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HLA*PRG:LA – HLA typing from linearly projected graph alignments [article]

Alexander T Dilthey, Alexander J Mentzer, Raphael Carapito, Clare Cutland, Nezih Cereb, Shabir A. Madhi, Arang Rhie, Sergey Koren, Seiamak Bahram, Gil McVean, Adam M Phillippy
2018 bioRxiv   pre-print
AbstractSummary:HLA*PRG:LA implements a new graph alignment model for HLA type inference, based on the projection of linear alignments onto a variation graph. It enables accurate HLA type inference from whole-genome (99% accuracy) and whole-exome (93% accuracy) Illumina data; from long-read Oxford Nanopore and Pacific Biosciences data (98% accuracy for whole-genome and targeted data); and from genome assemblies. Computational requirements for a typical sample vary between 0.7 and 14 CPU hours
more » ... r sample.Availability and Implementation:HLA*PRG:LA is implemented in C++ and Perl and freely available from https://github.com/DiltheyLab/HLA-PRG-LA (GPL v3).Contact:alexander.dilthey@med.uni-duesseldorf.deSupplementary informationSupplementary data are available online.
doi:10.1101/453555 fatcat:juirt2e2qzgrhidqmeyonc6ty4

HLA Diversity in the 1000 Genomes Dataset

Pierre-Antoine Gourraud, Pouya Khankhanian, Nezih Cereb, Soo Young Yang, Michael Feolo, Martin Maiers, John D. Rioux, Stephen Hauser, Jorge Oksenberg, Gualtiero I. Colombo
2014 PLoS ONE  
The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation by sequencing at a level that should allow the genome-wide detection of most variants with frequencies as low as 1%. However, in the major histocompatibility complex (MHC), only the top 10 most frequent haplotypes are in the 1% frequency range whereas thousands of haplotypes are present at lower frequencies. Given the limitation of both the coverage and the read length of the sequences generated
more » ... y the 1000 Genomes Project, the highly variable positions that define HLA alleles may be difficult to identify. We used classical Sanger sequencing techniques to type the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 genes in the available 1000 Genomes samples and combined the results with the 103,310 variants in the MHC region genotyped by the 1000 Genomes Project. Using pairwise identity-by-descent distances between individuals and principal component analysis, we established the relationship between ancestry and genetic diversity in the MHC region. As expected, both the MHC variants and the HLA phenotype can identify the major ancestry lineage, informed mainly by the most frequent HLA haplotypes. To some extent, regions of the genome with similar genetic or similar recombination rate have similar properties. An MHC-centric analysis underlines departures between the ancestral background of the MHC and the genome-wide picture. Our analysis of linkage disequilibrium (LD) decay in these samples suggests that overestimation of pairwise LD occurs due to a limited sampling of the MHC diversity. This collection of HLA-specific MHC variants, available on the dbMHC portal, is a valuable resource for future analyses of the role of MHC in population and disease studies.
doi:10.1371/journal.pone.0097282 pmid:24988075 pmcid:PMC4079705 fatcat:uttom5jcgbaatltcpon72twoju

