Major Histocompatibility Complex Region Research Articles

Targeted and complete genomic sequencing of the major histocompatibility complex in haplotypic form of individual heterozygous samples.

The human major histocompatibility complex (MHC) is a ∼4 Mb genomic segment on Chromosome 6 that plays a pivotal role in the immune response. Despite its importance in various traits and diseases, its complex nature makes it challenging to accurately characterize on a routine basis. We present a novel approach allowing targeted sequencing and de novo haplotypic assembly of the MHC region in heterozygous samples, using long-read sequencing technologies. Our approach is validated using two reference samples, two family trios, and an African-American sample. We achieved excellent coverage (96.6%-99.9% with at least 30× depth) and high accuracy (99.89%-99.99%) for the different haplotypes. This methodology offers a reliable and cost-effective method for sequencing and fully characterizing the MHC without the need for whole-genome sequencing, facilitating broader studies on this important genomic segment and having significant implications in immunology, genetics, and medicine.

Common and rare genetic variants predisposing females to unexplained recurrent pregnancy loss

Recurrent pregnancy loss (RPL) is a major reproductive health issue with multifactorial causes, affecting 2.6% of all pregnancies worldwide. Nearly half of the RPL cases lack clinically identifiable causes (e.g., antiphospholipid syndrome, uterine anomalies, and parental chromosomal abnormalities), referred to as unexplained RPL (uRPL). Here, we perform a genome-wide association study focusing on uRPL in 1,728 cases and 24,315 female controls of Japanese ancestry. We detect significant associations in the major histocompatibility complex (MHC) region at 6p21 (lead variant=rs9263738; P = 1.4 × 10−10; odds ratio [OR] = 1.51 [95% CI: 1.33–1.72]; risk allele frequency = 0.871). The MHC associations are fine-mapped to the classical HLA alleles, HLA-C*12:02, HLA-B*52:01, and HLA-DRB1*15:02 (P = 1.1 × 10−10, 1.5 × 10−10, and 1.2 × 10−9, respectively), which constitute a population-specific common long-range haplotype with a protective effect (P = 2.8 × 10−10; OR = 0.65 [95% CI: 0.57–0.75]; haplotype frequency=0.108). Genome-wide copy-number variation (CNV) calling demonstrates rare predicted loss-of-function (pLoF) variants of the cadherin-11 gene (CDH11) conferring the risk of uRPL (P = 1.3 × 10−4; OR = 3.29 [95% CI: 1.78–5.76]). Our study highlights the importance of reproductive immunology and rare variants in the uRPL etiology.

Exploring diverse aspects of celiac disease - A review

Celiac disease is a chronic inflammatory disorder triggered by the ingestion of gluten-containing foods in genetically susceptible individuals. This multifactorial disease has both genetic and environmental components, with gluten serving as the environmental trigger and specific genetic variations in the major histocompatibility complex region contributing to the genetic predisposition. Contrary to previous assumptions, celiac disease is not a rare disorder, with a global prevalence estimated at approximately 1%. However, it often remains under-recognized because many affected individuals do not exhibit the classic gastrointestinal symptoms associated with the condition. Instead, they may present with nonspecific manifestations of nutritional deficiencies or may be entirely asymptomatic. Celiac disease is associated with an increased incidence of autoimmune disorders, and its identification in asymptomatic or silent cases is crucial for managing associated conditions and preventing long-term complications such as lymphoma. The relationship between celiac disease and other autoimmune disorders, particularly type 1 diabetes, suggests a potential trigger role for gluten. In this article we review the development of celiac disease, including its types, pathogenesis, clinical features, and associated diseases or complications. We will also discuss available tests, treatments, and preventive approaches related to this subject.

