33 results on '"Roger Horton"'
Search Results
2. A Registry‐Led Initiative Supporting United Kingdom Transplant Centers in Selection, Requesting, and Handling of Cord Blood Units for Hematopoietic Stem Cell Transplantation
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Roger Horton, Laila Roberts, Rachael Cole, Daniel Gibson, Charlotte Green, Alexandra Ross, Nicole Stanley, Jessica Thew, Sharon Vivers, and Irina Evseeva
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Medicine (General) ,R5-920 ,Cytology ,QH573-671 - Published
- 2019
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3. Leukocytapheresis variables and transit time for allogeneic cryopreserved hpc: better safe than sorry
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Jesus Fernandez-Sojo, Roger Horton, Joan Cid, Carmen Azqueta, Ana Garcia-Buendia, Elena Valdivia, Lluis Martorell, Nuria Rubio-Lopez, Margarita Codinach, Gemma Aran, Julia Marsal, Alberto Mussetti, Rodrigo Martino, Cristina Diaz-de-Heredia, Christelle Ferra, David Valcarcel, Mónica Linares, Agueda Ancochea, Enric García-Rey, Nadia García-Muñoz, Laura Medina, Enric Carreras, Juliana Villa, Miquel Lozano, Daniel Gibson, and Sergio Querol
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Cryopreservation ,Transplantation ,Cell Survival ,Hematopoietic Stem Cell Transplantation ,COVID-19 ,Humans ,Antigens, CD34 ,Hematology ,Leukapheresis ,Hematopoietic Stem Cells ,Pandemics - Abstract
Cryopreservation was recommended to ensure continuity in allogeneic hematopoietic progenitor cells (HPC) transplantation during the COVID-19 pandemic. Several groups have shown no impact on clinical outcomes for patients who underwent HPC transplantation with cryopreserved products during the first months of this pandemic. However, concerns about quality control attributes after cryopreservation have been raised. We investigated, in 155 allogeneic peripheral blood cryopreserved HPC, leukocytapheresis characteristics influencing viable CD34(+) and CD3(+) cells, and CFU-GM recoveries after thawing. Collection characteristics such as volume, nucleated cells (NC)/mL and hematocrit correlated with viable CD34(+) and CD3(+) cells recoveries after thawing in univariate analysis but only CD3(+) cells remained statistically significant in multivariate analysis (r2 = 0.376; P = < 0.001). Additionally, transit time also showed correlation with viable CD34(+) (r2 = 0.186), CD3(+) (r2 = 0.376) and CFU-GM recoveries (r2 = 0.212) in multivariate analysis. Thus, diluting leukocytapheresis below 200 × 10(6) NC/mL, avoiding red cells contamination above 2%, cryopreserving below 250 × 10(6) NC/mL and minimizing transit time below 36 h, prevented poor viable CD34(+) and CD3(+) cells, and CFU-GM recoveries. In summary, optimizing leukocytapheresis practices and minimizing transportation time may better preserve the quality attributes of HPC when cryopreservation is indicated.
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- 2022
4. Ethnic diversity and cord blood banking: satisfying the unmet need
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Liam A. Wynn, Roger Horton, and Daniel Gibson
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Cancer Research ,Transplantation ,Immunology ,Graft Survival ,Graft vs Host Disease ,Cell Biology ,Fetal Blood ,Tissue Donors ,Oncology ,Ethnicity ,Immunology and Allergy ,Blood Banks ,Humans ,Cord Blood Stem Cell Transplantation ,Child ,Genetics (clinical) - Abstract
In this study, the authors sought to assess whether cord blood units (CBUs) collected from donors of non-European ethnic backgrounds are utilized for umbilical cord blood transplantation (UCBT) at a different rate than those of European ethnic backgrounds. The authors also examined potential methods of enriching these under-represented ethnic backgrounds in cord blood bank (CBB) inventories without increasing financial overheads and without compromising total inventory utilization or post-transplant outcomes.Data from N = 6506 searchable or shipped Anthony Nolan Cell Therapy Centre grafts were used in this study. Banked grafts were graded from A+ to D based on total nucleated cell and CD34+ cell content. Utilizations of each grade group were further stratified by graft ethnic background. The Mantel-Cox log-rank test was performed in conjunction with Kaplan-Meier survival analysis to compare utilization rates and post-transplant outcomes. For shipped grafts, levels of HLA matching at HLA-A, HLA-B and HLA-DR loci were also analyzed by graft ethnic background and grade using data from the Eurocord/EBMT registry.Overall utilization of non-European grafts did not significantly differ from that of European grafts (2.5% versus 2.2%, P = 0.23). However, significant differences were found when stratifying utilization rates by cell content. The probability of non-European D grade grafts being utilized was 3-fold higher than that of European D grade grafts (1.1% versus 0.4%, P = 0.03) and comparable to that of European C grade grafts (1.1% versus 0.9%, P = 0.90). No significant differences were found between D and C grade grafts in terms of overall survival (OS) (P = 0.12), in part due to a disproportionate utilization of D grade grafts for pediatric UCBT (74% versus 39%, age difference P0.001). Furthermore, non-European graft shipments were 4-fold less likely to be a 6/6 HLA match to their recipients relative to European graft shipments (7% versus 29%).The authors have identified a niche for CBUs of low cell content collected from donors of non-European ethnic backgrounds that has been overlooked by previous studies. Banking of these CBUs for pediatric UCBT instead of CBUs from European donors containing modestly higher cell content is an ethical approach to increasing the ethnic diversity of CBB inventory-and, consequently, the probability of non-European recipients finding a 6/6 HLA-matched graft-without compromising post-transplant OS or overall rate of inventory utilization.
