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1.
BMC Evol Biol ; 19(1): 107, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31113360

RESUMO

BACKGROUND: In the arms race between hosts and parasites, genes involved in the immune response are targets for natural selection. Toll-Like Receptor (TLR) genes play a role in parasite detection as part of the innate immune system whereas Major Histocompatibility Complex (MHC) genes encode proteins that display antigens as part of the vertebrate adaptive immune system. Thus, both gene families are under selection pressure from pathogens. The bananaquit (Coereba flaveola) is a passerine bird that is a common host of avian malarial parasites (Plasmodium sp. and Haemoproteus sp.). We assessed molecular variation of TLR and MHC genes in a wild population of bananaquits and identified allelic associations with resistance/susceptibility to parasitic infection to address hypotheses of avian immune response to haemosporidian parasites. RESULTS: We found that allele frequencies are associated with infection status at the immune loci studied. A consistent general trend showed the infected groups possessed more alleles at lower frequencies, and exhibited unique alleles, compared to the uninfected group. CONCLUSIONS: Our results support the theory of natural selection favoring particular alleles for resistance while maintaining overall genetic diversity in the population, a mechanism which has been demonstrated in some systems in MHC previously but understudied in TLRs.


Assuntos
Malária/parasitologia , Parasitos/genética , Passeriformes/genética , Passeriformes/imunologia , Animais , Frequência do Gene/genética , Loci Gênicos , Haemosporida/fisiologia , Imunogenética , Complexo Principal de Histocompatibilidade/genética , Passeriformes/parasitologia , Plasmodium/fisiologia , Análise de Sequência de DNA
2.
J Vet Sci ; 20(2): e5, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30944528

RESUMO

Long-term maintenance of transplanted organs is one of the major factors that increases survival time of recipients. Although obtaining a major histocompatibility complex (MHC)-matched donor with the recipient is essential for successful organ transplantation, there have been limited reports on MHC matching between dogs. In this study, we analyzed the canine MHC matching rates using Maltese, one of the most popular purebred dogs, and mongrel dogs in Korea. Genomic DNA was extracted from blood leukocytes and DNA was amplified by polymerase chain reaction with primers specific to MHC microsatellite markers. The MHC matching degree was confirmed by the microsatellite markers using polyacrylamide gel electrophoresis. The MHC matching rates of each donor-recipient groups including Maltese-Maltese, mongrel-mongrel and Maltese-mongrel were 4.76%, 5.13% and 6.67%, respectively. There were no significant differences in the MHC matching degree between each group. These results demonstrate that MHC-matched donors could be selected from other breeds as much as from the same breed for transplantation. Knowledge of the MHC matching degree of purebred and mongrel dogs would offer valuable information not only for improving the success rate of organ transplantation surgery in canine patients but also for transplantation research using experimental canine models.


Assuntos
Cães/genética , Complexo Principal de Histocompatibilidade/genética , Animais , Tipagem e Reações Cruzadas Sanguíneas/veterinária , Cães/imunologia , Eletroforese em Gel de Poliacrilamida/veterinária , Genes MHC Classe I/genética , Repetições de Microssatélites/genética , Reação em Cadeia da Polimerase/veterinária
3.
Nat Immunol ; 20(5): 652-662, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30858620

RESUMO

αß T cell antigen receptors (TCRs) bind complexes of peptide and major histocompatibility complex (pMHC) with low affinity, which poses a considerable challenge for the direct identification of αß T cell cognate peptides. Here we describe a platform for the discovery of MHC class II epitopes based on the screening of engineered reporter cells expressing novel pMHC-TCR (MCR) hybrid molecules carrying cDNA-derived peptides. This technology identifies natural epitopes of CD4+ T cells in an unbiased and efficient manner and allows detailed analysis of TCR cross-reactivity that provides recognition patterns beyond discrete peptides. We determine the cognate peptides of virus- and tumor-specific T cells in mouse disease models and present a proof of concept for human T cells. Furthermore, we use MCR to identify immunogenic tumor neo-antigens and show that vaccination with a peptide naturally recognized by tumor-infiltrating lymphocytes efficiently protects mice from tumor challenge. Thus, the MCR technology holds promise for basic research and clinical applications, allowing the personalized identification of T cell-specific neo-antigens in patients.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Humanos , Complexo Principal de Histocompatibilidade/genética , Camundongos Endogâmicos C57BL , Peptídeos/genética , Peptídeos/imunologia , Peptídeos/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo
4.
Nat Commun ; 10(1): 1019, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833553