Relationship between HLA genetic variations, COVID-19 vaccine antibody response, and risk of breakthrough outcomes

The rapid global distribution of COVID-19 vaccines, with over a billion doses administered, has been unprecedented. However, in comparison to most identified clinical determinants, the implications of individual genetic factors on antibody responses post-COVID-19 vaccination for breakthrough outcomes remain elusive. Here, we conducted a population-based study including 357,806 vaccinated participants with high-resolution HLA genotyping data, and a subset of 175,000 with antibody serology test results. We confirmed prior findings that single nucleotide polymorphisms associated with antibody response are predominantly located in the Major Histocompatibility Complex region, with the expansive HLA-DQB1*06 gene alleles linked to improved antibody responses. However, our results did not support the claim that this mutation alone can significantly reduce COVID-19 risk in the general population. In addition, we discovered and validated six HLA alleles (A*03:01, C*16:01, DQA1*01:02, DQA1*01:01, DRB3*01:01, and DPB1*10:01) that independently influence antibody responses and demonstrated a combined effect across HLA genes on the risk of breakthrough COVID-19 outcomes. Lastly, we estimated that COVID-19 vaccine-induced antibody positivity provides approximately 20% protection against infection and 50% protection against severity. These findings have immediate implications for functional studies on HLA molecules and can inform future personalised vaccination strategies.

Genomic variability of the MHC region: Empirical evidence from five horse breeds

The purpose of this study was to analyse the level of variability in the autosomal genome, especially in the equine major histocompatibility complex region, in five horse breeds and identify heterozygosity-rich regions and potential footprints of balancing selection. Depending on data quality control, the dataset consisted of 51,168 or 53,874 single nucleotide polymorphism markers, available for 514 individuals (89 Lipizzan, 238 Old Kladruber, 47 Shagya Arabian, 61 Czech Warmblood and 81 Slovak Warmblood horses). Genomic variability within and between breeds was examined based on levels of heterozygosity (observed and expected), genomic inbreeding, Wright's FIS index and linkage disequilibrium. Subsequently, the screening of heterozygosity-rich regions and balancing selection signals derived from Tajima's D positive values was performed. As expected, due to the polymorphic nature of the major histocompatibility complex, the genomic variability level was generally higher when analysing only markers located in this area (mainly around genes belonging to class I). The Slovak and Czech Warmblood horses, as breeds with open herdbook, showed higher average values of heterozygosity indices than Lipizzan, Old Kladruber or Shagya Arabian breeds. Concerning only markers in the major histocompatibility complex region in complete or very high linkage disequilibrium, common patterns were found close to EQMHCB2, MHCB3 and EQMHCC1 genes belonging to class I and DQA1, DRB2, DRB3 and HLA-DOB genes from class II. Genome-wide, the number of heterozygosity-rich regions per animal ranged from 345.25 (Old Kladruber) to 603.33 (Czech Warmblood). Across all breeds, 254 heterozygosity-rich regions were detected directly in the major histocompatibility complex region (194 in class I and 60 in class II). Among them, the highest overlap showed regions found in the genomes of historically connected Czech and Slovak Warmblood breeds. The results suggested that the frequency of markers in heterozygosity-rich regions increased in Lipizzan, Old Kladruber and Shagya Arabian breeds in the genomic region of EQMCE1 gene (class I) and in Czech and Slovak Warmblood horses in DQB1, DQA2, DQB2, DQA3 and DRB2 genes (class II). Although the identified heterozygosity-rich regions formed 330 islands across the genomes of tested breeds, these islands were outside the major histocompatibility complex region. On the other hand, four of 425 balancing selection signals detected across breeds were located directly in the major histocompatibility complex region, close to DRA, DRB1, DQA1, DQB1 and DQB2 genes (class II). Shared islands and balancing selection footprints among breeds were found mainly on chromosomes 7 and 11.

Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a rare autoimmune neurologic disorder, the genetic etiology of which remains poorly understood. Our study aims to investigate the genetic basis of this disease in the Chinese Han population. We performed a genome-wide association study and fine-mapping study within the major histocompatibility complex (MHC) region of 413 Chinese patients with anti-NMDAR encephalitis recruited from 6 large tertiary hospitals and 7,127 healthy controls. Our genome-wide association analysis identified a strong association at the IFIH1 locus on chromosome 2q24.2 (rs3747517, p = 1.06 × 10-8, OR = 1.55, 95% CI, 1.34-1.80), outside of the human leukocyte antigen (HLA) region. Furthermore, through a fine-mapping study of the MHC region, we discovered associations for 3 specific HLA class I and II alleles. Notably, HLA-DQB1*05:02 (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59) demonstrates the strongest association among classical HLA alleles, closely followed by HLA-A*11:01 (p = 4.36 × 10-7; OR, 1.52; 95% CI 1.29-1.79) and HLA-A*02:07 (p = 1.28 × 10-8; OR, 1.87; 95% CI 1.50-2.31). In addition, we uncovered 2 main HLA amino acid variation associated with anti-NMDAR encephalitis including HLA-DQβ1-126H (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59), exhibiting a predisposing effect, and HLA-B-97R (p = 3.40 × 10-8; OR, 0.63; 95% CI 0.53-0.74), conferring a protective effect. Computational docking analysis suggested a close relationship between the NR1 subunit of NMDAR and DQB1*05:02. Our findings indicate that genetic variation in IFIH1, involved in the type I interferon signaling pathway and innate immunity, along with variations in the HLA class I and class II genes, has substantial implications for the susceptibility to anti-NMDAR encephalitis in the Chinese Han population.

Common risk alleles for schizophrenia within the major histocompatibility complex predict white matter microstructure

Recent research has highlighted the role of complement genes in shaping the microstructure of the brain during early development, and in contributing to common allele risk for Schizophrenia. We hypothesised that common risk variants for schizophrenia within complement genes will associate with structural changes in white matter microstructure within tracts innervating the frontal lobe. Results showed that risk alleles within the complement gene set, but also intergenic alleles, significantly predict axonal density in white matter tracts connecting frontal cortex with parietal, temporal and occipital cortices. Specifically, risk alleles within the Major Histocompatibility Complex region in chromosome 6 appeared to drive these associations. No significant associations were found for the orientation dispersion index. These results suggest that changes in axonal packing - but not in axonal coherence - determined by common risk alleles within the MHC genomic region – including variants related to the Complement system - appear as a potential neurobiological mechanism for schizophrenia.

Haplotype-resolved assembly of diploid and polyploid genomes using quantum computing

Precision medicine's emphasis on individual genetic variants highlights the importance of haplotype-resolved assembly, a computational challenge in bioinformatics given its combinatorial nature. While classical algorithms have made strides in addressing this issue, the potential of quantum computing remains largely untapped. Here, we present the vehicle routing problem (VRP) assembler: an approach that transforms this task into a vehicle routing problem, an optimization formulation solvable on a quantum computer. We demonstrate its potential and feasibility through a proof of concept on short synthetic diploid and triploid genomes using a D-Wave quantum annealer. To tackle larger-scale assembly problems, we integrate the VRP assembler with Google's OR-Tools, achieving a haplotype-resolved local assembly across the human major histocompatibility complex (MHC) region. Our results show encouraging performance compared to Hifiasm with phasing accuracy approaching the theoretical limit, underscoring the promising future of quantum computing in bioinformatics.

SNP-based and haplotype-based genome-wide association on drug dependence in Han Chinese

BackgroundDrug addiction is a serious problem worldwide and is influenced by genetic factors. The present study aimed to investigate the association between genetics and drug addiction among Han Chinese.MethodsA total of 1000 Chinese users of illicit drugs and 9693 healthy controls were enrolled and underwent single nucleotide polymorphism (SNP)-based and haplotype-based association analyses via whole-genome genotyping.ResultsBoth single-SNP and haplotype tests revealed associations between illicit drug use and several immune-related genes in the major histocompatibility complex (MHC) region (SNP association: log10BF = 15.135, p = 1.054e-18; haplotype association: log10BF = 20.925, p = 2.065e-24). These genes may affect the risk of drug addiction via modulation of the neuroimmune system. The single-SNP test exclusively reported genome-wide significant associations between rs3782886 (SNP association: log10BF = 8.726, p = 4.842e-11) in BRAP and rs671 (SNP association: log10BF = 7.406, p = 9.333e-10) in ALDH2 and drug addiction. The haplotype test exclusively reported a genome-wide significant association (haplotype association: log10BF = 7.607, p = 3.342e-11) between a region with allelic heterogeneity on chromosome 22 and drug addiction, which may be involved in the pathway of vitamin B12 transport and metabolism, indicating a causal link between lower vitamin B12 levels and methamphetamine addiction.ConclusionsThese findings provide new insights into risk-modeling and the prevention and treatment of methamphetamine and heroin dependence, which may further contribute to potential novel therapeutic approaches.