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- 2022
5. Optimizing quality & compliance for cord blood-derived cells
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Roger Horton and Christopher Leonforte
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Compliance (physiology) ,medicine.medical_specialty ,business.industry ,Cord blood ,media_common.quotation_subject ,Emergency medicine ,medicine ,Quality (business) ,business ,General Economics, Econometrics and Finance ,media_common - Published
- 2019
6. Sequencing and comparative analysis of the gorilla MHC genomic sequence.
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Laurens G. Wilming, Elizabeth A. Hart, Penny C. Coggill, Roger Horton, James G. R. Gilbert, Chris Clee, Matt Jones 0003, Christine Lloyd, Sophie Palmer, Sarah Sims, Siobhan Whitehead, David Wiley, Stephan Beck 0002, and Jennifer L. Harrow
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- 2013
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7. Lysosomal lipid accumulation from oxidized low density lipoprotein is correlated with hypertrophy of the Golgi apparatus and trans-Golgi network
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W. Gray Jerome, Carol Cash, Richard Webber, Roger Horton, and Patricia G. Yancey
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atherosclerosis ,macrophage ,THP-1 ,pigeon ,acetylated LDL ,Biochemistry ,QD415-436 - Abstract
Lipid accumulation within macrophages is a major sequelae of atherosclerosis. Much of this lipid accumulation occurs within large, swollen lysosomes. We analyzed lipid accumulation in cultured macrophages using oxidized or acetylated low density lipoprotein (LDL) as the loading agent. Pigeon macrophages incubated for 48 h with mildly oxidized pigeon LDL (TBARS = 5–10 nmol/mg protein) showed significant increases in cellular cholesterol compared with untreated controls. Forty-eight percent of the increased cholesterol occurred as unesterified cholesterol. Treated cells had lipid-swollen lysosomes similar to those of atherosclerotic foam cells. The increase in lysosomal lipid was accompanied (correlation coefficient of 0.96) by increases in acid phosphatase staining cisternae of the Golgi and trans-Golgi network (TGN). THP-1 macrophages incubated with oxidized LDL showed similar lysosomal loading and Golgi/TGN hypertrophy. In contrast, macrophages incubated with acetylated LDL accumulated significant amounts of cholesterol but the increase occurred as cholesteryl ester (81% in pigeons) within cytoplasmic droplets and there was no associated increase in acid phosphatase-containing cisternae of Golgi or TGN. The correlation in both pigeon and THP-1 macrophages of oxidized LDL-induced lysosomal lipid accumulation and Golgi hypertrophy suggests a linkage of these two phenomena. This implicates intracellular membrane trafficking as a possible defect in foam cells of the atherosclerotic lesion.—Jerome, W. G., C. Cash, R. Webber, R. Horton, and P. G. Yancey. Lysosomal lipid accumulation from oxidizied low density lipoprotein is correlated with hypertrophy of the Golgi apparatus and trans-Golgi network. J. Lipid Res. 1998. 39: 1362–1371.
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- 1998
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8. Genetic analysis of completely sequenced disease-associated MHC haplotypes identifies shuffling of segments in recent human history.
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James A Traherne, Roger Horton, Anne N Roberts, Marcos M Miretti, Matthew E Hurles, C Andrew Stewart, Jennifer L Ashurst, Alexey M Atrazhev, Penny Coggill, Sophie Palmer, Jeff Almeida, Sarah Sims, Laurens G Wilming, Jane Rogers, Pieter J de Jong, Mary Carrington, John F Elliott, Stephen Sawcer, John A Todd, John Trowsdale, and Stephan Beck
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Genetics ,QH426-470 - Abstract
The major histocompatibility complex (MHC) is recognised as one of the most important genetic regions in relation to common human disease. Advancement in identification of MHC genes that confer susceptibility to disease requires greater knowledge of sequence variation across the complex. Highly duplicated and polymorphic regions of the human genome such as the MHC are, however, somewhat refractory to some whole-genome analysis methods. To address this issue, we are employing a bacterial artificial chromosome (BAC) cloning strategy to sequence entire MHC haplotypes from consanguineous cell lines as part of the MHC Haplotype Project. Here we present 4.25 Mb of the human haplotype QBL (HLA-A26-B18-Cw5-DR3-DQ2) and compare it with the MHC reference haplotype and with a second haplotype, COX (HLA-A1-B8-Cw7-DR3-DQ2), that shares the same HLA-DRB1, -DQA1, and -DQB1 alleles. We have defined the complete gene, splice variant, and sequence variation contents of all three haplotypes, comprising over 259 annotated loci and over 20,000 single nucleotide polymorphisms (SNPs). Certain coding sequences vary significantly between different haplotypes, making them candidates for functional and disease-association studies. Analysis of the two DR3 haplotypes allowed delineation of the shared sequence between two HLA class II-related haplotypes differing in disease associations and the identification of at least one of the sites that mediated the original recombination event. The levels of variation across the MHC were similar to those seen for other HLA-disparate haplotypes, except for a 158-kb segment that contained the HLA-DRB1, -DQA1, and -DQB1 genes and showed very limited polymorphism compatible with identity-by-descent and relatively recent common ancestry (
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- 2006
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9. MVE CryoShipper CT‐50 Tilt Validation for Cryogenic Cord Blood Shipments
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Christopher Leonforte, Roger Horton, Daniel Gibson, and Lee Berry
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lcsh:R5-920 ,lcsh:Cytology ,business.industry ,Cell Biology ,General Medicine ,General Biochemistry, Genetics and Molecular Biology ,Tilt (optics) ,Cord blood ,Technical Abstracts ,Medicine ,lcsh:QH573-671 ,General Agricultural and Biological Sciences ,lcsh:Medicine (General) ,Nuclear medicine ,business ,Developmental Biology - Published
- 2019
10. A Registry-Led Initiative Supporting United Kingdom Transplant Centers in Selection, Requesting, and Handling of Cord Blood Units for Hematopoietic Stem Cell Transplantation
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Jessica Thew, Roger Horton, Laila Roberts, Rachael Cole, Charlotte Green, Alexandra Ross, Daniel Gibson, Irina Evseeva, Sharon Vivers, and Nicole Stanley
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lcsh:R5-920 ,medicine.medical_specialty ,lcsh:Cytology ,business.industry ,medicine.medical_treatment ,Cell Biology ,General Medicine ,Hematopoietic stem cell transplantation ,Cord blood ,Technical Abstracts ,medicine ,lcsh:QH573-671 ,lcsh:Medicine (General) ,Intensive care medicine ,business ,Selection (genetic algorithm) ,Developmental Biology - Published
- 2019
11. The intron-enriched HERV-K(HML-10) family suppresses apoptosis, an indicator of malignant transformation
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Felix, Broecker, Roger, Horton, Jochen, Heinrich, Alexandra, Franz, Michal-Ruth, Schweiger, Hans, Lehrach, and Karin, Moelling
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Research ,Endogenous retrovirus ,DAP3 ,Death-associated protein 3 ,HERV-K(HML-10) ,Apoptosis ,HERV ,Cancer ,Gene regulation ,Genome evolution - Abstract
Background Human endogenous retroviruses (HERVs) constitute 8% of the human genome and contribute substantially to the transcriptome. HERVs have been shown to generate RNAs that modulate host gene expression. However, experimental evidence for an impact of these regulatory transcripts on the cellular phenotype has been lacking. Results We characterized the previously little described HERV-K(HML-10) endogenous retrovirus family on a genome-wide scale. HML-10 invaded the ancestral genome of Old World monkeys about 35 Million years ago and is enriched within introns of human genes when compared to other HERV families. We show that long terminal repeats (LTRs) of HML-10 exhibit variable promoter activity in human cancer cell lines. One identified HML-10 LTR-primed RNA was in opposite orientation to the pro-apoptotic Death-associated protein 3 (DAP3). In HeLa cells, experimental inactivation of HML-10 LTR-primed transcripts induced DAP3 expression levels, which led to apoptosis. Conclusions Its enrichment within introns suggests that HML-10 may have been evolutionary co-opted for gene regulation more than other HERV families. We demonstrated such a regulatory activity for an HML-10 RNA that suppressed DAP3-mediated apoptosis in HeLa cells. Since HML-10 RNA appears to be upregulated in various tumor cell lines and primary tumor samples, it may contribute to evasion of apoptosis in malignant cells. However, the overall weak expression of HML-10 transcripts described here raises the question whether our result described for HeLa represent a rare event in cancer. A possible function in other cells or tissues requires further investigation. Electronic supplementary material The online version of this article (doi:10.1186/s13100-016-0081-9) contains supplementary material, which is available to authorized users.
