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1.
Johannes Pr?ll Martin Danzer Stephanie Stabentheiner Norbert Niklas Christa Hackl Katja Hofer Sabine Atzmüller Peter Hufnagl Christian Gülly Hanns Hauser Otto Krieger Christian Gabriel 《DNA research》2011,18(4):201-210
How cells coordinate the immune system activities is important for potentially life-saving organ or stem cell transplantations. Polymorphic immunoregulatory genes, many of them located in the human major histocompatibility complex, impact the process and assure the proper execution of tolerance-versus-activity mechanisms. In haematopoietic stem cell transplantation, on the basis of fully human leukocyte antigen (HLA)-matched donor–recipient pairs, adverse effects like graft versus leukaemia and graft versus host are observed and difficult to handle. So far, high-resolution HLA typing was performed with Sanger sequencing, but for methodological reasons information on additional immunocompetent major histocompatibility complex loci has not been revealed. Now, we have used microarray sequence capture and targeted enrichment combined with next generation pyrosequencing for 3.5 million base pair human major histocompatibility complex resequencing in a clinical transplant setting and describe 3025 variant single nucleotide polymorphisms, insertions and deletions among recipient and donor in a single sequencing experiment. Taken together, the presented data show that sequence capture and massively parallel pyrosequencing can be used as a new tool for risk assessment in the setting of allogeneic stem cell transplantation. 相似文献
2.
Maureen P. Martin Anita Harding Robert Chadwick Mel Kronick Michael Cullen Ling Lin Emmanuel Mignot M. Carrington 《Immunogenetics》1997,47(2):131-138
The human genome contains a large number of interspersed microsatellite repeats which exhibit a high degree of polymorphism
and are inherited in a Mendelian fashion, making them extremely useful genetic markers. Several microsatellites have been
described in the HLA region, but allele nomenclature, a set of broadly distributed controls, and typing methods have not been standardized, which
has resulted in discrepant microsatellite data between laboratories. In this report we present a detailed protocol for genotyping
microsatellites using a semi-automated fluorescence-based method. Twelve microsatellites within or near the major histocompatibility
complex (MHC) were typed in the 10th International Histocompatibility Workshop homozygous typing cell lines (HTCs) and alleles
were designated based on size. All loci were sequenced in two HTCs providing some information on the level of complexity of
the repeat sequence. A comparison of allele size obtained by genotyping versus that obtained by direct sequencing showed minor
discrepancies in some cases, but these were not unexpected given the technical differences in the methodologies. Fluorescence-based
typing of microsatellites in the MHC described herein is highly efficient, accurate, and reproducible, and will allow comparison
of results between laboratories.
Received: 10 May 1997 / Revised: 1 August 1997 相似文献
3.
Martin Thomsen Claus Lundegaard Søren Buus Ole Lund Morten Nielsen 《Immunogenetics》2013,65(9):655-665
The identification of peptides binding to major histocompatibility complexes (MHC) is a critical step in the understanding of T cell immune responses. The human MHC genomic region (HLA) is extremely polymorphic comprising several thousand alleles, many encoding a distinct molecule. The potentially unique specificities remain experimentally uncharacterized for the vast majority of HLA molecules. Likewise, for nonhuman species, only a minor fraction of the known MHC molecules have been characterized. Here, we describe a tool, MHCcluster, to functionally cluster MHC molecules based on their predicted binding specificity. The method has a flexible web interface that allows the user to include any MHC of interest in the analysis. The output consists of a static heat map and graphical tree-based visualizations of the functional relationship between MHC variants and a dynamic TreeViewer interface where both the functional relationship and the individual binding specificities of MHC molecules are visualized. We demonstrate that conventional sequence-based clustering will fail to identify the functional relationship between molecules, when applied to MHC system, and only through the use of the predicted binding specificity can a correct clustering be found. Clustering of prevalent HLA-A and HLA-B alleles using MHCcluster confirms the presence of 12 major specificity groups (supertypes) some however with highly divergent specificities. Importantly, some HLA molecules are shown not to fit any supertype classification. Also, we use MHCcluster to show that chimpanzee MHC class I molecules have a reduced functional diversity compared to that of HLA class I molecules. MHCcluster is available at www.cbs.dtu.dk/services/MHCcluster-2.0. 相似文献
4.
