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Complete Haplotype Phasing of the MHC and KIR Loci with Targeted HaploSeq

ABSTRACT: Rapid advances in biochemical technologies have enabled several strategies for typing candidate HLA alleles, but linking them into a single MHC haplotype structure remains challenging. Here we have developed a multi-loci haplotype phasing technique and demonstrate its utility towards phasing of MHC and KIR loci in human samples. We accurately (~99%) reconstruct the complete haplotypes for over 90% of sequence variants spanning the 4-megabase region of these two loci. By haplotyping a majority of coding and non-coding alleles at the MHC and KIR loci in a single assay, this method has the potential to assist transplantation matching and facilitate investigation of the genetic basis of human immunity and disease. Complete haplotype phasing of 2 loci (MHC and KIR) in 1 human cell line.

ORGANISM(S): Homo sapiens

SUBMITTER: Anthony Schmitt

PROVIDER: E-GEOD-65726 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Complete haplotype phasing of the MHC and KIR loci with targeted HaploSeq.

Selvaraj Siddarth S Schmitt Anthony D AD Dixon Jesse R JR Ren Bing B

BMC genomics 20151105

<h4>Background</h4>The MHC and KIR loci are clinically relevant regions of the genome. Typing the sequence of these loci has a wide range of applications including organ transplantation, drug discovery, pharmacogenomics and furthering fundamental research in immune genetics. Rapid advances in biochemical and next-generation sequencing (NGS) technologies have enabled several strategies for precise genotyping and phasing of candidate HLA alleles. Nonetheless, as typing of candidate HLA alleles alo ...[more]

PMID: 26541200

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Complete Haplotype Phasing of the MHC and KIR Loci with Targeted HaploSeq

Project description:Rapid advances in biochemical technologies have enabled several strategies for typing candidate HLA alleles, but linking them into a single MHC haplotype structure remains challenging. Here we have developed a multi-loci haplotype phasing technique and demonstrate its utility towards phasing of MHC and KIR loci in human samples. We accurately (~99%) reconstruct the complete haplotypes for over 90% of sequence variants spanning the 4-megabase region of these two loci. By haplotyping a majority of coding and non-coding alleles at the MHC and KIR loci in a single assay, this method has the potential to assist transplantation matching and facilitate investigation of the genetic basis of human immunity and disease.

2016-02-01 | GSE65726 | GEO

Homo sapiens

Project description:Complete Haplotype Phasing of the MHC and KIR Loci with Targeted HaploSeq

| PRJNA274802 | ENA

MHC Transcriptomic landscape at haplotype-specific resolution

Project description:To explore the effect of human MHC haplotype on gene expression phenotype across the MHC, we examine the MHC transcriptomic landscape at the haplotype-specific resolution for three prominent MHC haplotypes (A2-B46-DR9, A33-B58-DR3 and A1-B8-DR3) derived from the RNA-sequencing of MHC-homozygous B-LCLs. We demonstrate that MHC-wide gene expression pattern is dictated by the underlying MHC haplotype and identify 37 differentially expressed genes among the haplotypes.

2017-07-07 | GSE83403 | GEO

Whole-genome Haplotype Reconstruction using Proximity-ligation and Shotgun Sequencing

Project description:Rapid advances in high-throughput DNA sequencing technologies are accelerating the pace of research into personalized medicine. While methods for variant discovery and genotyping from whole genome sequencing (WGS) datasets have been well established, linking variants together into a single haplotype remains a challenge. An understanding of complete haplotypes of an individual will help clarify the consequences of inheriting multiple alleles in combination, identify novel disease associations, and augment studies of gene regulation. Although numerous methods have been developed to reconstruct haplotypes from WGS data, chromosome-span haplotypes at high resolution have been difficult to obtain. Here we present a novel method to accurately reconstruct chromosome-span haplotypes from proximity-ligation and DNA shotgun sequencing. We demonstrate the utility of this approach in producing high-resolution chromosome-span haplotype phasing in mouse and human. While proximity-ligation based methods were originally designed to investigate spatial organization of the genome, our results lend support for their use as a general tool for haplotyping in the future. Hi-C experiments in two replicates of Human GM12878 Lymphoblastoid cells and two replicates of F123 mouse ES cells (4 total samples)