Association study of the complement component C4 gene and suicide risk in schizophrenia

Schizophrenia is a severe mental illness and a major risk factor for suicide, with approximately 50% of schizophrenia patients attempting and 10% dying from suicide. Although genetic components play a significant role in schizophrenia risk, the underlying genetic risk factors for suicide are poorly understood. The complement component C4 gene, an immune gene involved in the innate immune system and located in the major histocompatibility complex (MHC) region, has been identified to be strongly associated with schizophrenia risk. In addition, recent findings have also suggested that the MHC region has been associated with suicide risk across disorders, making C4 a potential candidate of interest for studying suicidality in schizophrenia patients. Despite growing interest in investigating the association between the C4 gene and schizophrenia, to our knowledge, no work has been done to examine the potential of C4 variants as suicide risk factors in patients with schizophrenia. In this study, we investigated the association between different C4 copy number variants and predicted C4 brain expression with suicidal outcomes (suicide attempts/suicidal ideation). We directly genotyped 434 schizophrenia patients to determine their C4A and C4B copy number variants. We found the C4AS copy number to be marginally and negatively associated with suicide risk, potentially being protective against suicide attempts (OR = 0.49; p = 0.05) and suicidal ideation (OR = 0.65; p = 0.07). Furthermore, sex-stratified analyses revealed that there are no significant differences between males and females. Our preliminary findings encourage additional studies of C4 and potential immune dysregulation in suicide.

Imputation-Based HLA Typing with GWAS SNPs.

SNP-based imputation approaches for human leukocyte antigen (HLA) typing take advantage of the haplotype structure within the major histocompatibility complex (MHC) region. These methods predict HLA classical alleles using dense SNP genotypes, commonly found on array-based platforms used in genome-wide association studies (GWAS). The analysis of HLA classical alleles can be conducted on current SNP datasets at no additional cost. Here, we describe the workflow of HIBAG, an imputation method with attribute bagging, to infer a sample's HLA classical alleles using SNP data. Two examples are offered to demonstrate the functionality using public HLA and SNP data from the latest release of the 1000 Genomes project: genotype imputation using pre-built classifiers in a GWAS, and model training to create a new prediction model. The GPU implementation facilitates model building, making it hundreds of times faster compared to the single-threaded implementation.

Copy number and selection of MHC genes in ruminants are related to habitat, average life span and diet

The ruminants, as the main group of livestock, have been extensively studied in terms of their physiology, endocrinology, biochemistry, genetics, and nutrition. Despite the wide geographic distribution and habitat diversity of animals in this group, their ecology and evolution remain poorly understood. In this study, we analyzed the gene copy number, selection, and ecological and evolutionary processes that have affected the evolution of major histocompatibility complex (MHC) genes across ruminant lineages based on available genomic data. The 51 species analyzed represented all six families of ruminants. Our finding indicated that the architecture of the MHC region is conserved in ruminants, but with variable copy numbers of MHC-I, MHC-IIA, and MHC-IIB genes. No lineage-specific gene duplication was observed in the MHC genes. The phylogenetic generalized least squares regression (PGLS) model revealed association between ecological and biological factors (habitat and lifespan) and gene duplication in DQA and DQB, but not in DRB. The selection pressure of DQA and DQB were related with lifespan, diet, and the ratio of genetic repeat elements. These results suggest that the MHC evolution in ruminants, including copy number and selection, has been influenced by genetic repeat elements, pathogen exposure risk, and intrinsic cost of possessing multiple MHC genes.