Sigrid N?ss Benedicte A. Lie Espen Melum Marita Olsson Johannes R. Hov Peter J. P. Croucher Jochen Hampe Erik Thorsby Annika Bergquist James A. Traherne Erik Schrumpf Kirsten Muri Boberg Stefan Schreiber Andre Franke Tom H. Karlsen 《PloS one》2014,9(12)
Background
Genetic variants within the major histocompatibility complex (MHC) represent the strongest genetic susceptibility factors for primary sclerosing cholangitis (PSC). Identifying the causal variants within this genetic complex represents a major challenge due to strong linkage disequilibrium and an overall high physical density of candidate variants. We aimed to refine the MHC association in a geographically restricted PSC patient panel.Methodology/Principal Findings
A total of 365 PSC cases and 368 healthy controls of Scandinavian ancestry were included in the study. We incorporated data from HLA typing (HLA-A, -B, -C, -DRB3, -DRB1, -DQB1) and single nucleotide polymorphisms across the MHC (n = 18,644; genotyped and imputed) alongside previously suggested PSC risk determinants in the MHC, i.e. amino acid variation of DRβ, a MICA microsatellite polymorphism and HLA-C and HLA-B according to their ligand properties for killer immunoglobulin-like receptors. Breakdowns of the association signal by unconditional and conditional logistic regression analyses demarcated multiple PSC associated MHC haplotypes, and for eight of these classical HLA class I and II alleles represented the strongest association. A novel independent risk locus was detected near NOTCH4 in the HLA class III region, tagged by rs116212904 (odds ratio [95% confidence interval] = 2.32 [1.80, 3.00], P = 1.35×10−11).Conclusions/Significance
Our study shows that classical HLA class I and II alleles, predominantly at HLA-B and HLA-DRB1, are the main risk factors for PSC in the MHC. In addition, the present assessments demonstrated for the first time an association near NOTCH4 in the HLA class III region. 相似文献5.
Specific HLA genotypes are known to be linked to either resistance or susceptibility to certain diseases or sensitivity to certain drugs. In addition, high accuracy HLA typing is crucial for organ and bone marrow transplantation. The most widespread high resolution HLA typing method used to date is Sanger sequencing based typing (SBT), and next generation sequencing (NGS) based HLA typing is just starting to be adopted as a higher throughput, lower cost alternative. By HLA typing the HapMap subset of the public 1000 Genomes paired Illumina data, we demonstrate that HLA-A, B and C typing is possible from exome sequencing samples with higher than 90% accuracy. The older 1000 Genomes whole genome sequencing read sets are less reliable and generally unsuitable for the purpose of HLA typing. We also propose using coverage % (the extent of exons covered) as a quality check (QC) measure to increase reliability. 相似文献
6.
Most studies on PRRSV evolution have been limited to a particular region of the viral genome. A thorough genome-wide understanding of the impact of different mechanisms on shaping PRRSV genetic diversity is still lacking. To this end, deep sequencing was used to obtain genomic sequences of a diverse set of 16 isolates from a region of Hong Kong with a complex PRRSV epidemiological record. Genome assemblies and phylogenetic typing indicated the co-circulation of strains of both genotypes (type 1and type 2) with varying Nsp2 deletion patterns and distinct evolutionary lineages (“High Fever”-like and local endemic type). Recombination analyses revealed genomic breakpoints in structural and non-structural regions of genomes of both genotypes with evidence of many recombination events originating from common ancestors. Additionally, the high fold of coverage per nucleotide allowed the characterization of minor variants arising from the quasispecies of each strain. Overall, 0.56–2.83% of sites were found to be polymorphic with respect to cognate consensus genomes. The distribution of minor variants across each genome was not uniform indicating the influence of selective forces. Proportion of variants capable of causing an amino acid change in their respective codons ranged between 25–67% with many predicted to be non-deleterious. Low frequency deletion variants were also detected providing one possible mechanism for their sudden emergence as cited in previous reports. 相似文献
7.