2013-11-03 | E-GEOD-48592 | biostudies-arrayexpress

The conformation of yeast chromosome III is mating type-dependent and controlled by the recombination enhancer

Project description:Yeast chromosome III contains the mating type loci that provide a paradigm for long-range interactions between distant loci. Yeast switch mating type by gene conversion between the MAT locus and either of two silent loci (HML or HMR) on opposite ends of the chromosome. This long-range process is mating type-specific so that MATa cells choose HML as template, while MATÎ± cells use HMR. The Recombination Enhancer (RE), located on the left arm regulates this process. One long-standing hypothesis is that switching is guided by mating type-specific, and possibly RE-dependent three-dimensional folding of chromosome III. Here we used Hi-C, 5C, and live cell imaging to characterize the conformation of chromosome III in both mating types in non-switching strains. We discovered a mating type-specific difference in the folding of the left arm: in MATa cells the left arm is located closely to the centromere-proximal portion of the chromosome as well as to MAT, whereas it is more extended away in MATÎ± cells. Deletion analysis showed that a 1 kb subregion within the RE, which is not necessary during switching, abolished mating type-dependent chromosome folding. In this mutant the conformation of chromosome III is the same in both mating types, but distinct from the wild type MATa or MATÎ± conformations, indicating that the RE induces conformational changes in both mating types. The RE is therefore a composite element with one subregion essential for selecting the appropriate donor during switching, and a separate region involved in modulating chromosome conformation prior to switching. This submission contain 2 biological replicates of Hi-C experiments done in MATa and MATalpha cells in Saccharamycese cerevisiae. It also contains 3 biological replicates of 13 5C experiments in various mutants in MATa and MATalpha cells.

2015-11-20 | E-GEOD-73890 | biostudies-arrayexpress

Custom MHC array analysis of lymphoblastoid cell lines

Project description:The human MHC is a paradigm for genomics, showing striking association with disease but functional variants remain largely unresolved. Using an original hybrid microarray (containing tiling and junction probes) for the MHC and accounting for known sequence diversity, we have drawn the first high-resolution, strand-specific transcriptional map of the MHC, defining differences in gene expression for three common haplotypes associated with autoimmune disease. In total, 6% of the MHC is transcribed with one transcript per 1.4kb, including previously unrecognized intergenic transcription. The distributions of differentially expressed probes and polymorphisms between haplotypes are significantly correlated, arguing for cis effects. Haplotype-specific transcription involved 96 differentially expressed genes, including ZFP57, which was validated in a cohort of healthy volunteers, while 526 exons show haplotypic differences. We also find splicing events are significantly more extensive in the MHC than in the rest of the genome. This study marks a new step in immunogenetics. The results files (.wig and .gff) contain tiling data for both the shared-path and the alternate paths (shared and haplotype-specific) , defining transcriptional activity across the entire MHC region in each sample. Lymphoblastoid cell lines carrying three common autoimmunity haplotypes (COX, PGF, QBL) were analysed in triplicate using the custom MHC array, under both unstimulated and stimulated (200nM PMA and 125nM ionomycin for 6 hours) conditions.

2011-05-23 | E-GEOD-22453 | biostudies-arrayexpress

Total RNA sequencing of KIR+ and KIR- NK cells from patients experiencing or not a Cytomegalovirus reactivation after haploidentical hematopoietic stem cell transplantation

