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Impact of genomic polymorphisms on the repertoire of human MHC class I-associated peptides

ABSTRACT: We developed a novel approach combining next generation sequencing, bioinformatics and mass spectrometry to assess the impact of non-MHC polymorphisms on the repertoire of MHC I-associated peptides (MIPs). We compared the genomic landscape of MIPs eluted from B lymphoblasts of two MHC-identical siblings and determined that MIPs mirror the genomic frequency of non-synonymous polymorphisms but they behave as recessive traits at the surface level. Moreover, we showed that 11.7% of the MIP coding exome is polymorphic at the population level. Our method provides fundamental insights into the relation between the genomic self and the immune self and accelerates the discovery of polymorphic MIPs (also known as minor histocompatibility antigens), which play a major role in allo-immune responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48918 | GEO | 2013/12/08

SECONDARY ACCESSION(S): PRJNA212311

REPOSITORIES: GEO

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Impact of genomic polymorphisms on the repertoire of human MHC class I-associated peptides

Project description:We developed a novel approach combining next generation sequencing, bioinformatics and mass spectrometry to assess the impact of non-MHC polymorphisms on the repertoire of MHC I-associated peptides (MIPs). We compared the genomic landscape of MIPs eluted from B lymphoblasts of two MHC-identical siblings and determined that MIPs mirror the genomic frequency of non-synonymous polymorphisms but they behave as recessive traits at the surface level. Moreover, we showed that 11.7% of the MIP coding exome is polymorphic at the population level. Our method provides fundamental insights into the relation between the genomic self and the immune self and accelerates the discovery of polymorphic MIPs (also known as minor histocompatibility antigens), which play a major role in allo-immune responses. RNA-seq of human B lymphoblasts derived from peripheral blood mononuclear cells from 2 HLA-identical female siblings.

2013-12-08 | E-GEOD-48918 | biostudies-arrayexpress

Comparison of the MHC I immunopeptidome repertoire of B-cell lymphoblasts using two isolation methods

Project description:Significant technological advances in both affinity chromatography and mass spectrometry have facilitated the identification of peptides associated with the major histocompatibility complex class I (MHC I) molecules, and enabled a greater understanding of the dynamic nature of the immunopeptidome of normal and neoplastic cells. While the isolation of MHC I-associated peptides (MIPs) typically used mild acid elution (MAE) or immunoprecipitation (IP), limited information currently exists regarding their respective analytical merits. Here, we present a comparison of these approaches for the isolation of two different B-cell lymphoblasts cell models, and report on the recovery, reproducibility, scalability and complementarity of identification from each method. Both approaches yielded reproducible datasets for peptide extracts obtained from 2 to 100 million cells, with 2016 to 5093 MIPs, respectively. The IP typically provides up to 6.4 fold increase in MIPs compared to the MAE. We extended the comprehensiveness of these immunopeptidome analyses using personalized genomic database of B-cell lymphoblasts, and discovered that 0.4 % of their respective MIP repertoire harbored non-synonymous single nucleotide variations (also known as minor histocompatibility antigens, MiHAs).

2018-03-09 | PXD007935 | Pride

MHC I-associated peptides preferentially derive from transcripts bearing miRNA response elements

Project description:MHC I-peptides (MIPs) play an essential role in normal homeostasis and diverse pathological conditions. MIPs derive mainly from defective ribosomal products (DRiPs), a subset of nascent proteins that fail to achieve a proper conformation and whose physical nature remains elusive. We used high-throughput proteomic and transcriptomic methods to unravel the structure and biogenesis of MIPs presented by HLA-A and -B molecules on human EBV-infected B lymphocytes from four subjects. We found that although HLA-different subjects present different MIPs derived from different proteins, these MIPs originate from proteins that are functionally interconnected and implicated in similar biological pathways. Secondly, the MIP repertoire of human B cells showed no bias toward conserved vs. polymorphic genomic sequences, derived preferentially from abundant transcripts and conveyed to the cell surface a cell type-specific signature. Finally, we discovered that MIPs derive preferentially from transcripts bearing miRNA response elements. Furthermore, while MIPs of HLA-disparate subjects are coded by different sets of transcripts, these transcripts are regulated by mostly similar miRNAs. Our data support an emerging model in which i) the generation of MIPs by a transcript depends on its abundance and DRiP rate, and ii) the DRiP rate is regulated to a large extent by miRNAs. We performed genome-wide miRNA expression profiling of B cells and non-lymphoid cells to confirm that miRNAs predicted to regulate transcripts source of MHC I-associated peptides are expressed in a cell-specific manner.