Celiac disease is a common autoimmune disease caused by sensitivity to the dietary protein gluten. Forty loci have been implicated in the disease. All disease loci have been characterized as low-penetrance, with the exception of the high-risk genotypes in the HLA-DQA1 and HLA-DQB1 genes, which are necessary but not sufficient to cause the disease. The very strong effects from the known HLA loci and the genetically complex nature of the major histocompatibility complex (MHC) have precluded a thorough investigation of the region. The purpose of this study was to test the hypothesis that additional celiac disease loci exist within the extended MHC (xMHC). A set of 1898 SNPs was analyzed for association across the 7.6 Mb xMHC region in 1668 confirmed celiac disease cases and 517 unaffected controls. Conditional recursive partitioning was used to create an informative indicator of the known HLA-DQA1 and HLA-DQB1 high-risk genotypes that was included in the association analysis to account for their effects. A linkage disequilibrium-based grouping procedure was utilized to estimate the number of independent celiac disease loci present in the xMHC after accounting for the known effects. There was significant statistical evidence for four new independent celiac disease loci within the classic MHC region. This study is the first comprehensive association analysis of the xMHC in celiac disease that specifically accounts for the known HLA disease genotypes and the genetic complexity of the region. 相似文献
8.
Sergey I. Nikolaev Christian Iseli Andrew J. Sharp Daniel Robyr Jacques Rougemont Corinne Gehrig Laurent Farinelli Stylianos E. Antonarakis 《PloS one》2009,4(8)
Detection of the rare polymorphisms and causative mutations of genetic diseases in a targeted genomic area has become a major goal in order to understand genomic and phenotypic variability. We have interrogated repeat-masked regions of 8.9 Mb on human chromosomes 21 (7.8 Mb) and 7 (1.1 Mb) from an individual from the International HapMap Project (NA12872). We have optimized a method of genomic selection for high throughput sequencing. Microarray-based selection and sequencing resulted in 260-fold enrichment, with 41% of reads mapping to the target region. 83% of SNPs in the targeted region had at least 4-fold sequence coverage and 54% at least 15-fold. When assaying HapMap SNPs in NA12872, our sequence genotypes are 91.3% concordant in regions with coverage≥4-fold, and 97.9% concordant in regions with coverage≥15-fold. About 81% of the SNPs recovered with both thresholds are listed in dbSNP. We observed that regions with low sequence coverage occur in close proximity to low-complexity DNA. Validation experiments using Sanger sequencing were performed for 46 SNPs with 15-20 fold coverage, with a confirmation rate of 96%, suggesting that DNA selection provides an accurate and cost-effective method for identifying rare genomic variants. 相似文献
9.
André Gomes-dos-Santos Elsa Froufe John M. Pfeiffer Nathan A. Johnson Chase H. Smith André M. Machado L. Filipe C. Castro Van Tu Do Akimasa Hattori Nicole Garrison Nathan V. Whelan Ivan N. Bolotov Ilya V. Vikhrev Alexander V. Kondakov Mohamed Ghamizi Vincent Prié Arthur E. Bogan Manuel Lopes Lima 《Molecular ecology resources》2023,23(6):1403-1422
The proliferation of genomic sequencing approaches has significantly impacted the field of phylogenetics. Target capture approaches provide a cost-effective, fast and easily applied strategy for phylogenetic inference of non-model organisms. However, several existing target capture processing pipelines are incapable of incorporating whole genome sequencing (WGS). Here, we develop a new pipeline for capture and de novo assembly of the targeted regions using whole genome re-sequencing reads. This new pipeline captured targeted loci accurately, and given its unbiased nature, can be used with any target capture probe set. Moreover, due to its low computational demand, this new pipeline may be ideal for users with limited resources and when high-coverage sequencing outputs are required. We demonstrate the utility of our approach by incorporating WGS data into the first comprehensive phylogenomic reconstruction of the freshwater mussel family Margaritiferidae. We also provide a catalogue of well-curated functional annotations of these previously uncharacterized freshwater mussel-specific target regions, representing a complementary tool for scrutinizing phylogenetic inferences while expanding future applications of the probe set. 相似文献
10.