Project description:AIM: To investigate the adaptive properties of NK cells, by comparing the expression profiles of FACS-sorted KIR+ (CD158b1b2j) and KIR- NK cells from patients experiencing or not a Cytomegalovirus (HCMV) reactivation after haploidentical hematopoietic stem cell transplantation (h-HSCT). RESULTS: Our flow cytometry data demonstrate that KIR+ NK cells are expanded in h-HSCT patients upon HCMV reactivation, thus suggesting that these cells could be important in controlling the viral infection and could be endowed with adaptive features. By comparing the expression profiles of KIR+ and KIR- NK cells from reacivated patients, we demonstrated a cytokine receptor unbalance, a prevalence of pathways associated to mitochondrial respiration and consequent ATP synthesis, a downregulation of genes involved in epigenetic reprogramming, all properties attributable adaptive NK cells. By comparing the molecular fingerprint of KIR+ NK cells between patients experiencing a HCMV reactivation and not reactivated patients, we observed in reactivated group an upregulation of INFG expression and in genes involved in Signaling receptor activity and MHC class II antigen presentation , thus strengthens the hypothesis that our KIR+ NK cells in reactevated h-HSCT patients are able to produce IFN-γ driving specific responses upon re-stimulation. However, the enrichment in PD-1 signaling, let us speculate that KIR+ NK cells from reactivated h-HSCT patients have impaired effector-functions.

2020-10-29 | GSE160362 | GEO

Affymetrix Human Exon 1.0 ST array analysis of lymphoblastoid cell lines

Project description:This experiment accompanies the main analysis using a custom MHC array to define the first high-resolution, strand-specific transcriptional map of the MHC, defining differences in gene expression for three common haplotypes associated with autoimmune disease. Unstimulated samples for each haplotype were hybridised to Affymetrix Human Exon 1.0 ST arrays as well the custom MHC array. Exon array data were used to assess the concordance of signal obtained from the two platforms and to investigate the extent of alternative splicing in the MHC, and how it compares to the rest of the genome. Lymphoblastoid cell lines carrying three common autoimmunity haplotypes (COX, PGF, QBL) were analysed in triplicate using the Affymetrix Human Exon 1.0 ST Array.

2011-05-23 | E-GEOD-22454 | biostudies-arrayexpress

Transcription profiling of human NKp80+ and NKp80- CD8+ CCR7- TCR alpha beta + T cells

Project description:We have performed whole genome expression arrays covering over 47000 transcripts comparing the transcriptional profile of NKp80+ to NKp80- CD8+ CCR7- alpha beta T cells. A highly similar global gene expression profile was observed between both memory phenotype T cell subsets. Interestingly, the majority of differentially expressed genes are immune-associated. NKp80+ cells contained markedly increased levels of transcripts encoding for MHC class I and II molecules and for numerous members of the KIR family. Also other NK-related transcripts were more abundantly expressed in the NKp80+ subset. With regards to cytokines, chemokines and their receptors, transcripts important for homeostasis and proliferation are expressed differently. Also transcripts encoding for adhesion molecules are present at different levels in both T cell subsets. Further cytotoxic effector molecules are expressed differently. Experiment Overall Design: We used CD4, CD14 depleted PBMCs pooled from six healthy donors. Following FACS sorting of NKp80+ CD8+ CCR7- alpha beta T cells and NKp80- cells, respectively, transcript levels of both subsets have been compared on human whole genome expression arrays.

2008-11-15 | E-GEOD-10178 | biostudies-arrayexpress

CRISPR-based targeted haplotype-resolved assembly of a megabase region [EPIC]

Project description:Constructing high-quality haplotype-resolved genome assemblies has substantially improved the ability to detect and characterize genetic variants. A targeted approach providing readily access to the rich information from haplotype-resolved genome assemblies will be appealing to groups of basic researchers and medical scientists focused on specific genomic regions. Here, using the 4.5 megabase, notoriously difficult-to-assemble major histocompatibility complex (MHC) region as an example, we demonstrated an approach to construct haplotype-resolved assembly of the targeted genomic region with the CRISPR-based enrichment. Compared to the results from haplotype-resolved genome assembly, our targeted approach achieved comparable completeness and accuracy with reduced computing complexity, sequencing cost, as well as the amount of starting materials. Moreover, using the targeted assembled personal MHC haplotypes as the reference both improves the quantification accuracy for sequencing data and enables allele-specific functional genomics analyses of the MHC region. Given its highly efficient use of resources, our approach can greatly facilitate population genetic studies of targeted regions, and may pave a new way to elucidate the molecular mechanisms in disease etiology.

2022-11-15 | GSE192501 | GEO

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