Cell cycle controlling the silencing and functioning of mammalian activators

Alan C. Mullen, Anne S. Hutchins, Alejandro V. Villarino, Hubert W. Lee, Frances A. High, Nezih Cereb, Soo Y. Yang, Xianxin Hua, Steven L. Reiner
2001 Current Biology  
Naïve CD4 ؉ helper T (T H ) cells respond to stimulation Results and discussion Heritable silencing of lineage-determining activators by terminally differentiating into two mature during the cell cycle classes, T H 1 cells, which express interferon ␥ (IFN-␥), Consistent with prior observations [2, 4] (see Figure 1a and T H 2 cells, which express interleukin 4 (IL-4) [1]. for diagram of experimental system), we found that the The transcriptional activators T-bet [2, 3] and Gata-3 transcriptional
more » ... activators T-bet and Gata-3 are reciprocally [4, 5] mediate commitment to the T H 1 and T H 2 fates, expressed in terminally differentiated T H 1 and T H 2 cells, respectively, including chromatin remodeling of respectively (Figure 1b). In newly differentiating cells, signature genes. The cytokine IL-12 fosters growth IL-12 and IL-4 can inhibit transcription of Gata-3 [7] and of committed T H 1 cells [3], while IL-4 fosters growth T-bet [3], respectively. Thus, we found that naïve cells of committed T H 2 cells [6]. IL-12 and IL-4 also play stimulated with mitogens (hereafter, simply "stimucritical roles in commitment by promoting lated") in the presence of recombinant (r) IL-12 plus antitranscriptional silencing of Gata-3 [7] and T-bet [3], IL-4 antibody (T H 1 conditions) exhibited repression of respectively. We now show that both T-bet and Gata-3, and cells stimulated in rIL-4 plus anti-IL-12 anti-Gata-3 are induced in a cell cycle-independent body (T H 2 conditions) exhibited repression of T-bet (Figmanner in bipotent progenitor cells. In contrast, both ure 1c). In contrast, cells stimulated in anti-IL-12 antibody lineage-restricted gene induction by the activator plus anti-IL-4 antibody expressed both activators (Figure proteins and heritable silencing of the transcription 1d). The negative regulation of activator expression by of each activator, the hallmarks of terminal IL-4 and IL-12 seems to play a causal role in cell fate, differentiation, are cell cycle dependent. We found since retroviral transduction of each activator under nonthat cells that cannot cycle remain uncommitted permissive conditions was sufficient to restore the prohiband bipotent in response to the most polarizing ited fate (Figure 1g) [2, 3, 7]. Furthermore, we found that signals for maturation. These results provide activator expression did not require entry into the cell mechanistic insight into a mammalian model of cycle (Figure 1d), and even appeared to be augmented terminal differentiation by illustrating that cell by G1 cell cycle arrest, using the drug mimosine. cycle-coupled epigenetic effects, as originally described in yeast [8, 9] , may represent an evolutionarily conserved strategy for organizing The preceding results suggest that, by default (in the signaling and cell fate. absence of IL-4 and IL-12), progenitor cells are bipotent, expressing both T-bet and Gata-3, prior to entry into S arrested in G1 using mimosine (Figure 1e,f) . We also § These two authors contributed equally to this work. tested if G1 arrest would prevent terminal T H commitment. Naïve cells were stimulated in prohibitive cyto-
doi:10.1016/s0960-9822(01)00533-4 pmid:11696328 fatcat:puiae5bjazfvtovwtwiwrzk7w4

HLA*LA – HLA typing from linearly projected graph alignments

Alexander T Dilthey, Alexander J Mentzer, Raphael Carapito, Clare Cutland, Nezih Cereb, Shabir A Madhi, Arang Rhie, Sergey Koren, Seiamak Bahram, Gil McVean, Adam M Phillippy, Bonnie Berger
2019 Bioinformatics  
HLA*LA implements a new graph alignment model for human leukocyte antigen (HLA) type inference, based on the projection of linear alignments onto a variation graph. It enables accurate HLA type inference from whole-genome (99% accuracy) and whole-exome (93% accuracy) Illumina data; from long-read Oxford Nanopore and Pacific Biosciences data (98% accuracy for whole-genome and targeted data) and from genome assemblies. Computational requirements for a typical sample vary between 0.7 and 14 CPU
more » ... rs per sample. HLA*LA is implemented in C++ and Perl and freely available as a bioconda package or from https://github.com/DiltheyLab/HLA-LA (GPL v3). Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btz235 pmid:30942877 pmcid:PMC6821427 fatcat:kw4v46i6mffc3hgdzqlskkrg2a

High-Accuracy HLA Type Inference from Whole-Genome Sequencing Data Using Population Reference Graphs

