Dataset Information

Adaptive Admixture of HLA Class I Allotypes Enhanced Genetically Determined Strength of Natural Killer Cells in East Asians.

ABSTRACT: Human natural killer (NK) cells are essential for controlling infection, cancer, and fetal development. NK cell functions are modulated by interactions between polymorphic inhibitory killer cell immunoglobulin-like receptors (KIR) and polymorphic HLA-A, -B, and -C ligands expressed on tissue cells. All HLA-C alleles encode a KIR ligand and contribute to reproduction and immunity. In contrast, only some HLA-A and -B alleles encode KIR ligands and they focus on immunity. By high-resolution analysis of KIR and HLA-A, -B, and -C genes, we show that the Chinese Southern Han (CHS) are significantly enriched for interactions between inhibitory KIR and HLA-A and -B. This enrichment has had substantial input through population admixture with neighboring populations, who contributed HLA class I haplotypes expressing the KIR ligands B*46:01 and B*58:01, which subsequently rose to high frequency by natural selection. Consequently, over 80% of Southern Han HLA haplotypes encode more than one KIR ligand. Complementing the high number of KIR ligands, the CHS KIR locus combines a high frequency of genes expressing potent inhibitory KIR, with a low frequency of those expressing activating KIR. The Southern Han centromeric KIR region encodes strong, conserved, inhibitory HLA-C-specific receptors, and the telomeric region provides a high number and diversity of inhibitory HLA-A and -B-specific receptors. In all these characteristics, the CHS represent other East Asians, whose NK cell repertoires are thus enhanced in quantity, diversity, and effector strength, likely augmenting resistance to endemic viral infections.

SUBMITTER: Deng Z

PROVIDER: S-EPMC8136484 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Adaptive Admixture of HLA Class I Allotypes Enhanced Genetically Determined Strength of Natural Killer Cells in East Asians.

Deng Zhihui Z Zhen Jianxin J Harrison Genelle F GF Zhang Guobin G Chen Rui R Sun Ge G Yu Qiong Q Nemat-Gorgani Neda N Guethlein Lisbeth A LA He Liumei L Tang Mingzhong M Gao Xiaojiang X Cai Siqi S Palmer William H WH Shortt Jonathan A JA Gignoux Christopher R CR Carrington Mary M Zou Hongyan H Parham Peter P Hong Wenxu W Norman Paul J PJ

Molecular biology and evolution 20210501 6

Human natural killer (NK) cells are essential for controlling infection, cancer, and fetal development. NK cell functions are modulated by interactions between polymorphic inhibitory killer cell immunoglobulin-like receptors (KIR) and polymorphic HLA-A, -B, and -C ligands expressed on tissue cells. All HLA-C alleles encode a KIR ligand and contribute to reproduction and immunity. In contrast, only some HLA-A and -B alleles encode KIR ligands and they focus on immunity. By high-resolution analysi ...[more]