RESUMO

The αß T cell receptor (TCR) repertoire on mature T cells is selected in the thymus, but the basis for thymic selection of MHC-restricted TCRs from a randomly generated pre-selection repertoire is not known. Here we perform comparative repertoire sequence analyses of pre-selection and post-selection TCR from multiple MHC-sufficient and MHC-deficient mouse strains, and find that MHC-restricted and MHC-independent TCRs are primarily distinguished by features in their non-germline CDR3 regions, with many pre-selection CDR3 sequences not compatible with MHC-binding. Thymic selection of MHC-independent TCR is largely unconstrained, but the selection of MHC-specific TCR is restricted by both CDR3 length and specific amino acid usage. MHC-restriction disfavors TCR with CDR3 longer than 13 amino acids, limits positively charged and hydrophobic amino acids in CDR3ß, and clonally deletes TCRs with cysteines in their CDR3 peptide-binding regions. Together, these MHC-imposed structural constraints form the basis to shape VDJ recombination sequences into MHC-restricted repertoires.


Assuntos
Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/imunologia , Timo/imunologia , Sequência de Aminoácidos , Animais , Regiões Determinantes de Complementaridade/genética , Ativação Linfocitária , Complexo Principal de Histocompatibilidade/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T/genética , Análise de Sequência de Proteína , Linfócitos T/imunologia , Linfócitos T/metabolismo , Recombinação V(D)J
5.
Poult Sci ; 98(7): 2734-2746, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30877744

RESUMO

Unraveling the genetic diversity of livestock species is central to understanding their value and importance for conservation and improvement in diverse production environments. In developing countries, information on genetic attributes of many livestock species is unfortunately scanty to support well-informed decision-making upon relevant management strategies. This study aimed at investigating allelic variability, genetic diversity, and genetic relationships of 10 indigenous chicken ecotypes from Southern Highlands of Tanzania using the Major Histocompatibility Complex-linked LEI0258 marker. A total of 400 DNA samples, 40 per ecotype, were genotyped by capillary electrophoresis. Thirty different alleles with sizes ranging from 197 to 569 bp were determined. The number of alleles ranged from 17 (Itunduma) to 21 (Mbeya), with an average of 19.20 alleles per ecotype. Allelic polymorphism was further evaluated through genotyping by Sanger sequencing. Thirty-three DNA samples with different fragment sizes were re-amplified and their alleles sequenced to depict polymorphism based on a combination of two repeat regions at 12 and 13 bp, respectively, and flanking regions with SNP and indels. The repeat region at 13 bp appeared 1 to 28 times, whereas the region at 12 bp appeared 3 to 19 times in all sequenced fragments. The numbers of indels and SNP determined were 7 and 9, respectively. From capillary electrophoresis, the Chunya and Msimbazi ecotypes exhibited the highest genetic diversity (0.937), whereas the lowest value (0.910) was observed from the Mbarali ecotype, with an average of 0.925. The Namtumbo and Wanging'ombe ecotypes showed high inbreeding coefficients (FIS > 0.05), whereas a high excess heterozygote value (FIS = -0.098) was observed from the Njombe ecotype. Two percent of the genetic diversity was due to differences among ecotypes, and the rest was due to differences among individuals within the ecotypes. Despite the overall low genetic differentiation, both fragment and sequencing analyses depicted a high allelic and genetic variability across 10 chicken ecotypes. These results therefore, underscore the importance of establishing appropriate conservation and management strategies to capitalize on observed variability and maintain genetic flexibility across diverse production environments.