- Published
- 2016
12. How to Chair a Session
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Roger Horton
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Engineering ,Multimedia ,business.industry ,Session (computer science) ,computer.software_genre ,business ,computer - Published
- 2011
13. Flow cytometry assessment of apoptotic CD34+ cells by annexin V labeling may improve prediction of cord blood potency for engraftment
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Salmah N. Mahmood, J. Alejandro Madrigal, Daniel Gibson, Laura J. Fry, Robert C. Davy, Richard Duggleby, Roger Horton, Sergio Querol, and Susana Gómez
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education.field_of_study ,Pathology ,medicine.medical_specialty ,Cord ,medicine.diagnostic_test ,Immunology ,Population ,CD34 ,Hematology ,Biology ,Flow cytometry ,Transplantation ,Andrology ,Annexin ,Cord blood ,medicine ,Immunology and Allergy ,Potency ,education - Abstract
BACKGROUND: Nonviable CD34+ cells are commonly assessed by standard flow cytometry using the nuclear stain 7-aminoactinomycin D (7AAD). 7AAD, however, only detects necrotic and late apoptotic cells, not earlier apoptosis, which engraft poorly in animal models of cord blood (cord) transplantation. The standard method, therefore, may overestimate engraftment potency of cord units under certain conditions. STUDY DESIGN AND METHODS: To detect apoptotic events, costaining with 7AAD and annexin V (AnnV), in parallel with the quantitative, standard enumeration, was used. Cord units were assessed before and after cryopreservation using both staining methods and colony-forming units (CFU) to determine if graft potency can be predicted using a “functional flow cytometry” approach. RESULTS: Significant numbers of CD34+ AnnV+ events were found within the 7AAD-gated population. Nonapoptotic cell dose (CD34+ AnnV−) correlated well with CFUs in both a small-scale (n = 10) and a large-scale banking study (n = 107). Finally, following samples postthaw with time showed increasing numbers of apoptotic CD34+ cells and consequently the AnnV assessed dose was better at predicting the CFU compared with just the standard enumeration. CONCLUSION: Defining the apoptotic population of CD34+ cells improved the prediction of CFU, making this method a rapid test of potency for assessment of cord units for clinical use.
- Published
- 2011
14. Association of Smoking Behavior with an Odorant Receptor Allele Telomeric to the Human Major Histocompatibility Complex
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George Füst, Stephan Beck, Andreas Ziegler, Barbara Uchanska-Ziegler, Chack-Yung Yu, Pablo Sandro Carvalho Santos, Marcos Mateo Miretti, Roger Horton, Armin Volz, and Zoltán Prohászka
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Linkage disequilibrium ,HLA haplotype ,Otras Ciencias Biológicas ,Single-nucleotide polymorphism ,Human leukocyte antigen ,Biology ,Receptors, Odorant ,Major histocompatibility complex ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,White People ,Article ,HLA-B8 Antigen ,Ciencias Biológicas ,Cohort Studies ,Major Histocompatibility Complex ,HLA-DR3 Antigen ,Polymorphism (computer science) ,Humans ,Genotyping ,Alleles ,HLA-A1 Antigen ,Genetics (clinical) ,HLA Complex ,Genetics ,Hungary ,Smoking ,Haplotype ,Telomere ,Haplotypes ,biology.protein ,Female ,CIENCIAS NATURALES Y EXACTAS - Abstract
Smoking behavior has been associated in two independent European cohorts with the most common Caucasian human leukocyte antigen (HLA) haplotype (A1-B8-DR3). We aimed to test whether polymorphic members of the two odorant receptor (OR) clusters within the extended HLA complex might be responsible for the observed association, by genotyping a cohort of Hungarian women in which the mentioned association had been found. One hundred and eighty HLA haplotypes from Centre d'Etude du Polymorphisme Humain families were analyzed in silico to identify single-nucleotide polymorphisms (SNPs) within OR genes that are in linkage disequilibrium with the A1-B8-DR3 haplotype, as well as with two other haplotypes indirectly linked to smoking behavior. A nonsynonymous SNP within the OR12D3 gene (rs3749971T) was found to be linked to the A1-B8-DR3 haplotype. This polymorphism leads to a 97Thr→Ile exchange that affects a putative ligand binding region of the OR12D3 protein. Smoking was found to be associated in the Hungarian cohort with the rs3749971T allele (p=1.05×10-2), with higher significance than with A1-B8-DR3 (p=2.38×10-2). Our results link smoking to a distinct OR allele, and demonstrate that the rs3749971T polymorphism is associated with the HLA haplotype-dependent differential recognition of cigarette smoke components, at least among Caucasian women. © Copyright 2008, Mary Ann Liebert, Inc. 2008. Fil: Santos, Pablo Sandro Carvalho. Charité – Universitätsmedizin Berlin; Fil: Füst, George. Semmelweis Egyetem; Fil: Prohászka, Zoltán. Magyar Tudomanyos Akademia; . Semmelweis Egyetem; Fil: Volz, Armin. Charité – Universitätsmedizin Berlin; Fil: Horton, Roger. Wellcome Trust Sanger Institute; Fil: Miretti, Marcos Mateo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Biología Subtropical. Universidad Nacional de Misiones. Instituto de Biología Subtropical; Argentina. Wellcome Trust Sanger Institute; Fil: Yu, Chack-Yung. Ohio State University; Estados Unidos Fil: Beck, Stephan G.. Ucl Cancer Institute; Fil: Uchanska-Ziegler, Barbara. Charité – Universitätsmedizin Berlin; Fil: Ziegler, Andreas. Charité – Universitätsmedizin Berlin
- Published
- 2008
15. A second major histocompatibility complex susceptibility locus for multiple sclerosis
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Lisa F. Barcellos, Adrian J. Ivinson, David A. Hafler, An Goris, Amie Walton, Emily Walsh, Alastair Compston, Mark J. Daly, Stephen Sawcer, Stephan Beck, Todd Green, John D. Rioux, Maria Ban, Jorge R. Oksenberg, Chiara Fenoglio, Margaret A. Pericak-Vance, Jonathan L. Haines, Cara S Wolfish, Simon G. Gregory, Tai Wai Yeo, Craig J. Taylor, James A. Traherne, John Trowsdale, Stephen L. Hauser, Philip L. De Jager, Eric S. Lander, Reyna S. Goodman, Stacy J. Caillier, Susan Pobywajlo, and Roger Horton