Clinical variables and genetic variants associated with perioperative anaphylaxis in Chinese Han population: A pilot study

BackgroundPerioperative anaphylaxis (POA) can lead to severe consequences. Identifying clinical risk factors and genetic loci associated with POA through pre-prescription screening may help reduce its incidence. MethodsUsing univariate regression and covariate-adjusted multivariate regression, we retrospectively analyzed the association between clinical characteristics and POA in 72 POA patients and 72 non-POA individuals. The discovery study of whole-exome association relied on whole-exome sequencing of 73 POA cases and 1339 healthy individuals. A replication study involving an independent set of 16 POA cases and 1339 healthy individuals confirmed this association. The accurate typing of human leucocyte antigen through exome sequencing (ATHLATES) algorithm and the whole-exome sequencing data were used for genotyping the human leucocyte antigen G (HLA-G) of 73 POA patients. The HLA-G of 16 POA cases and 122 non-POA patients were genotyped through Sanger sequencing. We used Fisher's exact probability method to compare the allele and carrier frequencies between POA patients and healthy individuals or non-POA patients. A Pc (P/Bonferroni correction coefficient) < 0.05 represents statistical significance. ResultsRegression analysis identified female sex, an unconfirmed food allergy label, and a history of prior surgery as clinical variables associated with POA. The whole-exome association discovery study identified a strong signal in the major histocompatibility complex region on chromosome 6, with the rs1130356 being the most significant locus (P = 1.5E-10, OR = 3.4, 95% CI = 2.4–4.9). The replication study verified the association between the rs1130356-T allele and POA cases (P = 1.0E-6, OR = 6.3, 95% CI = 3.1–12.7). Compared with non-POA patients, HLA-G∗01:01 (Pc = 2.4E-4, OR = 2.4, 95% CI = 1.6–3.6) was significantly enriched, while HLA-G∗01:04 (Pc = 1.2E-6, OR = 0.3, 95% CI = 0.2–0.5) was lessened in POA patients. ConclusionOur study suggested an association between POA and the risk factors of female sex, an unconfirmed food allergy label, and prior surgery. HLA-G, located in the human leucocyte antigen (HLA) region, may act as a surrogate genetic marker for POA. This suggests a causal relationship between this specific genomic region and POA. Our findings shed light on the contribution of human exome genetic variants to the susceptibility to POA.

Genetic Diversity and Sequence Conservation of Peptide-Binding Regions of MHC Class I Genes in Pig, Cattle, Chimpanzee, and Human.

Comparative analyses of MHC gene diversity and evolution across different species could offer valuable insights into the evolution of MHC genes. Intra- and inter-species sequence diversity and conservation of 12 classical major histocompatibility complex (MHC) class I genes from cattle, chimpanzees, pigs, and humans was analyzed using 20 representative allelic groups for each gene. The combined analysis of paralogous loci for each species revealed that intra-locus amino-acid sequence variations in the peptide-binding region (PBR) of MHC I genes did not differ significantly between species, ranging from 8.44% for SLA to 10.75% for BoLA class I genes. In contrast, intraspecies differences in the non-PBRs of these paralogous genes were more pronounced, varying from 4.59% for SLA to 16.89% for HLA. Interestingly, the Shannon diversity index and rate of nonsynonymous substitutions for PBR were significantly higher in SLA and BoLA than those in Patr and HLA. Analysis of peptide-binding pockets across all analyzed MHC class I genes of the four species indicated that pockets A and E showed the lowest and highest diversity, respectively. The estimated divergence times suggest that primate and artiodactyl MHC class I genes diverged 60.41 Mya, and BoLA and SLA genes diverged 35.34 Mya. These results offer new insights into the conservation and diversity of MHC class I genes in various mammalian species.

The HLA-B*57:01 allele corresponds to a very large MHC haploblock likely explaining its massive effect for HIV-1 elite control.

We have reanalyzed the genomic data of the International Collaboration for the Genomics of HIV (ICGH), centering on HIV-1 Elite Controllers. We performed a genome-wide Association Study comparing 543 HIV Elite Controllers with 3,272 uninfected controls of European descent. Using the latest database for imputation, we analyzed 35,552 Single Nucleotide Polymorphisms (SNPs) within the Major Histocompatibility Complex (MHC) region. Our analysis identified 2,626 SNPs significantly associated (p<5. 10-8) with elite control of HIV-1 infection, including well-established MHC signals such as the rs2395029-G allele which tags HLA-B*57:01. A thorough investigation of SNPs in linkage disequilibrium with rs2395029 revealed an extensive haploblock spanning 1.9 megabases in the MHC region tagging HLA-B*57:01, comprising 379 SNP alleles impacting 72 genes. This haploblock contains damaging variations in proteins like NOTCH4 and DXO and is also associated with a strong differential pattern of expression of multiple MHC genes such as HLA-B, MICB, and ZBTB12. The study was expanded to include two cohorts of seropositive African-American individuals, where a haploblock tagging the HLA-B*57:03 allele was similarly associated with control of viral load. The mRNA expression profile of this haploblock in African Americans closely mirrored that in the European cohort. These findings suggest that additional molecular mechanisms beyond the conventional antigen-presenting role of class I HLA molecules may contribute to the observed influence of HLA-B*57:01/B*57:03 alleles on HIV-1 elite control. Overall, this study has uncovered a large haploblock associated with HLA-B*57 alleles, providing novel insights into their massive effect on HIV-1 elite control.