Assuntos
Galinhas/genética , Variação Genética , Repetições de Microssatélites , Animais , Galinhas/classificação , Ecótipo , Feminino , Genótipo , Complexo Principal de Histocompatibilidade/genética , Masculino , Análise de Sequência de DNA , Tanzânia
6.
Arch Dermatol Res ; 311(4): 277-285, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30826962

RESUMO

To verify whether PsA-associated HLA alleles proposed in other populations are also related to PsA in Chinese Han population, a study of PsA susceptible alleles in the HLA-A, HLA-B, HLA-C and HLA-DRB1 alleles was presented for Chinese Han population. Genotyping was performed by Illumina Miseq platform (Illumina, USA). 50 subtypes and 77 subtypes of HLA-A, HLA-B, HLA-C and HLA-DRB1 with minor allele frequency (MAF) > 1% were genotyped from two-digit and four-digit resolution analysis in 111 PsA and 207 HCs (healthy controls) collected from Chinese Han population, respectively. Data handling, quality control and association analysis were performed using SPSS 25.0 software. In risk estimate, by mean of Bonferroni correction, a newfound four-digit allele HLA-A*01:01 [P = 5.5 × 10-4, OR 3.35 (1.69-6.66)], four-digit allele HLA-C*06:02 [P = 8.5 × 10-7, OR 3.80 (2.23-6.47)] and six two-digit alleles HLA-A*01 [P = 5.2 × 10-5, OR 3.43 (1.89-6.23)], HLA-B*13 [P = 4.0 × 10-6, OR 2.65 (1.76-4.01)], HLA-B*27 [P = 7.5 × 10-4, OR 5.84 (2.09-16.29)], HLA-B*57 [P = 5.8 × 10-5, OR 20.10 (4.65-86.83)], HLA-C*03 [P = 2.1 × 10-4, OR 0.40 (0.25-0.65)], HLA-C*06 [P = 1.9 × 10-12, OR 4.48 (2.95-6.81)] showed statistical significance by the univariate binary logistic regression analysis. Besides, in the binary logistic regression analysis with multiple variables, when the two alleles HLA-A*01:01 and HLA-C*06:02 were considered as covariates, HLA-A*01:01 [P = 2.7 × 10-3,OR 2.95 (1.46-5.98)] also showed significant association for PsA as risk factor, but may be not the main risk factor [HLA-C*06:02, P = 3.0 × 10-6, OR 3.68 (2.13-6.37)]. When all the above two-digit alleles were included as covariates, HLA-A*01 [P = 4.8 × 10-2, OR 2.00 (1.01-3.94)], HLA-B*13 [P = 4.2 × 10-5, OR 2.62 (1.65-4.16)], HLA-B*27 [P = 1.7 × 10-4, OR 7.62 (2.64-21.96)], HLA-B*57 [P = 2.97 × 10-4, OR 15.90 (3.55-71.18)], HLA-C*06 [P = 6.1 × 10-5, OR 2.70 (1.66-4.40)] showed significant for PsA as risk factors, HLA-C*03 [OR 0.65 (0.39-1.09), P = 0.10] showed no association with PsA. In conclusion, we assessed HLA-A, HLA-B, HLA-C and HLA-DRB1 alleles in PsA cohort of Chinese Han population, found HLA-A*01:01 and HLA-A*01 may be the susceptible genes associated with PsA, and also confirmed the association of four loci with PsA in Chinese Han population. These findings may extend the susceptibility HLA alleles of PsA and help in developing possible genetic markers to predict PsA.


Assuntos
Artrite Psoriásica/genética , Genótipo , Antígeno HLA-A1/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Estudos de Coortes , Feminino , Frequência do Gene , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Complexo Principal de Histocompatibilidade/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Risco , Adulto Jovem
7.
Cells ; 8(3)2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893784

RESUMO

Few major histocompatibility complex (MHC)-based mate choice studies include all MHC genes at the inter-individual, sperm-egg, and mother-fetus recognition levels. We tested three hypotheses of female mate choice in a 17-year study of the giant panda (Ailuropoda melanoleuca) while using ten functional MHC loci (four MHC class I loci: Aime-C, Aime-F, Aime-I, and Aime-L; six MHC class II loci: Aime-DRA, Aime-DRB3, Aime-DQA1, Aime-DQA2, Aime-DQB1, and Aime-DQB2); five super haplotypes (SuHa, SuHaI, SuHaII, DQ, and DR); and, seven microsatellites. We found female choice for heterozygosity at Aime-C, Aime-I, and DQ and for disassortative mate choice at Aime-C, DQ, and DR at the inter-individual recognition level. High mating success occurred in MHC-dissimilar mating pairs. No significant results were found based on any microsatellite parameters, suggesting that MHCs were the mate choice target and there were no signs of inbreeding avoidance. Our results indicate Aime-DQA1- and Aime-DQA2-associated disassortative selection at the sperm-egg recognition level and a possible Aime-C- and Aime-I-associated assortative maternal immune tolerance mechanism. The MHC genes were of differential importance at the different recognition levels, so all of the functional MHC genes should be included when studying MHC-dependent reproductive mechanisms.