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Adult ,Male ,Linkage disequilibrium ,Multiple Sclerosis ,Population ,Clinical Sciences ,Single-nucleotide polymorphism ,Locus (genetics) ,Human leukocyte antigen ,Biology ,Neurodegenerative ,Autoimmune Disease ,Polymorphism, Single Nucleotide ,Major Histocompatibility Complex ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,2.1 Biological and endogenous factors ,Humans ,Genetic Predisposition to Disease ,Allele ,Polymorphism ,Aetiology ,10. No inequality ,education ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,HLA-D Antigens ,Neurology & Neurosurgery ,Inflammatory and immune system ,Haplotype ,Human Genome ,Neurosciences ,Single Nucleotide ,Middle Aged ,Brain Disorders ,Neurology ,Allelic heterogeneity ,Original Article ,Female ,Neurology (clinical) ,030215 immunology ,Microsatellite Repeats - Abstract
It is well established that the major histocompatibility complex (MHC) on chromosome 6p21 contains at least one gene that influences susceptibility to multiple sclerosis.1–6 Although this association was first identified more than 30 years ago1 through the study of class I human leukocyte antigens (HLAs), it was quickly realized that this signal was predominantly, if not exclusively, the result of linkage disequilibrium (LD) with class II HLA genes, and that these exert the primary effect on susceptibility.7, 8 The complex nature of the MHC, especially its high gene content, extreme polymorphism, and extensive LD,9 has confounded efforts to resolve the nature of the MHC association in multiple sclerosis, although progress and useful clarifications have been made, especially in recent years. In virtually every population studied, multiple sclerosis is found to be associated with the DRB1*1501 allele.10 The only exceptions are those populations where this allele has a low frequency, and analysis is therefore underpowered; but even in these situations, DRB1*1501 is generally overrepresented in cases.11 The DRB1*1501 allele is carried on a particularly extensive haplotype,12 the most common DR15 haplotype found in white Europeans. As a result, many variants from flanking genes, even some located quite a distance from DRB1, have sufficient LD with DRB1*1501 that they invariably also show evidence for association with the disease in any population where association with DRB1*1501 can be demonstrated.11, 13–17 This extensive LD has made it difficult to establish which of the variants making up this haplotype is primarily responsible for the association. The distinction between DRB1*1501 and DQB1*0602 has been particularly taxing because the LD between these closely mapped genes is especially tight in those populations where the disease is frequent, that is, white Europeans and their migrant descendants. However, recent studies in the admixed African American population indicate the supremacy of the DRB1*1501 allele.18 In the presence of one susceptibility allele it is difficult to identify effects attributable to a second allele,19 especially if the second allele exerts a more modest effect or has a low frequency, or both. However, by analyzing populations where DR15 haplotypes are less common, and by using large cohorts, it has been possible to demonstrate that the DRB1*0301 allele also confers susceptibility to multiple sclerosis, thereby confirming allelic heterogeneity at the DRB1 locus.4, 6, 18, 20 Furthermore available evidence suggests that the susceptibility effects of the DRB1*1501 allele may be modulated by other DRB1 alleles.6, 20 The relation between the MHC and multiple sclerosis is further complicated by the accumulating evidence suggesting that MHC loci mapping outside DRB1 also influence susceptibility to the disease.11, 13–16 Work in animal models suggests that clustering of susceptibility loci is a common phenomenon in complex disease,21 and it therefore appears reasonable to expect that other genes from the MHC region may influence susceptibility to multiple sclerosis. The observation of positive logarithm of odds scores in the MHC region in linkage studies stratified for the effects of DRB1 supports the existence of secondary loci,22–24 although none of these data reaches a level providing statistical confidence. In considering these linkage data, it is important to remember that early linkage studies in multiple sclerosis25–27 were significantly underpowered,28 to the point that they could not even convincingly demonstrate evidence for linkage resulting from the effects of DRB1. Confirmation of linkage in this region has been established only in more recent studies involving many hundreds of families.23, 24, 29 Given the inherently limited resolution of linkage-based studies,28 the absence of statistically significant linkage in the MHC region after exclusion of primary effects attributable to DRB1 does not exclude the presence of secondary loci. Several authors have attempted to identify secondary loci using more powerful association-based methods. Two groups have typed dense microsatellite maps of the region and both found evidence for a secondary locus maximal in a region close to HLA-A: one group identifying the marker D6S1683 just telomeric of HLA-A,11 and the second group implicating a region including HLA-A extending from MOGCA to D6S265 marker.14 Follow-up studies in Norway also found evidence implicating the D6S265 marker.16 In another smaller study, a microsatellite marker close to HLA-C (marker C1_3_2) also showed evidence for an independent effect.15 In contrast, a systematic effort to screen the MHC and flanking regions using single nucleotide polymorphisms (SNPs) found no evidence for association beyond that attributable to DRB1*1501, although this study was limited by a high genotyping failure rate (40%) and, more importantly, a distribution of markers leaving regions close to the classical loci essentially unexplored.17 In all of these studies, statistical power has inevitably been reduced by the processes required to filter out the primary effect attributable to DRB1 and the large correction required for multiple testing. Unfortunately, none of the published studies has used sufficient samples to compensate for these statistical penalties, and thus none is able to provide unequivocal evidence supporting any particular secondary locus.
