. Additionally, the greatest genetic differentiation across the whole genome between southern and northern East Asians was observed for the East Asian haplotype of putative Neanderthal origin. The frequency decreased from southern to northern East Asia and correlated positively with the genome-wide proportion of southern East Asian ancestry, indicating that this putative positive selection likely occurred in the common ancestor of southern East Asian populations before the admixture with northern East Asian populations.

Ancestral Origins and Admixture History of Kazakhs.

Kazakh people, like many other populations that settled in Central Asia, demonstrate an array of mixed anthropological features of East Eurasian (EEA) and West Eurasian (WEA) populations, indicating a possible scenario of biological admixture between already differentiated EEA and WEA populations. However, their complex biological origin, genomic makeup, and genetic interaction with surrounding populations are not well understood. To decipher their genetic structure and population history, we conducted, to our knowledge, the first whole-genome sequencing study of Kazakhs residing in Xinjiang (KZK). We demonstrated that KZK derived their ancestries from 4 ancestral source populations: East Asian (∼39.7%), West Asian (∼28.6%), Siberian (∼23.6%), and South Asian (∼8.1%). The recognizable interactions of EEA and WEA ancestries in Kazakhs were dated back to the 15th century BCE. Kazakhs were genetically distinctive from the Uyghurs in terms of their overall genomic makeup, although the 2 populations were closely related in genetics, and both showed a substantial admixture of western and eastern peoples. Notably, we identified a considerable sex-biased admixture, with an excess of western males and eastern females contributing to the KZK gene pool. We further identified a set of genes that showed remarkable differentiation in KZK from the surrounding populations, including those associated with skin color (SLC24A5, OCA2), essential hypertension (HLA-DQB1), hypertension (MTHFR, SLC35F3), and neuron development (CNTNAP2). These results advance our understanding of the complex history of contacts between Western and Eastern Eurasians, especially those living or along the old Silk Road.

Genetic Origins and Adaptive Evolution of the Deng People on the Tibetan Plateau.

The Tibetan Plateau is populated by diverse ethnic groups, but most of them are underrepresented in genomics studies compared with the Tibetans (TIB). Here, to gain further insight into the genetic diversity and evolutionary history of the people living in the Tibetan Plateau, we sequenced 54 whole genomes of the Deng people with high coverage (30-60×) and analyzed the data together with that of TIB and Sherpas, as well as 968 ancient Asian genomes and available archaic and modern human data. We identified 17.74 million novel single-nucleotide variants from the newly sequenced genomes, although the Deng people showed reduced genomic diversity and a relatively small effective population size. Compared with the other Tibetan highlander groups which are highly admixed, the Deng people are dominated by a sole ancestry that could be traced to some ancient northern East Asian populations. The divergence between Deng and Tibetan people (∼4,700-7,200 years) was more recent than that between highlanders and the Han Chinese (Deng-HAN, ∼9,000-14,000 years; TIB-HAN, 7,200-10,000 years). Adaptive genetic variants (AGVs) identified in the Deng are only partially shared with those previously reported in the TIB like HLA-DQB1, whereas others like KLHL12 were not reported in TIB. In contrast, the top candidate genes harboring AGVs as previously identified in TIB, like EPAS1 and EGLN1, do not show strong positive selection signals in Deng. Interestingly, Deng also showed a different archaic introgression scenario from that observed in the TIB. Our results suggest that convergent adaptation might be prevalent on the Tibetan Plateau.

Genetic Origins and Sex-Biased Admixture of the Huis.