Alexander T. Dilthey, Pierre-Antoine Gourraud, Alexander J. Mentzer, Nezih Cereb, Zamin Iqbal, Gil McVean, Andre Franke
2016 PLoS Computational Biology  
Genetic variation at the Human Leucocyte Antigen (HLA) genes is associated with many autoimmune and infectious disease phenotypes, is an important element of the immunological distinction between self and non-self, and shapes immune epitope repertoires. Determining the allelic state of the HLA genes (HLA typing) as a by-product of standard wholegenome sequencing data would therefore be highly desirable and enable the immunogenetic characterization of samples in currently ongoing population
more » ... ncing projects. Extensive hyperpolymorphism and sequence similarity between the HLA genes, however, pose problems for accurate read mapping and make HLA type inference from wholegenome sequencing data a challenging problem. We describe how to address these challenges in a Population Reference Graph (PRG) framework. First, we construct a PRG for 46 (mostly HLA) genes and pseudogenes, their genomic context and their characterized sequence variants, integrating a database of over 10,000 known allele sequences. Second, we present a sequence-to-PRG paired-end read mapping algorithm that enables accurate read mapping for the HLA genes. Third, we infer the most likely pair of underlying alleles at G group resolution from the IMGT/HLA database at each locus, employing a simple likelihood framework. We show that HLA*PRG, our algorithm, outperforms existing methods by a wide margin. We evaluate HLA*PRG on six classical class I and class II HLA genes (HLA-A, -B, -C, -DQA1, -DQB1, -DRB1) and on a set of 14 samples (3 samples with 2 x 100bp, 11 samples with 2 x 250bp Illumina HiSeq data). Of 158 alleles tested, we correctly infer 157 alleles (99.4%). We also identify and re-type two erroneous alleles in the original validation data. We conclude that HLA*PRG for the first time achieves accuracies comparable to gold-standard reference methods from standard whole-genome sequencing data, though high computational demands (currently~30-250 CPU hours per sample) remain a significant challenge to practical application. PLOS Computational Biology |
doi:10.1371/journal.pcbi.1005151 pmid:27792722 pmcid:PMC5085092 fatcat:y5jdvexhr5hmzcnwv6x32eybum

Recombinant structures expand and contract inter and intragenic diversification at the KIR locus

Chul-Woo Pyo, Ruihan Wang, Quyen Vu, Nezih Cereb, Soo Young Yang, Fuh-Mei Duh, Steven Wolinsky, Maureen P Martin, Mary Carrington, Daniel E Geraghty
2013 BMC Genomics  
The human KIR genes are arranged in at least six major gene-content haplotypes, all of which are combinations of four centromeric and two telomeric motifs. Several less frequent or minor haplotypes also exist, including insertions, deletions, and hybridization of KIR genes derived from the major haplotypes. These haplotype structures and their concomitant linkage disequilibrium among KIR genes suggest that more meaningful correlative data from studies of KIR genetics and complex disease may be
more » ... chieved by measuring haplotypes of the KIR region in total. Results: Towards that end, we developed a KIR haplotyping method that reports unambiguous combinations of KIR gene-content haplotypes, including both phase and copy number for each KIR. A total of 37 different gene content haplotypes were detected from 4,512 individuals and new sequence data was derived from haplotypes where the detailed structure was not previously available. Conclusions: These new structures suggest a number of specific recombinant events during the course of KIR evolution, and add to an expanding diversity of potential new KIR haplotypes derived from gene duplication, deletion, and hybridization.
doi:10.1186/1471-2164-14-89 pmid:23394822 pmcid:PMC3606631 fatcat:khh7xldtmndnzikxnskkxqhp6q

Histoimmunogenetics Markup Language 1.0: Reporting Next Generation Sequencing-based HLA and KIR Genotyping [article]