- Published
- 2007
16. DNA methylation profiling of human chromosomes 6, 20 and 22
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Rene Cortese, John Attwood, Jane Rogers, Christoph Koenig, Kevin L. Howe, Roger Horton, Florian Eckhardt, Joern Lewin, David K. Jackson, Roger Pettett, David Niblett, Thomas A. Down, Robert L. Davies, Carolina Haefliger, Stephan Beck, Jan Kunde, Kurt Berlin, Tony West, Matthias Burger, Stefanie Seemann, Alex Olek, Thomas J. Otto, Christian Thompson, Vardhman K. Rakyan, Tony Cox, John Burton, and Jennifer Liddle
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Adult ,Male ,Transcription, Genetic ,Chromosomes, Human, Pair 22 ,Bisulfite sequencing ,Chromosomes, Human, Pair 20 ,Biology ,Article ,Epigenesis, Genetic ,Evolution, Molecular ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Epigenetics of physical exercise ,Species Specificity ,Genetics ,Animals ,Humans ,Methylated DNA immunoprecipitation ,Promoter Regions, Genetic ,RNA-Directed DNA Methylation ,Aged ,030304 developmental biology ,Epigenomics ,Sex Characteristics ,0303 health sciences ,Age Factors ,DNA Methylation ,Middle Aged ,Differentially methylated regions ,Organ Specificity ,030220 oncology & carcinogenesis ,DNA methylation ,Illumina Methylation Assay ,Chromosomes, Human, Pair 6 ,CpG Islands ,Female ,5' Untranslated Regions - Abstract
DNA methylation constitutes the most stable type of epigenetic modifications modulating the transcriptional plasticity of mammalian genomes. Using bisulfite DNA sequencing, we report high-resolution methylation reference profiles of human chromosomes 6, 20 and 22, providing a resource of about 1.9 million CpG methylation values derived from 12 different tissues. Analysis of 6 annotation categories, revealed evolutionary conserved regions to be the predominant sites for differential DNA methylation and a core region surrounding the transcriptional start site as informative surrogate for promoter methylation. We find 17% of the 873 analyzed genes differentially methylated in their 5′-untranslated regions (5′-UTR) and about one third of the differentially methylated 5′-UTRs to be inversely correlated with transcription. While our study was controlled for factors reported to affect DNA methylation such as sex and age, we did not find any significant attributable effects. Our data suggest DNA methylation to be ontogenetically more stable than previously thought.
- Published
- 2006
17. Gene map of the extended human MHC
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Stephan Beck, Vikki Rand, Laurens G. Wilming, H Wain, Roger Horton, Andreas Ziegler, Ruth C. Lovering, C. Conover Talbot, Michael J. Lush, Mathew W. Wright, Elspeth A. Bruford, Varsha K. Khodiyar, John Trowsdale, and Sue Povey
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chemical and pharmacologic phenomena ,Computational biology ,Biology ,Major histocompatibility complex ,Genome ,Autoimmune Diseases ,Major Histocompatibility Complex ,RNA, Transfer ,Gene mapping ,Genetics ,Humans ,Molecular Biology ,Gene ,Genetics (clinical) ,Comparative genomics ,Polymorphism, Genetic ,Gene map ,Genome, Human ,Immunity ,Chromosome Mapping ,Multigene Family ,Hereditary hemochromatosis ,biology.protein ,Chromosomes, Human, Pair 6 ,Human genome - Abstract
The major histocompatibility complex (MHC) is the most important region in the vertebrate genome with respect to infection and autoimmunity, and is crucial in adaptive and innate immunity. Decades of biomedical research have revealed many MHC genes that are duplicated, polymorphic and associated with more diseases than any other region of the human genome. The recent completion of several large-scale studies offers the opportunity to assimilate the latest data into an integrated gene map of the extended human MHC. Here, we present this map and review its content in relation to paralogy, polymorphism, immune function and disease.