Assuntos
Feto/fisiologia , Complexo Principal de Histocompatibilidade/genética , Óvulo/fisiologia , Reprodução/genética , Espermatozoides/fisiologia , Ursidae/genética , Ursidae/fisiologia , Alelos , Animais , Feminino , Variação Genética , Haplótipos/genética , Heterozigoto , Homozigoto , Masculino , Repetições de Microssatélites/genética
8.
PLoS Biol ; 17(1): e3000131, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30703088

RESUMO

Central players of the adaptive immune system are the groups of proteins encoded in the major histocompatibility complex (MHC), which shape the immune response against pathogens and tolerance to self-peptides. The corresponding genomic region is of particular interest, as it harbors more disease associations than any other region in the human genome, including associations with infectious diseases, autoimmune disorders, cancers, and neuropsychiatric diseases. Certain MHC molecules can bind to a much wider range of epitopes than others, but the functional implication of such an elevated epitope-binding repertoire has remained largely unclear. It has been suggested that by recognizing more peptide segments, such promiscuous MHC molecules promote immune response against a broader range of pathogens. If so, the geographical distribution of MHC promiscuity level should be shaped by pathogen diversity. Three lines of evidence support the hypothesis. First, we found that in pathogen-rich geographical regions, humans are more likely to carry highly promiscuous MHC class II DRB1 alleles. Second, the switch between specialist and generalist antigen presentation has occurred repeatedly and in a rapid manner during human evolution. Third, molecular positions that define promiscuity level of MHC class II molecules are especially diverse and are under positive selection in human populations. Taken together, our work indicates that pathogen load maintains generalist adaptive immune recognition, with implications for medical genetics and epidemiology.


Assuntos
Imunidade Adaptativa/genética , Antígenos de Histocompatibilidade Classe II/genética , Complexo Principal de Histocompatibilidade/genética , Sequência de Aminoácidos/genética , Animais , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Evolução Biológica , Patógenos Transmitidos pelo Sangue , Epitopos/genética , Epitopos/fisiologia , Evolução Molecular , Variação Genética/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Complexo Principal de Histocompatibilidade/fisiologia , Peptídeos/genética , Seleção Genética/genética
9.
Hum Immunol ; 80(4): 243-247, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30769034

RESUMO

The Major Histocompatibility Complex (MHC) harbors key genes of the immune response that are likely useful as biomarkers for infectious diseases. However, little is known about their microRNAs and what role they play in infections. The present study aimed to describe the miRNA genes in the MHC (MHC-miRNA), their variability and associations with infectious diseases. Additionally, MHC-miRNA host and target genes were also evaluated in associations with infectious diseases. Surveys in several databases and literature reviews identified 48 MHC-miRNA genes, with high SNP and CNV variability able to disrupt MHC-miRNA expression and putatively under selective pressure. Eight MHC-miRNAs were found inside or close regions of classical MHC rearrangements (RCCX and DRB genome organization). The proportion of MHC-miRNAs associated with infections (23%) was higher than the proportion found for the 1917 hsa-miRNA (4%). Additionally, 35 MHC-miRNAs (57%) have at least one of their target genes associated with infectious diseases, while all nine MHC-miRNA whose host genes were associated with infections have also their target genes associated with infections, being host and target genes of five MHC-miRNAs reported to be associated with the same diseases. This finding may reflect a concerted miRNA-mediated immune response mechanism triggered by infection.