Robert P Milius, Michael Heuer, Daniel Valiga, Kathryn J Doroschak, Caleb J. Kennedy, Yung-Tsi Bolon, Joel Schneider, Jane Pollack, Hwa Ran Kim, Nezih Cereb, Jill A Hollenbach, Steven J Mack (+1 others)
2015 bioRxiv   pre-print
We present an electronic format for exchanging data for HLA and KIR genotyping with extensions for next-generation sequencing (NGS). This format addresses NGS data exchange by refining the Histoimmunogenetics Markup Language (HML) to conform to the proposed Minimum Information for Reporting Immunogenomic NGS Genotyping (MIRING) reporting guidelines (miring.immunogenomics.org). Our refinements of HML include two major additions. First, NGS is supported by new XML structures to capture additional
more » ... NGS data and metadata required to produce a genotyping result, including analysis-dependent (dynamic) and method-dependent (static) components. A full genotype, consensus sequence, and the surrounding metadata are included directly, while the raw sequence reads and platform documentation are externally referenced. Second, genotype ambiguity is fully represented by integrating Genotype List Strings, which use a hierarchical set of delimiters to represent allele and genotype ambiguity in a complete and accurate fashion. HML also continues to enable the transmission of legacy methods (e.g. site-specific oligonucleotide, sequence-specific priming, and sequence based typing (SBT)), adding features such as allowing multiple group-specific sequencing primers, and fully leveraging techniques that combine multiple methods to obtain a single result, such as SBT integrated with NGS.
doi:10.1101/014951 fatcat:636yonxbqjb7vjfs6xb37fon4y

Regional HLA Differences in Poland and Their Effect on Stem Cell Donor Registry Planning

Alexander H. Schmidt, Ute V. Solloch, Julia Pingel, Jürgen Sauter, Irina Böhme, Nezih Cereb, Kinga Dubicka, Stephan Schumacher, Jacek Wachowiak, Gerhard Ehninger, Vassiliki A. Boussiotis
2013 PLoS ONE  
Regional HLA frequency differences are of potential relevance for the optimization of stem cell donor recruitment. We analyzed a very large sample (n = 123,749) of registered Polish stem cell donors. Donor figures by 1-digit postal code regions ranged from n = 5,243 (region 9) to n = 19,661 (region 8). Simulations based on region-specific haplotype frequencies showed that donor recruitment in regions 0, 2, 3 and 4 (mainly located in the south-eastern part of Poland) resulted in an above-average
more » ... increase of matching probabilities for Polish patients. Regions 1, 7, 8, 9 (mainly located in the northern part of Poland) showed an opposite behavior. However, HLA frequency differences between regions were generally small. A strong indication for regionally focused donor recruitment efforts can, therefore, not be derived from our analyses. Results of haplotype frequency estimations showed sample size effects even for sizes between n<5,000 and n<20,000. This observation deserves further attention as most published haplotype frequency estimations are based on much smaller samples. Citation: Schmidt AH, Solloch UV, Pingel J, Sauter J, Bö hme I, et al. (2013) Regional HLA Differences in Poland and Their Effect on Stem Cell Donor Registry Planning. PLoS ONE 8(9): e73835.
doi:10.1371/journal.pone.0073835 pmid:24069237 pmcid:PMC3772002 fatcat:sytgw7vqfzeztjouyppp6azb3e

Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles

James Robinson, Lisbeth A. Guethlein, Nezih Cereb, Soo Young Yang, Paul J. Norman, Steven G. E. Marsh, Peter Parham, Brendan J. Keating
2017 PLoS Genetics  
HLA class I glycoproteins contain the functional sites that bind peptide antigens and engage lymphocyte receptors. Recently, clinical application of sequence-based HLA typing has uncovered an unprecedented number of novel HLA class I alleles. Here we define the nature and extent of the variation in 3,489 HLA-A, 4,356 HLA-B and 3,111 HLA-C alleles. This analysis required development of suites of methods, having general applicability, for comparing and analyzing large numbers of homologous
more » ... es. At least three amino-acid substitutions are present at every position in the polymorphic α 1 and α 2 domains of HLA-A, -B and -C. A minority of positions have an incidence >1% for the 'second' most frequent nucleotide, comprising 70 positions in HLA-A, 85 in HLA-B and 54 in HLA-C. The majority of these positions have three or four alternative nucleotides. These positions were subject to positive selection and correspond to binding sites for peptides and receptors. Most alleles of HLA class I (>80%) are very rare, often identified in one person or family, and they differ by point mutation from older, more common alleles. These alleles with single nucleotide polymorphisms reflect the germ-line mutation rate. Their frequency predicts the human population harbors 8-9 million HLA class I variants. The common alleles of human populations comprise 42 core alleles, which represent all selected polymorphism, and recombinants that have assorted this polymorphism.
doi:10.1371/journal.pgen.1006862 pmid:28650991 pmcid:PMC5507469 fatcat:ozspuiacs5hsdmodrbsgmprg64