SM Lank BA Golbach HM Creager RW Wiseman DB Keskin EL Reinherz V Brusic DH O'Connor 《BMC genomics》2012,13(1):378
ABSTRACT: BACKGROUND: High-resolution HLA genotyping is a critical diagnostic and research assay. Current methods rarely achieve unambiguous high-resolution typing without making population-specific frequency inferences due to a lack of locus coverage and difficulty in exon-phase matching. Achieving high-resolution typing is also becoming more challenging with traditional methods as the database of known HLA alleles increases. RESULTS: We designed a cDNA amplicon-based pyrosequencing method to capture 94% of the HLA class I open-reading-frame with only two amplicons per sample, and an analogous method for class II HLA genes, with a primary focus on sequencing the DRB loci. We present a novel Galaxy server-based analysis workflow for determining genotype. During assay validation, we performed two GS Junior sequencing runs to determine the accuracy of the HLA class I amplicons and DRB amplicon at different levels of multiplexing. When 116 amplicons were multiplexed, we unambiguously resolved 99%of class I alleles to four- or six-digit resolution, as well as 100% unambiguous DRB calls. The second experiment, with 271 multiplexed amplicons, missed some alleles, but generated high-resolution, concordant typing for 93% of class I alleles, and 96% for DRB1 alleles. In a third, preliminary experiment we attempted to sequence novel amplicons for other class II loci with mixed success. CONCLUSIONS: The presented assay is higher-throughput and higher-resolution than existing HLA genotyping methods, and suitable for allele discovery or large cohort sampling. The validated class I and DRB primers successfully generated unambiguously high-resolution genotypes, while further work is needed to validate additional class II genotyping amplicons. 相似文献
11.
Dr. Patrick Chardon Marek Kirszenbaum Philippa R. Cullen Claudine Geffrotin Charles Auffray Jack L. Strominger Daniel Cohen Marcel Vaiman 《Immunogenetics》1985,22(4):349-358
Four cDNA probes for the human major histocompatibility complex (MHC) were used to investigate the sheep MHC, in conjunction with serological typing for ovine lymphocyte antigen (OLA). Lymphocytes from a family (two parents and five offspring) of Romanov sheep were subjected to genomic DNA digestion by the restriction endonuclease Eco RI, followed by gel electrophoresis. A single Southern blot representing all seven individuals was then consecutively hybridized with the class I, alpha-DC, beta-DR, and C4 probes, which were originally designed to identify HLA class I, class II (DC and DR), and C4 products, respectively. Using each of the three class I/class II probes, several bands showing DNA polymorphism were detected. The segregation of these bands in the five offspring exactly paralleled the OLA haplotype segregation established by serological typing. A further eight individuals carrying haplotypes which were phenotypically identical to those in the above-mentioned family showed bands in the corresponding positions when tested with the same three probes. Using the C4 probe, no polymorphism was detected in these fifteen individuals.Abbreviations used in this paper MHC
major histocompatibility complex
- OLA
ovine lymphocyte antigen
- kbp
kilobase pair(s)
- MLR
mixed lymphocyte reaction
- RFLP
restriction fragment length polymorphism 相似文献
12.
Genetic rearrangement by recombination is one of the major driving forces for genome
evolution, and recombination is known to occur in non-random, discreet recombination sites
within the genome. Mapping of recombination sites has proved to be difficult,
particularly, in the human MHC region that is complicated by both population variation and
highly polymorphic HLA genes. To overcome these problems, HLA-typed individuals
from three representative populations: Asian, European and African were used to generate
phased HLA haplotypes. Extended haplotype homozygosity (EHH) plots constructed from the
phased haplotype data revealed discreet EHH drops corresponding to recombination events
and these signatures were observed to be different for each population. Surprisingly, the
majority of recombination sites detected are unique to each population, rather than being
common. Unique recombination sites account for 56.8% (21/37 of total sites) in
the Asian cohort, 50.0% (15/30 sites) in Europeans and 63.2% (24/38
sites) in Africans. Validation carried out at a known sperm typing recombination site of
45 kb (HLA-F-telomeric) showed that EHH was an efficient method to narrow
the recombination region to 826 bp, and this was further refined to 660 bp
by resequencing. This approach significantly enhanced mapping of the genomic architecture
within the human MHC, and will be useful in studies to identify disease risk genes. 相似文献
13.