PMID: 33616658

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Project description:BackgroundThe association of HLA-B*27 with AS is amongst the strongest of any known association of a common variant with any human disease. Nonetheless, there is strong evidence indicating that other HLA-B alleles are involved in the disease. European ethnicity studies have demonstrated risk associations with HLA-B*40 and multiple other HLA-B, HLA-A, and HLA class II alleles, and demonstrated that in that ethnic group, the amino acid sequence at position 97 in HLA-B is the key determinant of HLA associations with AS. A recent study in Korean AS cases and controls additionally identified association at HLA-C*15:02. In the current study, we examined the MHC associations of AS in an expanded East Asian cohort.MethodsA total of 1637 Chinese, Taiwanese, and Korean AS cases meeting the modified New York Criteria for AS, and 1589 ethnically matched controls, were genotyped with the Illumina Immunochip, including a dense coverage of the MHC region. HLA genotypes and amino acid composition were imputed using the SNP2HLA programme using the Han-MHC reference panel based on the data of Han Chinese subjects (n = 9689), and association tested using logistic regression controlling for population stratification effects.ResultsA strong association was seen with HLA-B*27 (odds ratio (OR) = 205.3, P = 5.76 × 10-244). Controlling for this association, the strongest risk association is seen with HLA-C*15 at genome-wide significant level (OR = 7.62, P = 9.30 × 10-19), and confirmed association is also seen with HLA-B*40 at suggestive level (OR = 1.65, P = 2.54 × 10-4). At amino acid level, the strongest association seen in uncontrolled analysis was with histidine at position 114 in HLA-B (P = 7.24 × 10-241), but conditional analyses suggest that the primary amino acid associations are with lysine at position 70 and asparagine at position 97. Restriction of the ERAP1 association with HLA-B27-positive AS, previously reported in European subjects, was confirmed in East Asians.ConclusionsThis study confirms in East Asians that the HLA associations of AS are multiple, including previously reported associations at HLA-B*27, HLA-B*40, and HLA-C*15, as well as novel association with HLA-DQB1*04. The HLA-B associations are driven by the amino acids at positions 70 and 97, in the B pocket of HLA-B.

Project description:The Tibetan Plateau (TP) is considered to be one of the last terrestrial environments conquered by the anatomically modern human. Understanding of the genetic background of highland Tibetans plays a pivotal role in archeology, anthropology, genetics, and forensic investigations. Here, we genotyped 22 forensic genetic markers in 1,089 Tibetans residing in Nagqu Prefecture and collected 1,233,013 single nucleotide polymorphisms (SNPs) in the highland East Asians (Sherpa and Tibetan) from the Simons Genome Diversity Project and ancient Tibetans from Nepal and Neolithic farmers from northeastern Qinghai-Tibetan Plateau from public databases. We subsequently merged our two datasets with other worldwide reference populations or eastern ancient Eurasians to gain new insights into the genetic diversity, population movements, and admixtures of high-altitude East Asians via comprehensive population genetic statistical tools [principal component analysis (PCA), multidimensional scaling plot (MDS), STRUCTURE/ADMIXTURE, f3 , f4 , qpWave/qpAdm, and qpGraph]. Besides, we also explored their forensic characteristics and extended the Chinese National Database based on STR data. We identified 231 alleles with the corresponding allele frequencies spanning from 0.0005 to 0.5624 in the forensic low-density dataset, in which the combined powers of discrimination and the probability of exclusion were 1-1.22E-24 and 0.999999998, respectively. Additionally, comprehensive population comparisons in our low-density data among 57 worldwide populations via the Nei's genetic distance, PCA, MDS, NJ tree, and STRUCTURE analysis indicated that the highland Tibeto-Burman speakers kept the close genetic relationship with ethnically close populations. Findings from the 1240K high-density dataset not only confirmed the close genetic connection between modern Highlanders, Nepal ancients (Samdzong, Mebrak, and Chokhopani), and the upper Yellow River Qijia people, suggesting the northeastern edge of the TP served as a geographical corridor for ancient population migrations and interactions between highland and lowland regions, but also evidenced that late Neolithic farmers permanently colonized into the TP by adopting cold-tolerant barley agriculture that was mediated via the acculturation of idea via the millet farmer and not via the movement of barley agriculturalist as no obvious western Eurasian admixture signals were identified in our analyzed modern and ancient populations. Besides, results from the qpAdm-based admixture proportion estimation and qpGraph-based phylogenetic relationship reconstruction consistently demonstrated that all ancient and modern highland East Asians harbored and shared the deeply diverged Onge/Hoabinhian-related eastern Eurasian lineage, suggesting a common Paleolithic genetic legacy existed in high-altitude East Asians as the first layer of their gene pool.

Dataset Information

Adaptive Admixture of HLA Class I Allotypes Enhanced Genetically Determined Strength of Natural Killer Cells in East Asians.

Publications

Adaptive Admixture of HLA Class I Allotypes Enhanced Genetically Determined Strength of Natural Killer Cells in East Asians.

Similar Datasets

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