Histoimmunogenetics Markup Language 1.0: Reporting next generation sequencing-based HLA and KIR genotyping

Robert P. Milius, Michael Heuer, Daniel Valiga, Kathryn J. Doroschak, Caleb J. Kennedy, Yung-Tsi Bolon, Joel Schneider, Jane Pollack, Hwa Ran Kim, Nezih Cereb, Jill A. Hollenbach, Steven J. Mack (+1 others)
2015 Human Immunology  
We present an electronic format for exchanging data for HLA and KIR genotyping with extensions for next-generation sequencing (NGS). This format addresses NGS data exchange by refining the Histoimmunogenetics Markup Language (HML) to conform to the proposed Minimum Information for Reporting Immunogenomic NGS Genotyping (MIRING) reporting guidelines (miring.immunogenomics. org). Our refinements of HML include two major additions. First, NGS is supported by new XML structures to capture
more » ... NGS data and metadata required to produce a genotyping result, including analysisdependent (dynamic) and method-dependent (static) components. A full genotype, consensus sequence, and the surrounding metadata are included directly, while the raw sequence reads and platform documentation are externally referenced. Second, genotype ambiguity is fully represented by integrating Genotype List Strings, which use a hierarchical set of delimiters to represent allele and genotype ambiguity in a complete and accurate fashion. HML also continues to enable the transmission of legacy methods (e.g. site-specific oligonucleotide, sequence-specific priming, and Sequence Based Typing (SBT)), adding features such as allowing multiple group-specific sequencing primers, and fully leveraging techniques that combine multiple methods to obtain a single result, such as SBT integrated with NGS.
doi:10.1016/j.humimm.2015.08.001 pmid:26319908 pmcid:PMC4674307 fatcat:csy73ai3n5hchkhkwpoe7szrhm

Donor Killer Cell Immunoglobulin-Like Receptor Genotype Does Not Improve Graft-versus-Leukemia Responses in Chronic Lymphocytic Leukemia after Unrelated Donor Transplant: A Center for International Blood and Marrow Transplant Research Analysis

Veronika Bachanova, Daniel J. Weisdorf, Tao Wang, Steven G.E. Marsh, Nezih Cereb, Michael D. Haagenson, Stephen R. Spellman, Stephanie J. Lee, Lisbeth A. Guethlein, Peter Parham, Jeffrey S. Miller, Sarah A. Cooley
2018 Biology of Blood and Marrow Transplantation  
Allogeneic hematopoietic cell transplantation (alloHCT) remains the sole curative therapy for patients with chronic lymphocytic leukemia (CLL), leading to 40% to 45% long-term survival. The impact of donor killer immunoglobulin-like receptor (KIR) genotype on outcomes of unrelated donor (URD) alloHCT for CLL is unknown. We examined 573 adult URD CLL recipient pairs. KIR genotype (presence/absence) was determined for each donor, and comprehensive modeling of interactions with recipient HLA class
more » ... I loci (KIR ligands) was used to evaluate their effect on relapse and survival. Recipients had a median age of 56 years, and most were not in remission (65%). Both 8/8 HLA-matched (81%) or 7/8 HLA matched grafts (19%) were studied. Factors associated with improved overall survival (OS) were reduced-intensity conditioning (hazard ratio [HR] of death, .76) and good performance status (HR, .46), whereas alloHCT in nonremission (HR, 1.96) and mismatched donors (HR, 2.01) increased mortality. No models demonstrated a relationship between donor KIR genotype and transplant outcomes. Cox regression models comparing donors with A/A versus B/x KIR haplotypes and those with KIR gene content scores of 0 versus 1 versus ≥2 yielded similar rates of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), and chronic GVHD and the same progression-free survival and OS. Relapse risk was not different for grafts from donors with KIR3DL1 transplanted into HLA C1/1 versus C2 recipients. This large analysis failed to demonstrate an association between URD KIR genotype and transplant outcome for patients with CLL, and thus KIR genotyping should not be used as a donor selection criterion in this setting.
doi:10.1016/j.bbmt.2018.12.763 pmid:30594542 pmcid:PMC6511301 fatcat:netrcrmv7vfyzl22jvoarom3w4