Philip K Ehrenberg Aviva Geretz Karen M Baldwin Richard Apps Victoria R Polonis Merlin L Robb Jerome H Kim Nelson L Michael Rasmi Thomas 《BMC genomics》2014,15(1)
Background
Unambiguous human leukocyte antigen (HLA) typing is important in transplant matching and disease association studies. High-resolution HLA typing that is not restricted to the peptide-binding region can decrease HLA allele ambiguities. Cost and technology constraints have hampered high-throughput and efficient high resolution unambiguous HLA typing. We have developed a method for HLA genotyping that preserves the very high-resolution that can be obtained by next-generation sequencing (NGS) but also achieves substantially increased efficiency. Unambiguous HLA-A, B, C and DRB1 genotypes can be determined for 96 individuals in a single run of the Illumina MiSeq.Results
Long-range amplification of full-length HLA genes from four loci was performed in separate polymerase chain reactions (PCR) using primers and PCR conditions that were optimized to reduce co-amplification of other HLA loci. Amplicons from the four HLA loci of each individual were then pooled and subjected to enzymatic library generation. All four loci of an individual were then tagged with one unique index combination. This multi-locus individual tagging (MIT) method combined with NGS enabled the four loci of 96 individuals to be analyzed in a single 500 cycle sequencing paired-end run of the Illumina-MiSeq. The MIT-NGS method generated sequence reads from the four loci were then discriminated using commercially available NGS HLA typing software. Comparison of the MIT-NGS with Sanger sequence-based HLA typing methods showed that all the ambiguities and discordances between the two methods were due to the accuracy of the MIT-NGS method.Conclusions
The MIT-NGS method enabled accurate, robust and cost effective simultaneous analyses of four HLA loci per sample and produced 6 or 8-digit high-resolution unambiguous phased HLA typing data from 96 individuals in a single NGS run.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-864) contains supplementary material, which is available to authorized users. 相似文献14.
Michael Wittig Jarl A. Anmarkrud Jan C. K?ssens Simon Koch Michael Forster Eva Ellinghaus Johannes R. Hov Sascha Sauer Manfred Schimmler Malte Ziemann Siegfried G?rg Frank Jacob Tom H. Karlsen Andre Franke 《Nucleic acids research》2015,43(11):e70
The human leukocyte antigen (HLA) complex contains the most polymorphic genes in the human genome. The classical HLA class I and II genes define the specificity of adaptive immune responses. Genetic variation at the HLA genes is associated with susceptibility to autoimmune and infectious diseases and plays a major role in transplantation medicine and immunology. Currently, the HLA genes are characterized using Sanger- or next-generation sequencing (NGS) of a limited amplicon repertoire or labeled oligonucleotides for allele-specific sequences. High-quality NGS-based methods are in proprietary use and not publicly available. Here, we introduce the first highly automated open-kit/open-source HLA-typing method for NGS. The method employs in-solution targeted capturing of the classical class I (HLA-A, HLA-B, HLA-C) and class II HLA genes (HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, HLA-DPB1). The calling algorithm allows for highly confident allele-calling to three-field resolution (cDNA nucleotide variants). The method was validated on 357 commercially available DNA samples with known HLA alleles obtained by classical typing. Our results showed on average an accurate allele call rate of 0.99 in a fully automated manner, identifying also errors in the reference data. Finally, our method provides the flexibility to add further enrichment target regions. 相似文献
15.