Assuntos
Doenças Transmissíveis/genética , Complexo Principal de Histocompatibilidade/genética , MicroRNAs/genética , Bases de Dados de Ácidos Nucleicos , Perfilação da Expressão Gênica , Estudos de Associação Genética , Genoma , Humanos , Imunidade/genética , Polimorfismo de Nucleotídeo Único
10.
Hum Immunol ; 80(4): 257-262, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30790598

RESUMO

INTRODUCTION: Chromosomal abnormalities are frequent events in hematological malignancies. The degree of HLA compatibility between donor and recipient in hematopoietic stem cell transplantation is critical. PURPOSE OF THE STUDY: In this report, we describe an acute myeloid leukemia case with loss of heterozygosity (LOH) encompassing the entire HLA. MATERIALS AND METHODS: HLA molecular typing was performed on peripheral blood (PB) and buccal swabs (BS). Chromosomal microarray analysis (CMA) was performed using a whole genome platform. RESULTS: Typing results on PB sample collected during blast crisis demonstrated homozygosity at the -A, -B, -C, -DR, and -DQ loci. A BS sample demonstrated heterozygosity at all loci. A subsequent PB sample drawn after count recovery confirmed heterozygosity. The CMA performed on PB samples collected during and after blast crisis revealed a large terminal region of copy-neutral LOH involving chromosome region 6p25.3p21.31, spanning approximately 35.9 Mb. The results of the CMA assay on sample collected after count recovery did not demonstrate LOH. CONCLUSIONS: LOH at the HLA gene locus may significantly influence the donor search resulting in mistakenly choosing homozygous donors. We recommend confirming the HLA typing of recipients with hematological malignancies when homozygosity is detected at any locus by using BS samples, or alternatively from PB when remission is achieved.


Assuntos
Medula Óssea/fisiologia , Genoma/genética , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/genética , Leucócitos Mononucleares/fisiologia , Perda de Heterozigosidade , Complexo Principal de Histocompatibilidade/genética , Idoso , Circulação Sanguínea , Feminino , Teste de Histocompatibilidade , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Análise em Microsséries , Técnicas de Diagnóstico Molecular , Indução de Remissão
11.
Nat Commun ; 10(1): 260, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651564

RESUMO

Rapid innovation in sequencing technologies and improvement in assembly algorithms have enabled the creation of highly contiguous mammalian genomes. Here we report a chromosome-level assembly of the water buffalo (Bubalus bubalis) genome using single-molecule sequencing and chromatin conformation capture data. PacBio Sequel reads, with a mean length of 11.5 kb, helped to resolve repetitive elements and generate sequence contiguity. All five B. bubalis sub-metacentric chromosomes were correctly scaffolded with centromeres spanned. Although the index animal was partly inbred, 58% of the genome was haplotype-phased by FALCON-Unzip. This new reference genome improves the contig N50 of the previous short-read based buffalo assembly more than a thousand-fold and contains only 383 gaps. It surpasses the human and goat references in sequence contiguity and facilitates the annotation of hard to assemble gene clusters such as the major histocompatibility complex (MHC).


Assuntos
Búfalos/genética , Cromossomos de Mamíferos/genética , Mapeamento de Sequências Contíguas/métodos , Genoma/genética , Cabras/genética , Animais , Cromatina/química , Cromatina/genética , Feminino , Genômica/métodos , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Complexo Principal de Histocompatibilidade/genética , Anotação de Sequência Molecular/métodos , Família Multigênica/genética , Sequências Repetitivas de Ácido Nucleico/genética , Sequenciamento Completo do Genoma
12.
BMC Evol Biol ; 19(1): 17, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30630408

RESUMO

BACKGROUND: The aim of the study was to use hybrid populations as well as island populations of the European brown hare (Lepus europaeus) to explore the effect of evolutionary events, such as the post-deglaciation translocations, spontaneous and human-mediated, local adaptation and the genetic drift in the shaping of the phylogeographic patterns of the species. For this purpose, we used molecular markers, both nuclear and mitochondrial, that are indicative for local adaptation as well as neutral markers to elucidate the patterns of population differentiation based on geographic isolation and the clade of origin. To broaden our analysis, we included data from our previous studies concerning mainland populations, to explore the genetic differentiation in the base of the geographic origin (mainland/island) of the populations. RESULTS: Our results suggest that local adaptation shapes the differentiation in both genomes, favoring specific alleles in nuclear genes (e.g. DQA) or haplotypes in mtDNA (e.g. Control Region, CR). mtDNA variation was found to be in a higher level and was able to give a phylogeographic signal for the populations. Furthermore, the degree of variation was influenced not only by the geographic origin, but also by the clade of origin, since specific island populations of Anatolian origin showed a greater degree of variation compared to specific mainland populations of the European clade. Concerning the hybrid population, we confirmed the existence of both clades in the territory and we provided a possible explanation for the lack of introgression between the clades. CONCLUSION: Our results indicate that the Quaternary's climatic oscillations played a major role in the shaping of the phylogeographic patterns of the species, by isolating populations in the distinct refugia, where they adapted and differentiate in allopatry, leading to genome incompatibilities observed nowadays.