The Hui people are unique among Chinese ethnic minorities in that they speak the same language as Han Chinese (HAN) but practice Islam. However, as the second-largest minority group in China numbering well over 10 million, the Huis are under-represented in both global and regional genomic studies. Here, we present the first whole-genome sequencing effort of 234 Hui individuals (NXH) aged over 60 who have been living in Ningxia, where the Huis are mostly concentrated. NXH are genetically more similar to East Asian than to any other global populations. In particular, the genetic differentiation between NXH and HAN (FST = 0.0015) is only slightly larger than that between northern and southern HAN (FST = 0.0010), largely attributed to the western ancestry in NXH (∼10%). Highly differentiated functional variants between NXH and HAN were identified in genes associated with skin pigmentation (e.g., SLC24A5), facial morphology (e.g., EDAR), and lipid metabolism (e.g., ABCG8). The Huis are also distinct from other Muslim groups such as the Uyghurs (FST = 0.0187), especially, NXH derived much less western ancestry (∼10%) compared with the Uyghurs (∼50%). Modeling admixture history indicated that NXH experienced an episode of two-wave admixture. An ancient admixture occurred ∼1,025 years ago, reflecting the intensive west-east contacts during the late Tang Dynasty, and the Five Dynasties and Ten Kingdoms period. A recent admixture occurred ∼500 years ago, corresponding to the Ming Dynasty. Notably, we identified considerable sex-biased admixture, that is, excess of western males and eastern females contributing to the NXH gene pool. The origins and the genomic diversity of the Hui people imply the complex history of contacts between western and eastern Eurasians.

PGG.Han: the Han Chinese genome database and analysis platform.

As the largest ethnic group in the world, the Han Chinese population is nonetheless underrepresented in global efforts to catalogue the genomic variability of natural populations. Here, we developed the PGG.Han, a population genome database to serve as the central repository for the genomic data of the Han Chinese Genome Initiative (Phase I). In its current version, the PGG.Han archives whole-genome sequences or high-density genome-wide single-nucleotide variants (SNVs) of 114 783 Han Chinese individuals (a.k.a. the Han100K), representing geographical sub-populations covering 33 of the 34 administrative divisions of China, as well as Singapore. The PGG.Han provides: (i) an interactive interface for visualization of the fine-scale genetic structure of the Han Chinese population; (ii) genome-wide allele frequencies of hierarchical sub-populations; (iii) ancestry inference for individual samples and controlling population stratification based on nested ancestry informative markers (AIMs) panels; (iv) population-structure-aware shared control data for genotype-phenotype association studies (e.g. GWASs) and (v) a Han-Chinese-specific reference panel for genotype imputation. Computational tools are implemented into the PGG.Han, and an online user-friendly interface is provided for data analysis and results visualization. The PGG.Han database is freely accessible via http://www.pgghan.org or https://www.hanchinesegenomes.org.

Archaic introgression contributed to the pre-agriculture adaptation of vitamin B1 metabolism in East Asia.

Thiamine (vitamin B1) is an essential micronutrient. Genes involved in thiamine metabolisms, such as SLC19A2, SLC35F3, and SLC35F4, were assumed to be underlying positive selection in East Asians, but the detailed mechanism remains unknown. Here, we analyzed genome data of 3,823 individuals representing 223 global populations and identified the adaptive haplotypes at thiamine genes. Interestingly, the putative adaptive haplotype at SLC35F4 was of Neanderthal ancestry, while that at SLC35F3 was also likely of archaic origins. Leveraging new methods and available ancient DNA data, we further demonstrated that the beneficial haplotypes reached a high frequency at least 10,000 years ago and are maintained persistently in present-day East Asians. We argue that pathogens, rather than agriculture developed ∼10,000 years ago in East Asia, were likely the initial driving force of the putative positive selection. Notably, the first American people did not carry the putative adaptive haplotype at SLC35F4.

Refining models of archaic admixture in Eurasia with ArchaicSeeker 2.0.

We developed a method, ArchaicSeeker 2.0, to identify introgressed hominin sequences and model multiple-wave admixture. The new method enabled us to discern two waves of introgression from both Denisovan-like and Neanderthal-like hominins in present-day Eurasian populations and an ancient Siberian individual. We estimated that an early Denisovan-like introgression occurred in Eurasia around 118.8-94.0 thousand years ago (kya). In contrast, we detected only one single episode of Denisovan-like admixture in indigenous peoples eastern to the Wallace-Line. Modeling ancient admixtures suggested an early dispersal of modern humans throughout Asia before the Toba volcanic super-eruption 74 kya, predating the initial peopling of Asia as proposed by the traditional Out-of-Africa model. Survived archaic sequences are involved in various phenotypes including immune and body mass (e.g., ZNF169), cardiovascular and lung function (e.g., HHAT), UV response and carbohydrate metabolism (e.g., HYAL1/HYAL2/HYAL3), while "archaic deserts" are enriched with genes associated with skin development and keratinization.