- Published
- 2004
18. DNA sequence and analysis of human chromosome 9
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L K Colman, S S White, R Heathcott, K D Ambrose, C Griffiths, C L Bagguley, Christine Lloyd, Jim Davies, James G. R. Gilbert, Richard Durbin, Carol Scott, Rebekah Hall, Graeme Bethel, Adrienne Hunt, C Carder, A Tromans, G Tamlyn-Hall, Jane Rogers, J Garnett, L M Faulkner, J C Chapman, Benjamin Phillimore, M Grant, A Wild, Christopher J. Gillson, S Hammond, A K Babbage, Sophie Palmer, C. D. Skuce, V. Cobley, Margaret A. Leversha, Robert W. Plumb, J. M. Wallis, Lucy Matthews, Sarah E. Smith, Mark Griffiths, Karen Oliver, J Tester, Christopher M. Johnson, M Earthrowl, K L Novik, Graeme T Clark, Kirsten McLay, Michelle Smith, R M Younger, T Nickerson, K F Barlow, A. King, S. M. Clegg, Mark T. Ross, K M Culley, R. E. Collier, K Bates, Nigel P. Carter, Sarah E. Hunt, Matthew Humphries, Kevin L. Howe, R Ainscough, Matthew Jones, J P Almeida, Laurens G. Wilming, R Patel, C M Clee, A M Kimberley, David Niblett, Gareth Maslen, Jane E. Loveland, Pawandeep Dhami, J C Wyatt, Philip Howden, Harminder Sehra, N Corby, Stephan Beck, Andrew J. Mungall, Cordelia Langford, Mohammed J. R. Ghori, O. T. McCann, Sarah Milne, Ian Dunham, C A Edwards, J Y Brown, Matthew Dunn, A J Theaker, Darren Grafham, Alan Tracey, S. Searle, Anne Parker, John Burton, Amanda McMurray, H Whittaker, R I S Ashwell, M Mashreghi-Mohammadi, P Garner, A J Brown, O. Beasley, Michele Clamp, A Thorpe, Daniel Leongamornlert, Alan Coulson, Y. Ramsey, Paul Wray, N Sycamore, Helen Beasley, M. J F Moore, Dave Willey, K M Porter, S Y Clark, A I Peck, Tim Hubbard, D. M. Lloyd, David R. Bentley, A Joy, Joanna Harley, L Spraggon, J Lovell, Anthony P. West, E. Hart, Adam Frankish, M. Kay, Catherine M. Rice, Matthew D. Francis, S A Ranby, Duncan W. Thomas, Elizabeth J. Huckle, T. E. Wilmer, Sean Humphray, L Young, W Burrill, David Beare, B Tubby, S Lawlor, E Sheridan, Susan M. Gribble, J Frankland, A E Ellington, Charles A. Steward, K S Halls, Roger Horton, Melanie M. Wall, James C. Mullikin, D C Burford, S. Holmes, L M Gilby, T D Andrews, Christine P. Bird, Gareth R. Howell, Stephen Keenan, Joanna Collins, S. Squares, Ruby Banerjee, Jennifer L. Ashurst, Sarah Sims, S Bray-Allen, Lisa French, G. J. Coville, Paul Heath, A. V. Pearce, S. Whitehead, Sancha Martin, J Bailey, J Brook, Darren Barker, Rebecca Glithero, Jonathan Wood, E K Overton-Larty, K A Evans, S. Blakey, John Sulston, Gavin K. Laird, Sam Phillips, and S J McLaren
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Male ,Genetics, Medical ,Biology ,Article ,Euchromatin ,Evolution, Molecular ,Chromosome 15 ,Chromosome 16 ,Genes, Duplicate ,Gene Duplication ,Heterochromatin ,Neoplasms ,Chromosome 19 ,Humans ,Chromosome 13 ,Genetics ,Base Composition ,Multidisciplinary ,Genetic Variation ,Neurodegenerative Diseases ,Genomics ,Sequence Analysis, DNA ,Sex Determination Processes ,Physical Chromosome Mapping ,Chromosome 17 (human) ,Genes ,Chromosome 3 ,Female ,Chromosomes, Human, Pair 9 ,Chromosome 21 ,Chromosome 22 ,Pseudogenes - Abstract
Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6–8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.
- Published
- 2004
19. Characterization of Clustered MHC-Linked Olfactory Receptor Genes in Human and Mouse
- Author
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Stephan Beck, Claire Amadou, Sarah Milne, John Trowsdale, Anke Ehlers, Andreas Ziegler, Roger Horton, Andrew J. Mungall, Armin Volz, Kirsten Fischer Lindahl, Simon Forbes, Ruth Younger, and Graeme Bethel
- Subjects
Genetic Linkage ,Pseudogene ,Molecular Sequence Data ,Olfaction ,Receptors, Odorant ,Major histocompatibility complex ,Major Histocompatibility Complex ,Mice ,Gene Order ,Genetics ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Gene ,Phylogeny ,Genetics (clinical) ,Base Composition ,Base Sequence ,biology ,Haplotype ,Chromosome Mapping ,Sequence Analysis, DNA ,biology.organism_classification ,medicine.anatomical_structure ,Multigene Family ,biology.protein ,Human genome ,Drosophila melanogaster ,Olfactory epithelium ,Reports - Abstract
Olfactory receptor (OR) loci frequently cluster and are present on most human chromosomes. They are members of the seven transmembrane receptor (7-TM) superfamily and, as such, are part of one of the largest mammalian multigene families, with an estimated copy number of up to 1000 ORs per haploid genome. As their name implies, ORs are known to be involved in the perception of odors and possibly also in other, nonolfaction-related, functions. Here, we report the characterization of ORs that are part of the MHC-linked OR clusters in human and mouse (partial sequence only). These clusters are of particular interest because of their possible involvement in olfaction-driven mate selection. In total, we describe 50 novel OR loci (36 human, 14 murine), making the human MHC-linked cluster the largest sequenced OR cluster in any organism so far. Comparative and phylogenetic analyses confirm the cluster to be MHC-linked but divergent in both species and allow the identification of at least one ortholog that will be useful for future regulatory and functional studies. Quantitative feature analysis shows clear evidence of duplications of blocks of OR genes and reveals the entire cluster to have a genomic environment that is very different from its neighboring regions. Based on in silico transcript analysis, we also present evidence of extensive long-distance splicing in the 5′-untranslated regions and, for the first time, of alternative splicing within the single coding exon of ORs. Taken together with our previous finding that ORs are also polymorphic, the presented data indicate that the expression, function, and evolution of these interesting genes might be more complex than previously thought.[The sequence data described in this paper have been submitted to the EMBL nucleotide data library under accession nos.Z84475, Z98744, Z98745, AL021807, AL021808, AL022723, AL022727,AL031893, AL035402, AL035542, AL050328, AL050339, AL078630, AL096770,AL121944, AL133160, and AL133267.]
- Published
- 2001
20. The LRC haplotype project: a resource for killer immunoglobulin-like receptor-linked association studies
- Author
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Jennifer G. Sambrook, Rosemary Ward, Jen Harrow, Sarah Sims, Sophie Palmer, Jane Rogers, James A. Traherne, Harminder Sehra, Stephan Beck, Penny Coggill, Mary Carrington, John Trowsdale, Roger Horton, and Marcos Mateo Miretti
- Subjects
Genetic Research ,Receptor complex ,Immunology ,Human leukocyte antigen ,Major histocompatibility complex ,Biochemistry ,Article ,Receptors, KIR ,Databases, Genetic ,Genetic variation ,Genetics ,Humans ,Immunology and Allergy ,Receptors, Immunologic ,Gene ,Genetic association ,Internet ,biology ,Haplotype ,Chromosome Mapping ,Genetic Variation ,General Medicine ,Haplotypes ,biology.protein ,Epistasis - Abstract
There is increasing evidence for epistatic interactions between gene products (e.g. KIR) encoded within the Leukocyte Receptor Complex (LRC) with those (e.g. HLA) of the Major Histocompatibility Complex (MHC), resulting in susceptibility to disease. Identification of such associations at the DNA level requires comprehensive knowledge of the genetic variation and haplotype structure of the underlying loci. The LRC haplotype project aims to provide this knowledge by sequencing common LRC haplotypes.