Common, Intermediate and Well‐Documented HLA Alleles in World Populations: CIWD Version 3.0.0

Carolyn Katovich Hurley, Jane Kempenich, Kim Wadsworth, Jürgen Sauter, Jan A. Hofmann, Daniel Schefzyk, Alexander H. Schmidt, Pablo Galarza, Maria Belen Rodriguez Cardozo, Malgorzata Dudkiewicz, Lucie Houdova, Pavel Jindra (+26 others)
2020 HLA  
A catalog of common, intermediate and well-documented (CIWD) HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQB1 and -DPB1 alleles has been compiled from over 8 million individuals using data from 20 unrelated hematopoietic stem cell volunteer donor registries. Individuals are divided into seven geographic/ancestral/ethnic groups and data are summarized for each group and for the total population. P (two-field) and G group assignments are divided into one of four frequency categories: common (>1
more » ... 10,000), intermediate (>1 in 100,000), well-documented (>5 occurrences) or not-CIWD. Overall 26% of alleles in IPD-IMGT/HLA version 3.31.0 at P group resolution fall into the three CIWD categories. The two-field catalog includes 18% (n=545) common, 17% (n=513) intermediate, and 65% (n=1997) well-documented alleles. Full-field allele frequency data are provided but are limited in value by the variations in resolution used by the registries. A recommended CIWD list is based on the most frequent category in the total or any of the seven geographic/ancestral/ethnic groups. Data are also provided so users can compile a catalog specific to the population groups that they serve. Comparisons are made to three previous CWD reports representing more limited population groups. This catalog, CIWD version 3.0.0, is a step closer to the collection of global HLA frequencies and to a clearer view of HLA diversity in the human population as a whole. This article is protected by copyright. All rights reserved.
doi:10.1111/tan.13811 pmid:31970929 pmcid:PMC7317522 fatcat:34w3hay2p5bdhkrps4bh5tqgme

The killer immunoglobulin-like receptor KIR3DL1 in combination with HLA-Bw4 is protective against multiple sclerosis in African Americans

J A Hollenbach, M J Pando, S J Caillier, P-A Gourraud, J R Oksenberg
2016 Genes and Immunity  
We also thank Nezih Cereb and Soo Young Yang at Histogenetics Inc., and Hanne Harbo for useful discussion.  ... 
doi:10.1038/gene.2016.5 pmid:26866467 pmcid:PMC5105680 fatcat:cbpyqioaw5fvxfinhd6qzbkfga

Graph-Guided Assembly For Novel HLA Allele Discovery [article]

Heewook Lee, Carl Kingsford
2017 bioRxiv   pre-print
BMC Genomics, 16(Suppl 2):S7, 2015. 478 [12] Alexander T Dilthey, Pierre-Antoine Gourraud, Alexander J Mentzer, Nezih Cereb, Zamin Iqbal, and 479 Gil McVean.  ...  Nature, 526 Pierre-Antoine Gourraud, Pouya Khankhanian, Nezih Cereb, Soo Young Yang, Michael Feolo, Martin Maiers, John D Rioux, Stephen Hauser, and Jorge Oksenberg.  ... 
doi:10.1101/138826 fatcat:jsbe7nha4fh2jga2vofao2pvse

Dynamic expression of transcription factors T-bet and GATA-3 by regulatory T cells maintains immunotolerance

Fang Yu, Suveena Sharma, Julie Edwards, Lionel Feigenbaum, Jinfang Zhu
2014 Nature Immunology  
Nezih Cereb and Soo Young Yang at Histogenetics (Ossining, NY) and Dr.  ... 
doi:10.1038/ni.3053 pmid:25501630 pmcid:PMC4297509 fatcat:uwed4gczkjadffirzexqfcipy4
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