2012-03-25 | GSE35319 | GEO

Transcripts coding MHC I-associated peptides are enriched in microRNA-binding sites

2012-03-25 | E-GEOD-35319 | biostudies-arrayexpress

Systematic identification of balanced transposition polymorphisms in Saccharomyces cerevisiae

Project description:High-throughput techniques for detecting DNA polymorphisms generally do not identify changes in which the genomic position of a sequence, but not its copy number, varies among individuals. To explore such balanced structural polymorphisms, we used array-based Comparative Genomic Hybridization (aCGH) to conduct a genome-wide screen for single-copy genomic segments that occupy different genomic positions in the standard laboratory strain of Saccharomyces cerevisiae (S90) and a polymorphic wild isolate (Y101) through analysis of six tetrads from a cross of these two strains. Paired-end high-throughput sequencing of Y101 validated four of the predicted rearrangements. The transposed segments contained one to four annotated genes each, yet crosses between S90 and Y101 yielded mostly viable tetrads. The longest segment comprised 13.5 kb near the telomere of chromosome XV in the S288C reference strain and Southern blotting confirmed its predicted location on chromosome IX in Y101. Interestingly, inter-locus crossover events between copies of this segment occurred at a detectable rate. The presence of low-copy repetitive sequences at the junctions of this segment suggests that it may have arisen through ectopic recombination. Our methodology and findings provide a starting point for exploring the origins, phenotypic consequences, and evolutionary fate of this largely unexplored form of genomic polymorphism.

2009-05-07 | GSE14223 | GEO

Systematic identification of balanced transposition polymorphisms in Saccharomyces cerevisiae

2010-05-19 | E-GEOD-14223 | biostudies-arrayexpress

Development of the Restriction Site Tiling Analysis (RSTA) method: Accurate discovery and quantitative genotyping of genome-wide polymorphisms using nucleotide arrays

Project description:Here we developed a new high-throughput polymorphism detection and genotyping method based on identifying restriction cut site polymorphisms using a microarray platform. We compared the genomes of 20 individual urchins; 10 from the northern part of the species range (Boiler Bay, OR) and 10 from the southern part of the range (San Diego, CA). Genomic DNA from each individual was extracted, randomly sheared, then divided in half. Half was restriction digested and labeled with Cy3, half was treated as control and labeled with Cy5. Labeled DNA from a single individual was then competitively hybridized to the custom, species-specific array that had probe sequences designed to be centered on known restriction cut sites. Resulting log ratio data reflected the three possible genotypes in clusters when arrays from multiple individuals were examined at a given polymorphic locus.

2010-03-12 | E-GEOD-20857 | biostudies-arrayexpress

Murine Allogeneic CAR-T Cells Integrated Before or Early After Posttransplant Cyclophosphamide Exert Anti-Tumor Effects

Project description:The direct integration of chimeric-antigen-receptor (CAR) T cell with allogeneic hematopoietic cell transplantation (allo-HCT) carries the risk of graft-versus-host disease (GVHD) induction by allogeneic CAR-T cells. Based on our past experiments, it has been shown that post-transplantation cyclophosphamide (PTCy) prevents GVHD induction by other cell infusions after T-cell-replete MHC-haploidentical murine allo-HCT models. In this study, we investigated whether CAR-T cells, given in a similar manner in the same MHC-haploidentical murine allo-HCT model, could safely exert anti-tumor effects. We showed that anti-CD19 CAR-T cells administered early after (day +5 of transplant) or prior to (day 0 of transplant) PTCy for allo-HCT cleared leukemia without toxicity or GVHD exacerbation. Using next generation single-cell RNA sequencing approaches, we demonstrated that in comparison to CAR-T cells infused early after PTCy (day +5), CAR-T cells infused prior to PTCy (day 0) exhibited transcriptional changes consistent with increased CD4+ T-cell activation and CD8+ T-cell cytotoxicity.

2022-10-09 | GSE214788 | GEO

A Systematic Interrogation of MHC Class I Antigen Presentation Identifies Constitutive and Compensatory Protein Degradation Pathways

Project description:Peptides presented by MHC Class I were purified from B lymphoblasts or breast cancer cell lines following protein degradation pathway perturbations. Approximately 1E8 total cells were used for each experiment.

2023-08-03 | PXD032167 | Pride

Allelic imbalance sequencing reveals that single-nucleotide polymorphisms frequently alter microRNA-directed repression

Project description:Genetic changes that help explain the differences between two individuals might create or disrupt sites complementary to microRNAs (miRNAs), but the extent to which such polymorphic sites influence miRNA-mediated repression is unknown. Here, we describe a method to measure mRNA allelic imbalances associated with a regulatory site found in mRNA transcribed from one allele but not found in that transcribed from the other. Applying this method, called allelic imbalance sequencing, to sites for three miRNAs (miR-1, miR-133 and miR-122) provided quantitative measurements of repression in vivo without altering either the miRNAs or their targets. A substantial fraction of polymorphic sites mediated repression in tissues that expressed the cognate miRNA, and downregulation was correlated with site type and site context. Extrapolating these results to the other broadly conserved miRNAs suggests that when comparing two mouse strains (or two human individuals), polymorphic miRNA sites cause expression of many genes (often hundreds) to differ. There are four distinct samples (pool1-4), each of which is a pool of ~60 distinct PCR or RT-PCR products. The samples were loaded into different segments of the same pyrosequencing plate. Three sequencing runs (run1-3) were performed for each sample pool. Any amplicons of the four pools are for miR-1, miR-122, miR-133 or control sites. To control for allele-specific PCR bias, genomic DNA was also used as a template for generating amplicons.

2009-04-26 | E-GEOD-15675 | biostudies-arrayexpress

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