Evangelos Bellos Vikrant Kumar Clarabelle Lin Jordi Maggi Zai Yang Phua Ching-Yu Cheng Chui Ming Gemmy Cheung Martin L. Hibberd Tien Yin Wong Lachlan J. M. Coin Sonia Davila 《Nucleic acids research》2014,42(20):e158
Targeted resequencing technologies have allowed for efficient and cost-effective detection of genomic variants in specific regions of interest. Although capture sequencing has been primarily used for investigating single nucleotide variants and indels, it has the potential to elucidate a broader spectrum of genetic variation, including copy number variants (CNVs). Various methods exist for detecting CNV in whole-genome and exome sequencing datasets. However, no algorithms have been specifically designed for contiguous target sequencing, despite its increasing importance in clinical and research applications. We have developed cnvCapSeq, a novel method for accurate and sensitive CNV discovery and genotyping in long-range targeted resequencing. cnvCapSeq was benchmarked using a simulated contiguous capture sequencing dataset comprising 21 genomic loci of various lengths. cnvCapSeq was shown to outperform the best existing exome CNV method by a wide margin both in terms of sensitivity (92.0 versus 48.3%) and specificity (99.8 versus 70.5%). We also applied cnvCapSeq to a real capture sequencing cohort comprising a contiguous 358 kb region that contains the Complement Factor H gene cluster. In this dataset, cnvCapSeq identified 41 samples with CNV, including two with duplications, with a genotyping accuracy of 99%, as ascertained by quantitative real-time PCR. 相似文献
16.
Jackie Lighten Cock van Oosterhout Ian G. Paterson Mark McMullan Paul Bentzen 《Molecular ecology resources》2014,14(4):753-767
We address the bioinformatic issue of accurately separating amplified genes of the major histocompatibility complex (MHC) from artefacts generated during high‐throughput sequencing workflows. We fit observed ultra‐deep sequencing depths (hundreds to thousands of sequences per amplicon) of allelic variants to expectations from genetic models of copy number variation (CNV). We provide a simple, accurate and repeatable method for genotyping multigene families, evaluating our method via analyses of 209 b of MHC class IIb exon 2 in guppies (Poecilia reticulata). Genotype repeatability for resequenced individuals (N = 49) was high (100%) within the same sequencing run. However, repeatability dropped to 83.7% between independent runs, either because of lower mean amplicon sequencing depth in the initial run or random PCR effects. This highlights the importance of fully independent replicates. Significant improvements in genotyping accuracy were made by greatly reducing type I genotyping error (i.e. accepting an artefact as a true allele), which may occur when using low‐depth allele validation thresholds used by previous methods. Only a small amount (4.9%) of type II error (i.e. rejecting a genuine allele as an artefact) was detected through fully independent sequencing runs. We observed 1–6 alleles per individual, and evidence of sharing of alleles across loci. Variation in the total number of MHC class II loci among individuals, both among and within populations was also observed, and some genotypes appeared to be partially hemizygous; total allelic dosage added up to an odd number of allelic copies. Collectively, observations provide evidence of MHC CNV and its complex basis in natural populations. 相似文献
17.
Rhesus macaques (Macaca mulatta) provide well-established models for studying human disease pathogenesis and vaccine development. When challenged with infectious agents, macaques exhibit individual differences in susceptibility. An important determinant of these differences is the complement of major histocompatability complex (MHC) class I sequences expressed by each animal. Although previous studies have reported strong associations between MHC expression and disease outcome, a rapid, cost-effective method for high-resolution MHC genotyping in macaques is lacking. In this study, we adapted a modified heteroduplex assay, reference strand-mediated conformational analysis (RSCA) to an ABI 3130xl capillary electrophoresis genetic analyzer for macaque MHC class I genotyping. For validation, we investigated the concordance of RSCA genotyping for 14 MHC class I sequences in 12 Chinese rhesus macaques whose genotypes were established through complementary DNA cloning and sequencing of MHC class I sequences. We observed a concordance greater than 98% between RSCA and the cloning and sequencing data. Furthermore, RSCA confirmed the presence of MHC haplotype sharing between three macaques as predicted previously by microsatellite analysis. RSCA genotyping of an additional 25 Chinese rhesus macaques demonstrated that the frequency of these 14 MHC class I sequences ranged from 5% to 32%, with the Mamu-A1*2601 sequence being most common in this cohort. Capillary RSCA genotyping has the potential to enable researchers to rapidly evaluate MHC class I genotypes in rhesus macaques and associate specific MHC sequences with disease susceptibility. 相似文献
18.