- Published
- 2006
21. Variation analysis and gene annotation of eight MHC haplotypes: The MHC Haplotype Project
- Author
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E. Hart, J P Almeida, John F. Elliott, David K. Jackson, John A. Todd, Stephen Sawcer, Penny Coggill, Anne N. Roberts, Steve Trevanion, C. Andrew Stewart, John Trowsdale, Sarah Sims, Sophie Palmer, Pieter J. de Jong, Simon A. Forbes, James A. Traherne, Laurens G. Wilming, Kevin L. Howe, Karen Halls, Jennifer Harrow, Richard Gibson, Marcos Mateo Miretti, Stephan Beck, James G. R. Gilbert, Jane Rogers, Richard J.N. Allcock, and Roger Horton
- Subjects
dbSNP ,Population genetics ,Immunology ,Major histocompatibility complex ,Genetic predisposition to disease ,HAPLOTYPE ,Human leukocyte antigen ,GENETIC PREDISPOSITION TO DISEASE ,Biology ,Ciencias Biológicas ,03 medical and health sciences ,Genética y Herencia ,0302 clinical medicine ,HLA Antigens ,Terminology as Topic ,POPULATION GENETICS ,Databases, Genetic ,Genetics ,Haplotype ,Humans ,Polymorphism ,030304 developmental biology ,0303 health sciences ,Original Paper ,Genome, Human ,Computational Biology ,Genetic Variation ,Gene Annotation ,RETROELEMENT ,POLYMORPHISM ,3. Good health ,MAJOR HISTOCOMPATIBILITY COMPLEX ,Haplotypes ,biology.protein ,Human genome ,Haplotype estimation ,Retroelement ,CIENCIAS NATURALES Y EXACTAS ,030215 immunology ,Reference genome - Abstract
The human major histocompatibility complex (MHC) is contained within about 4 Mb on the short arm of chromosome 6 and is recognised as the most variable region in the human genome. The primary aim of the MHC Haplotype Project was to provide a comprehensively annotated reference sequence of a single, human leukocyte antigen-homozygous MHC haplotype and to use it as a basis against which variations could be assessed from seven other similarly homozygous cell lines, representative of the most common MHC haplotypes in the European population. Comparison of the haplotype sequences, including four haplotypes not previously analysed, resulted in the identification of >44,000 variations, both substitutions and indels (insertions and deletions), which have been submitted to the dbSNP database. The gene annotation uncovered haplotype-specific differences and confirmed the presence of more than 300 loci, including over 160 protein-coding genes. Combined analysis of the variation and annotation datasets revealed 122 gene loci with coding substitutions of which 97 were non-synonymous. The haplotype (A3-B7-DR15; PGF cell line) designated as the new MHC reference sequence, has been incorporated into the human genome assembly (NCBI35 and subsequent builds), and constitutes the largest single-haplotype sequence of the human genome to date. The extensive variation and annotation data derived from the analysis of seven further haplotypes have been made publicly available and provide a framework and resource for future association studies of all MHC-associated diseases and transplant medicine. © 2007 The Author(s). Fil: Horton, Roger. Wellcome Trust Sanger Institute; Reino Unido Fil: Gibson, Richard. Wellcome Trust Sanger Institute; Reino Unido Fil: Coggill, Penny. Wellcome Trust Sanger Institute; Reino Unido Fil: Miretti, Marcos Mateo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Biología Subtropical. Universidad Nacional de Misiones. Instituto de Biología Subtropical; Argentina. Wellcome Trust Sanger Institute; Reino Unido Fil: Allcock, Richard J.. University of Western Australia; Australia Fil: Almeida, Jeff. Wellcome Trust Sanger Institute; Reino Unido Fil: Forbes, Simon. Wellcome Trust Sanger Institute; Reino Unido Fil: Gilbert, James G. R.. Wellcome Trust Sanger Institute; Reino Unido Fil: Halls, Karen. Wellcome Trust Sanger Institute; Reino Unido. University of Cambridge; Reino Unido Fil: Harrow, Jennifer L.. Wellcome Trust Sanger Institute; Reino Unido Fil: Hart, Elizabeth. Wellcome Trust Sanger Institute; Reino Unido Fil: Howe, Kevin. Cruk Cambridge Research Institute; Reino Unido Fil: Jackson, David K.. Wellcome Trust Sanger Institute; Reino Unido Fil: Palmer, Sophie. Wellcome Trust Sanger Institute; Reino Unido Fil: Roberts, Anne N.. University of Cambridge; Reino Unido Fil: Sims, Sarah. Wellcome Trust Sanger Institute; Reino Unido Fil: Stewart, C. Andrew. National Cancer Institute At Frederick; Estados Unidos Fil: Traherne, James A.. University of Cambridge; Reino Unido Fil: Trevanion, Steve. Wellcome Trust Sanger Institute; Reino Unido Fil: Wilming, Laurens. Wellcome Trust Sanger Institute; Reino Unido Fil: Rogers, Jane. Wellcome Trust Sanger Institute; Reino Unido Fil: De Jong, Pieter J.. Children's Hospital Oakland Research Institute; Estados Unidos Fil: Elliott, John F.. University of Alberta; Canadá Fil: Sawcer, Stephen. University of Cambridge; Reino Unido Fil: Todd, John A.. University of Cambridge; Reino Unido Fil: Trowsdale, John. University of Cambridge; Reino Unido Fil: Beck, Stephan G.. Wellcome Trust Sanger Institute; Reino Unido
- Published
- 2008
22. Complete MHC haplotype sequencing for common disease gene mapping
- Author
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Sarah Sims, C. Andrew Stewart, Joanna M. M. Howson, Ian Dunham, Alexey Atrazhev, Richard J.N. Allcock, Jane Rogers, John A. Todd, Anne N. Roberts, Stephan Beck, Penny Coggill, Roger Horton, Pieter J. de Jong, Stephen Sawcer, Kazutoyo Osoegawa, Sean Humphray, John Trowsdale, Jennifer L. Ashurst, Laurens G. Wilming, Karen Halls, Yu Wang, Sophie Palmer, Simon A. Forbes, Sarah E. Hunt, Andrew J. Mungall, and John F. Elliott
- Subjects