Transcript-Level Analysis of Detoxification Gene Mutation-Mediated Chlorpyrifos Resistance in Laodelphax striatellus (Hemiptera: Delphacidae).

Enhanced detoxification and target mutations that weaken insecticide binding ability are major mechanisms of insecticide resistance. Among these, over-expression or site mutations of carboxylesterase (CarE), cytochrome P450s (CYP450), and glutathione-S-transferase (GST) were the main form responsible for insecticide detoxification; however, transcript-level analysis of the relationship of detoxification gene mutations with chlorpyrifos (an organophosphorus insecticide) resistance is scarce thus far. In this study, multiple sites exhibiting polymorphisms within three detoxification genes were firstly examined via sequencing among different chlorpyrifos-resistant and susceptible individuals of Laodelphax striatellus. For example, the mutation frequencies of A374V in LsCarE16 were 83, 33, and 3%, S277A in LsCarE24 were 88, 28, and 3%, E36K in LsCYP426A1 were 100, 65, and 0% for chlorpyrifos-resistant, resistant decay, and susceptible individuals, respectively. Analysis also found expression levels of GSTd1, GSTt1, GSTs2, CYP4DE1U1, and CYP425B1 are coordinated with chlorpyrifos resistance levels; moreover, we found the deficiencies of 43S and 44A as well as two point mutations of E60D and Q61H at N-terminal region of the OP potential target acetylcholinesterase (AChE) in high resistant but not in low-chlorpyrifos resistant individuals. The results above all demonstrated the dynamic evolutionary process of insecticide resistance and revealed some resistance factors that only played roles at certain resistance level; high insecticide resistance in this example is the result of synergistic impact from multiple resistance factors.

Comparative genetic architectures of schizophrenia in East Asian and European populations.

Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.

Comparison of Genetic Variants in Cancer-Related Genes between Chinese Hui and Han Populations.

BACKGROUND: The Chinese Hui population, as the second largest minority ethnic group in China, may have a different genetic background from Han people because of its unique demographic history. In this study, we aimed to identify genetic differences between Han and Hui Chinese from the Ningxia region of China by comparing eighteen single nucleotide polymorphisms in cancer-related genes. METHODS: DNA samples were collected from 99 Hui and 145 Han people from the Ningxia Hui Autonomous Region in China, and SNPs were detected using an improved multiplex ligase detection reaction method. Genotyping data from six 1000 Genomes Project population samples (99 Utah residents with northern and western European ancestry (CEU), 107 Toscani in Italy (TSI), 108 Yoruba in Ibadan (YRI), 61 of African ancestry in the southwestern US (ASW), 103 Han Chinese in Beijing (CHB), and 104 Japanese in Tokyo (JPT)) were also included in this study. Differences in the distribution of alleles among the populations were assessed using χ2 tests, and FST was used to measure the degree of population differentiation. RESULTS: We found that the genetic diversity of many SNPs in cancer-related genes in the Hui Chinese in Ningxia was different from that in the Han Chinese in Ningxia. For example, the allele frequencies of four SNPs (rs13361707, rs2274223, rs465498, and rs753955) showed different genetic distributions (p<0.05) between Chinese Ningxia Han and Chinese Ningxia Hui. Five SNPs (rs730506, rs13361707, rs2274223, rs465498 and rs753955) had different FST values (FST>0.000) between the Hui and Han populations. CONCLUSIONS: These results suggest that some SNPs associated with cancer-related genes vary among different Chinese ethnic groups. We suggest that population differences should be carefully considered in evaluating cancer risk and prognosis as well as the efficacy of cancer therapy.