High-resolution DNA methylation screening of the major histocompatibility complex in multiple sclerosis.

The HLA-DRB1 gene in the major histocompatibility complex (MHC) region in chromosome 6p21 is the strongest genetic factor identified as influencing multiple sclerosis (MS) susceptibility. DNA methylation changes associated with MS have been consistently detected at the MHC region. However, understanding the full scope of epigenetic regulations of the MHC remains incomplete, due in part to the limited coverage of this region by standard whole genome bisulfite sequencing or array-based methods. We developed and validated an MHC capture protocol coupled with bisulfite sequencing and conducted a comprehensive analysis of the MHC methylation landscape in blood samples from 147 treatment naïve MS study participants and 129 healthy controls. We identified 132 differentially methylated region (DMRs) within MHC region associated with disease status. The DMRs overlapped with established MS risk loci. Integration of the MHC methylome with human leukocyte antigen (HLA) genetic data indicate that the methylation changes are significantly associated with HLA genotypes. Using DNA methylation quantitative trait loci (mQTL) mapping and the causal inference test (CIT), we identified 643 cis-mQTL-DMRs paired associations, including 71 DMRs possibly mediating causal relationships between 55 single nucleotide polymorphisms (SNPs) and MS risk. The results describe MS-associated methylation changes in MHC region and highlight the association between HLA genotypes and methylation changes. Results from the mQTL and CIT analyses provide evidence linking MHC region variations, methylation changes, and disease risk for MS.

A chromosome-level genome assembly for the Silkie chicken resolves complete sequences for key chicken metabolic, reproductive, and immunity genes

A set of high-quality pan-genomes would help identify important genes that are still hidden/incomplete in bird reference genomes. In an attempt to address these issues, we have assembled a de novo chromosome-level reference genome of the Silkie (Gallus gallus domesticus), which is an important avian model for unique traits, like fibromelanosis, with unclear genetic foundation. This Silkie genome includes the complete genomic sequences of well-known, but unresolved, evolutionarily, endocrinologically, and immunologically important genes, including leptin, ovocleidin-17, and tumor-necrosis factor-α. The gap-less and manually annotated MHC (major histocompatibility complex) region possesses 38 recently identified genes, with differentially regulated genes recovered in response to pathogen challenges. We also provide whole-genome methylation and genetic variation maps, and resolve a complex genetic region that may contribute to fibromelanosis in these animals. Finally, we experimentally show leptin binding to the identified leptin receptor in chicken, confirming an active leptin ligand-receptor system. The Silkie genome assembly not only provides a rich data resource for avian genome studies, but also lays a foundation for further functional validation of resolved genes.

Major Histocompatibility Complex Region and Diversity of the Local Chicken Populations In Niger

Introduction: The major histocompatibility complex (MHC) of chicken is highly polymorphic, and it is linked to several disease resistance or susceptibility traits. Therefore, the current study aimed to analyze the genetic diversity in the MHC region of Nigerien local chicken (Dourgou, Goggori, Kolonto, Tchagara, Gouzou-gouzou, and Popular) using a high polymorphic microsatellite marker named LEI0258 to determine the diversity of chickens kept at the four agroecological zones in Niger. Materials and methods: A total of 601 chickens from six local Nigerien chickens were sampled. By capillary electrophoresis using LEI0258 marker, 403 samples with different fragment sizes were randomly chosen and sequenced. Results: The findings indicated 80 different alleles ranging in size from 181 to 474 bp. A total of 22 new alleles and 39 private alleles (that existed in only one breed) were detected. The alleles 309, 295, and 193 were the most predominant in the Nigerien local chicken population. Nine polymorphisms were observed along the LEI0258 sequence, including three in the upstream (one indel and two Single Nucleotide Polymorphism [SNP]), one in the repeat region at the last R12 (SNP), and five in the downstream (two indels and three SNPs). Conclusion: The chickens are not clustering according to their agroecological zone of origin. They are randomly distributed across the four investigated agroecological zones. The information found in this study is invaluable in breeding and conservation programs associated with several disease resistance or susceptibility traits.