Assuntos
Lebres/genética , Hibridização Genética , Ilhas , Filogeografia , Alelos , Animais , DNA Mitocondrial/genética , Éxons/genética , Frequência do Gene/genética , Variação Genética , Haplótipos , Complexo Principal de Histocompatibilidade/genética , Repetições de Microssatélites/genética , Mitocôndrias/genética , Filogenia
13.
Nat Genet ; 51(3): 470-480, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30692682

RESUMO

To perform detailed fine-mapping of the major-histocompatibility-complex region, we conducted next-generation sequencing (NGS)-based typing of the 33 human leukocyte antigen (HLA) genes in 1,120 individuals of Japanese ancestry, providing a high-resolution allele catalog and linkage-disequilibrium structure of both classical and nonclassical HLA genes. Together with population-specific deep-whole-genome-sequencing data (n = 1,276), we conducted NGS-based HLA, single-nucleotide-variant and indel imputation of large-scale genome-wide-association-study data from 166,190 Japanese individuals. A phenome-wide association study assessing 106 clinical phenotypes identified abundant, significant genotype-phenotype associations across 52 phenotypes. Fine-mapping highlighted multiple association patterns conferring independent risks from classical HLA genes. Region-wide heritability estimates and genetic-correlation network analysis elucidated the polygenic architecture shared across the phenotypes.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Complexo Principal de Histocompatibilidade/genética , Alelos , Linhagem Celular , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
14.
Immunogenetics ; 71(4): 283-297, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30671674

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune multi-organ disorder that presents itself in a thousand ways. Its clinical course is extremely unpredictable, which makes diagnosis and treatment a challenge for clinicians. It appears that the clinical course of SLE is determined by genetic material in combination with environmental factors. In this article, we review recent findings on the pathogenesis of SLE from the perspective of genetics, focusing on defects in the clearance of apoptotic bodies and immune complexes, on alterations in the innate immune system response, and on impaired pathways in the adaptive immune system. Furthermore, the major histocompatibility complex (MHC) and non-MHC genes discovered during genome-wide association studies (GWASs) in SLE patients are also evaluated. In addition, the effect of these polymorphisms on the function of their related transcripts and their association with the clinical manifestations of SLE and its pathophysiology are explained. Finally, the association of genetic polymorphisms with clinical responses to common medications used in the treatment of SLE is also discussed.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético/genética , Imunidade Adaptativa/genética , Autoimunidade/genética , Humanos , Imunidade Inata/genética , Lúpus Eritematoso Sistêmico/terapia , Complexo Principal de Histocompatibilidade/genética
15.
Vet Immunol Immunopathol ; 207: 53-61, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30593351

RESUMO

Phagocytic activity of leukocytes in whole blood was assessed as a potential immune competence trait in chickens. A flow cytometry based whole blood phagocytosis (WBP) assay was set up and evaluated using blood from chickens homozygous for four different MHC haplotypes, B12, B15, B19 and B21. Fluorescent latex beads and two serotypes of fluorescently labelled heat-killed bacteria (Salmonella Infantis and Salmonella. Typhimurium) were evaluated as phagocytic targets. In addition, the opsonophagocytic potential (OPp) of individual sera from the birds was included in a phagocytosis assay using the HD11 chicken macrophage cell line. Results showed that both serotypes of bacteria but not the latex beads were effectively phagocytosed by leukocytes in the whole blood cultures. Differences were observed in the phagocytic capacity of monocytes and thrombocyte/lymphocytes, respectively between the different MHC lines. No significant differences on the OPp of serum was identified between MHC lines. In addition, for both phagocytic activity of leukocytes and OPp of serum large variations between individuals were observed within MHC haplotypes. No significant relationships were observed between the phagocytic activity of leukocytes and serum OPp or Salmonella-specific IgY levels. In conclusion, our results suggest that the WBP assay, using a no-lyse no-wash single staining method, is a rapid and convenient method to assess phagocytic functions of different leukocyte populations.