DNA variants, such as single nucleotide polymorphisms (SNPs) and copy number variants (CNVs), are unevenly distributed across the human genome. Currently, dbSNP contains more than 6 million human SNPs, and whole-genome genotyping arrays can assay more than 4 million of them simultaneously. In our study, we first questioned whether published genome-wide association studies (GWASs) assays cover all regions well in the genome. Using dbSNP build 135 data, we identified 50 genomic regions longer than 100 Kb that do not contain any common SNPs, i.e., those with minor allele frequency (MAF)≥1%. Secondly, because conserved regions are generally of functional importance, we tested genes in those large genomic regions without common SNPs. We found 97 genes and were enriched for reproduction function. In addition, we further filtered out regions with CNVs listed in the Database of Genomic Variants (DGV), segmental duplications from Human Genome Project and common variants identified by personal genome sequencing (UCSC). No region survived after those filtering. Our analysis suggests that, while there may not be many large genomic regions free of common variants, there are still some “holes” in the current human genomic map for common SNPs. Because GWAS only focused on common SNPs, interpretation of GWAS results should take this limitation into account. Particularly, two recent GWAS of fertility may be incomplete due to the map deficit. Additional SNP discovery efforts should pay close attention to these regions. 相似文献
19.
Progress towards developing vaccines that can stimulate an immune response against growing tumours has involved the identification
of the protein antigens associated with a given tumour type. Epitope mapping of tumour antigens for HLA class I- and class
II-restricted binding motifs followed by immunization with these peptides has induced protective immunity in murine models
against cancers expressing the antigen. MHC class I molecules presenting the appropriate peptides are necessary to provide
the specific signals for recognition and killing by cytotoxic T cells (CTL). The principle mechanism of tumour escape is the
loss, downregulation or alteration of HLA profiles that may render the target cell resistant to CTL lysis, even if the cell
expresses the appropriate tumour antigen. In human tumours HLA loss may be as high as 50%, inferring that a reduction in protein
levels might offer a survival advantage to the tumour cells. Alternatively, MHC loss may render tumour cells susceptible to
natural killer cell-mediated lysis because they are known to act as ligands for killer inhibitory receptors (KIRs). We review
the molecular features of MHC class I and class II antigens and discuss how surface MHC expression may be regulated upon cellular
transformation. In addition, selective loss of MHC molecules may alter target tumour cell susceptibility to lymphocyte killing.
The development of clinical immunotherapy will need to consider not only the expression of relevant CTL target MHC proteins,
but also HLA inhibitory to NK and T cells.
Received: 20 March 1999 / Accepted: 3 May 1999 相似文献
20.
Microsatellite typing of the rhesus macaque MHC region 总被引:16,自引:8,他引:8
Penedo MC Bontrop RE Heijmans CM Otting N Noort R Rouweler AJ de Groot N de Groot NG Ward T Doxiadis GG 《Immunogenetics》2005,57(3-4):198-209
To improve the results gained by serotyping rhesus macaque major histocompatibility complex (MHC) antigens, molecular typing techniques have been established for class I and II genes. Like the rhesus macaque Mamu-DRB loci, the Mamu-A and -B are not only polymorphic but also polygenic. As a consequence, sequence-based typing of these genes is time-consuming. Therefore, eight MHC-linked microsatellites, or short tandem repeats (STRs), were evaluated for their use in haplotype characterization. Polymorphism analyses in rhesus macaques of Indian and Chinese origin showed high STR allelic diversity in both populations but different patterns of allele frequency distribution between the groups. Pedigree data for class I and II loci and the eight STRs allowed us to determine extended MHC haplotypes in rhesus macaque breeding groups. STR sequencing and comparisons with the complete rhesus macaque MHC genomic map allowed the exact positioning of the markers. Strong linkage disequilibria were observed between Mamu-DR and -DQ loci and adjacent STRs. Microsatellite typing provides an efficient, robust, and quick method of genotyping and deriving MHC haplotypes for rhesus macaques regardless of their geographical origin. The incorporation of MHC-linked STRs into routine genetic tests will contribute to efforts to improve the genetic characterization of the rhesus macaque for biomedical research and can provide comparative information about the evolution of the MHC region. 相似文献