Regulation of expression quantitative trait loci by SVA retrotransposons within the major histocompatibility complex.

Genomic and transcriptomic studies of expression quantitative trait loci (eQTL) revealed that SINE-VNTR-Alu (SVA) retrotransposon insertion polymorphisms (RIPs) within human genomes markedly affect the co-expression of many coding and noncoding genes by coordinated regulatory processes. This study examined the polymorphic SVA modulation of gene co-expression within the major histocompatibility complex (MHC) genomic region where more than 160 coding genes are involved in innate and adaptive immunity. We characterized the modulation of SVA RIPs utilizing the genomic and transcriptomic sequencing data obtained from whole blood of 1266 individuals in the Parkinson's Progression Markers Initiative (PPMI) cohort that included an analysis of human leukocyte antigen (HLA)-A regulation in a subpopulation of the cohort. The regulatory properties of eight SVAs located within the class I and class II MHC regions were associated with differential co-expression of 71 different genes within and 75 genes outside the MHC region. Some of the same genes were affected by two or more different SVA. Five SVA are annotated in the human genomic reference sequence GRCh38.p14/hg38, whereas the other three were novel insertions within individuals. We also examined and found distinct structural effects (long and short variants and the CT internal variants) for one of the SVA (R_SVA_24) insertions on the differential expression of the HLA-A gene within a subpopulation (550 individuals) of the PPMI cohort. This is the first time that many HLA and non-HLA genes (multilocus expression units) and splicing mechanisms have been shown to be regulated by eight structurally polymorphic SVA within the MHC genomic region by applying precise statistical analysis of RNA data derived from the blood samples of a human cohort population. This study shows that SVA within the MHC region are important regulators or rheostats of gene co-expression that might have potential roles in diversity, health, and disease.

Association Study Identified HLA-DQA1 as a Novel Genetic Risk of Systemic Lupus Erythematosus-Associated Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a severe complication of systemic lupus erythematosus (SLE). However, the genetic signatures of SLE-associated PAH have not been well studied. We aimed to identify genetic variants implicated in SLE-associated PAH susceptibility within the major histocompatibility complex (MHC) region and assess the contribution to clinical outcomes. A total of 172 patients with SLE-associated PAH confirmed by right heart catheterization, 1,303 patients with SLE without PAH, and 9,906 healthy controls were included. Deep sequencing of the MHC region was performed to identify alleles, single-nucleotide polymorphisms, and amino acids. We compared patients with SLE-associated PAH with patients with SLE without PAH and healthy controls. Clinical association study was conducted to explore the contribution to phenotypes. A total of 19,881 genetic variants were identified within the MHC region. HLA-DQA1*03:02 was identified as a novel genetic variant associated with SLE-associated PAH in the discovery cohort (P = 5.68 × 10-12 ) and authenticated in an independent replication cohort (P = 1.30 × 10-9 ). The strongest associated amino acid position was mapped to HLA-DQα1 in the region affecting MHC/peptide-CD4+ T cell receptor affinity and antigen binding. Clinical association study demonstrated that patients with SLE-associated PAH with HLA-DQA1*03:02 had significantly lower rates of target role achievement (P = 0.005) and survival (P = 0.04). This study, based on the largest cohort of SLE-associated PAH, is the first to investigate how MHC region genetic variants contribute to SLE-associated PAH susceptibility. HLA-DQA1*03:02 is a novel genetic risk factor and a prognostic factor in SLE-associated PAH. Patients with SLE with this allele require regular monitoring and careful follow-up for early diagnosis and interventions for potential PAH.