Assuntos
Galinhas/imunologia , Citometria de Fluxo/veterinária , Leucócitos/imunologia , Fagocitose/imunologia , Animais , Plaquetas/imunologia , Galinhas/sangue , Galinhas/genética , Feminino , Citometria de Fluxo/métodos , Haplótipos/genética , Haplótipos/imunologia , Linfócitos/imunologia , Complexo Principal de Histocompatibilidade/genética , Monócitos/imunologia
16.
Gastroenterology ; 156(5): 1496-1507.e7, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30593799

RESUMO

BACKGROUND & AIMS: Spontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance, but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry. METHODS: We performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina (San Diego, CA) arrays and statistically imputed to the 1000 Genomes Project. For each ancestry group, the association of single-nucleotide polymorphisms with HCV clearance was tested by log-additive analysis, and then a meta-analysis was performed. RESULTS: In the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4-IFNL3 (19q13.2) (P = 5.99 × 10-50) and the MHC locus 6p21.32 (P = 1.15 × 10-21). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P = 1.80 × 10-07). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared with individuals carrying none or 1 of the clearance-associated variants. CONCLUSIONS: In a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4-IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Hepacivirus/fisiologia , Hepatite C/genética , Hispano-Americanos/genética , Feminino , Estudo de Associação Genômica Ampla , Hepatite C/diagnóstico , Hepatite C/etnologia , Hepatite C/virologia , Interações Hospedeiro-Patógeno , Humanos , Interleucinas/genética , Complexo Principal de Histocompatibilidade/genética , Masculino , Receptores Acoplados a Proteínas-G/genética , Remissão Espontânea , Estados Unidos/epidemiologia , Carga Viral
17.
Mol Ecol ; 28(4): 833-846, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30582649

RESUMO

To increase fitness, a wide range of vertebrates preferentially mate with partners that are dissimilar at the major histocompatibility complex (MHC) or that have high MHC diversity. Although MHC often can be assessed through olfactory cues, the mechanism by which MHC genes influence odour remains largely unclear. MHC class IIB molecules, which enable recognition and elimination of extracellular bacteria, have been suggested to influence odour indirectly by shaping odour-producing microbiota, i.e. bacterial communities. However, there is little evidence of the predicted covariation between an animal's MHC genotype and its bacterial communities in scent-producing body surfaces. Here, using high-throughput sequencing, we tested the covariation between MHC class IIB genotypes and feather microbiota in the blue petrel (Halobaena caerulea), a seabird with highly developed olfaction that has been suggested to rely on oduor cues during an MHC-based mate choice. First, we show that individuals with similar MHC class IIB profiles also have similar bacterial assemblages in their feathers. Then, we show that individuals with high MHC diversity have less diverse feather microbiota and also a reduced abundance of a bacterium of the genus Arsenophonus, a genus in which some species are symbionts of avian ectoparasites. Our results, showing that feather microbiota covary with MHC, are consistent with the hypothesis that individual MHC genotype may shape the semiochemical-producing microbiota in birds.


Assuntos
Aves/metabolismo , Aves/microbiologia , Microbiota/fisiologia , Animais , Genes MHC da Classe II/genética , Genes MHC da Classe II/fisiologia , Genótipo , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/fisiologia , Microbiota/genética
18.
Allergol. immunopatol ; 46(3): 263-275, mayo-jun. 2018. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-172946

RESUMO

The MHC II deficiency is a rare autosomal recessive primary immunodeficiency syndrome with increased susceptibility to respiratory and gastrointestinal infections, failure to thrive and early mortality. This syndrome is caused by mutations in transcription regulators of the MHC II gene and results in development of blind lymphocytes due to the lack of indicatory MHC II molecules. Despite homogeneity of clinical manifestations of patients with MHC II deficiency, the genetic defects underlying this disease are heterogeneous. Herein, we report an Iranian patient with MHC II deficiency harbouring a novel mutation in RFXANK and novel misleading clinical features. He had ataxic gait and dysarthria from 30 months of age. Epidemiology, clinical and immunological features, therapeutic options and prognosis of patients with MHC II are reviewed in this paper (AU)


No disponible


Assuntos
Humanos , Masculino , Pré-Escolar , Antígenos de Histocompatibilidade Classe II/genética , Síndromes de Imunodeficiência/genética , Fatores de Transcrição/genética , Complexo Principal de Histocompatibilidade/genética , Mutação , Irã (Geográfico)
19.
BMC Evol Biol ; 18(1): 63, 2018 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-29747567

RESUMO

BACKGROUND: One explanation for the persistence of schizophrenia despite the reduced fertility of patients is that it is a by-product of recent human evolution. This hypothesis is supported by evidence suggesting that recently-evolved genomic regions in humans are involved in the genetic risk for schizophrenia. Using summary statistics from genome-wide association studies (GWAS) of schizophrenia and 11 other phenotypes, we tested for enrichment of association with GWAS traits in regions that have undergone methylation changes in the human lineage compared to Neanderthals and Denisovans, i.e. human-specific differentially methylated regions (DMRs). We used analytical tools that evaluate polygenic enrichment of a subset of genomic variants against all variants. RESULTS: Schizophrenia was the only trait in which DMR SNPs showed clear enrichment of association that passed the genome-wide significance threshold. The enrichment was not observed for Neanderthal or Denisovan DMRs. The enrichment seen in human DMRs is comparable to that for genomic regions tagged by Neanderthal Selective Sweep markers, and stronger than that for Human Accelerated Regions. The enrichment survives multiple testing performed through permutation (n = 10,000) and bootstrapping (n = 5000) in INRICH (p < 0.01). Some enrichment of association with height was observed at the gene level. CONCLUSIONS: Regions where DNA methylation modifications have changed during recent human evolution show enrichment of association with schizophrenia and possibly with height. Our study further supports the hypothesis that genetic variants conferring risk of schizophrenia co-occur in genomic regions that have changed as the human species evolved. Since methylation is an epigenetic mark, potentially mediated by environmental changes, our results also suggest that interaction with the environment might have contributed to that association.


Assuntos
Metilação de DNA/genética , Evolução Molecular , Esquizofrenia/genética , Adulto , Transtorno Bipolar/genética , Estatura/genética , Índice de Massa Corporal , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Complexo Principal de Histocompatibilidade/genética , Masculino , Anotação de Sequência Molecular , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
20.
Gigascience ; 7(5)2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29722814

RESUMO

Background: The Mikado pheasant (Syrmaticus mikado) is a nearly endangered species indigenous to high-altitude regions of Taiwan. This pheasant provides an opportunity to investigate evolutionary processes following geographic isolation. Currently, the genetic background and adaptive evolution of the Mikado pheasant remain unclear. Results: We present the draft genome of the Mikado pheasant, which consists of 1.04 Gb of DNA and 15,972 annotated protein-coding genes. The Mikado pheasant displays expansion and positive selection of genes related to features that contribute to its adaptive evolution, such as energy metabolism, oxygen transport, hemoglobin binding, radiation response, immune response, and DNA repair. To investigate the molecular evolution of the major histocompatibility complex (MHC) across several avian species, 39 putative genes spanning 227 kb on a contiguous region were annotated and manually curated. The MHC loci of the pheasant revealed a high level of synteny, several rapidly evolving genes, and inverse regions compared to the same loci in the chicken. The complete mitochondrial genome was also sequenced, assembled, and compared against four long-tailed pheasants. The results from molecular clock analysis suggest that ancestors of the Mikado pheasant migrated from the north to Taiwan about 3.47 million years ago. Conclusions: This study provides a valuable genomic resource for the Mikado pheasant, insights into its adaptation to high altitude, and the evolutionary history of the genus Syrmaticus, which could potentially be useful for future studies that investigate molecular evolution, genomics, ecology, and immunogenetics.


Assuntos
Adaptação Fisiológica/genética , Evolução Molecular , Galliformes/genética , Sequenciamento Completo do Genoma/métodos , Substituição de Aminoácidos/genética , Animais , Galinhas/genética , Mapeamento de Sequências Contíguas , DNA/genética , Feminino , Genoma , Hemoglobinas/genética , Complexo Principal de Histocompatibilidade/genética , Anotação de Sequência Molecular , Família Multigênica , Fases de Leitura Aberta/genética , Filogenia , Seleção Genética , Especificidade da Espécie
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