Chromosomes, Artificial, Bacterial ,HLA-C Antigens ,HLA-A3 Antigen ,Major histocompatibility complex ,Genome ,Linkage Disequilibrium ,White People ,Autoimmune Diseases ,Cell Line ,HLA-B8 Antigen ,Major Histocompatibility Complex ,Consanguinity ,HLA-DR3 Antigen ,Gene mapping ,Chromosome regions ,Genetics ,Humans ,Genetic Predisposition to Disease ,Gene ,Genetics (clinical) ,HLA-A1 Antigen ,Bacterial artificial chromosome ,Polymorphism, Genetic ,biology ,Genome, Human ,Haplotype ,Chromosome Mapping ,Genetic Variation ,Resources ,Genes ,Haplotypes ,biology.protein ,Human genome - Abstract
The future systematic mapping of variants that confer susceptibility to common diseases requires the construction of a fully informative polymorphism map. Ideally, every base pair of the genome would be sequenced in many individuals. Here, we report 4.75 Mb of contiguous sequence for each of two common haplotypes of the major histocompatibility complex (MHC), to which susceptibility to >100 diseases has been mapped. The autoimmune disease-associated-haplotypes HLA-A3-B7-Cw7-DR15 and HLA-A1-B8-Cw7-DR3 were sequenced in their entirety through a bacterial artificial chromosome (BAC) cloning strategy using the consanguineous cell lines PGF and COX, respectively. The two sequences were annotated to encompass all described splice variants of expressed genes. We defined the complete variation content of the two haplotypes, revealing >18,000 variations between them. Average SNP densities ranged from less than one SNP per kilobase to >60. Acquisition of complete and accurate sequence data over polymorphic regions such as the MHC from large-insert cloned DNA provides a definitive resource for the construction of informative genetic maps, and avoids the limitation of chromosome regions that are refractory to PCR amplification.
- Published
- 2004
23. Accessing HLA Sequencing Data Through the 6ace Database
- Author
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Roger Horton and Stephan Beck
- Subjects
Database ,business.industry ,Interface (Java) ,Suite ,Human leukocyte antigen ,Biology ,computer.software_genre ,Genome ,The Internet ,Human genome ,User interface ,Graphics ,business ,computer - Abstract
The chromosome 6 database (6ace) is one of a suite of databases available at the Sanger Centre, which serve the human genome sequencing communities of several chromosomes (1, 6, 20, 22, and X). Data may be retrieved in graphical or textural form using interactive windows and menus or simple command texts. The database and its management system are based on ACEDB and can be accessed via three main routes, a graphics interface, a text interface, and a Web interface. Here, we describe 6ace with particular emphasis on how to access major histocompatibility complex (MHC) and human leukocyte antigen (HLA) associated data.
- Published
- 2003
24. Accessing HLA sequencing data through the 6ace database
- Author
-
Roger, Horton and Stephan, Beck
- Subjects
Major Histocompatibility Complex ,Internet ,User-Computer Interface ,Genome, Human ,HLA Antigens ,Animals ,Humans ,Chromosomes, Human, Pair 6 ,Sequence Analysis, DNA ,Databases, Nucleic Acid ,Alleles ,Software - Published
- 2002
25. Assessing the Convenience Factor in Relocating a Day Care Center
- Author
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Barbara Ann Norton Dauterman and Terry Roger Horton
- Subjects
Nursing ,business.industry ,Day care center ,Medicine ,business - Published
- 2000
26. Large-scale sequence comparisons reveal unusually high levels of variation in the HLA-DQB1 locus in the class II region of the human MHC
- Author
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Sophie Palmer, David Niblett, Ben Tubby, John Trowsdale, Roger Horton, Sarah Milne, and Stephan Beck
- Subjects
endocrine system diseases ,Genes, MHC Class II ,Molecular Sequence Data ,chemical and pharmacologic phenomena ,Locus (genetics) ,Nerve Tissue Proteins ,Biology ,Major histocompatibility complex ,DNA sequencing ,Structural Biology ,HLA-DQ Antigens ,HLA-DQ beta-Chains ,Humans ,Allele ,Molecular Biology ,Gene ,Ataxin-1 ,Sequence Deletion ,Genetics ,HLA-DQB1 ,Chromosome Mapping ,Genetic Variation ,Nuclear Proteins ,Sequence Analysis, DNA ,Long terminal repeat ,Mutagenesis, Insertional ,Retroviridae ,Ataxins ,Gene Expression Regulation ,biology.protein ,Human genome ,Chromosomes, Human, Pair 6 - Abstract
Comparison of genomic sequences flanking the HLA-DQB1 locus in the human MHC class II region reveals local sequence variation of up to 10%, which is the highest level of sequence variation found in the human genome so far. The variation is haplotype-specific and extends far beyond the transcriptional unit of the DQB1 gene, suggesting hitch-hiking along with functionally selected alleles as the most likely mechanism. All major insertions/deletions (indels) were found to be of retroviral origin and in the immediate upstream region of DQB1. Possible cis-acting effects of these indels on the transcriptional regulation of DQB1 are discussed.
- Published
- 1998
27. The MHC haplotype project: A resource for HLA-linked association studies
- Author
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Stephan Beck, K. Halls, Simon Forbes, Jane Rogers, John F. Elliott, Kazutoyo Osoegawa, Alexey Atrazhev, John Trowsdale, Roger Horton, Y. Wang, Richard J.N. Allcock, Scott M. Williams, John A. Todd, P. J. De Jong, and Stephen Sawcer
- Subjects
Genetics ,Resource (biology) ,Immunology ,Haplotype ,biology.protein ,Immunology and Allergy ,General Medicine ,Human leukocyte antigen ,Biology ,Major histocompatibility complex ,Biochemistry ,Genetic association - Published
- 2002
28. Genetic Analysis of Completely Sequenced Disease-Associated MHC Haplotypes Identifies Shuffling of Segments in Recent Human History
- Author
-
C. Andrew Stewart, Jennifer L. Ashurst, Jane Rogers, Stephan Beck, Sarah Sims, Stephen Sawcer, John Trowsdale, James A. Traherne, Anne N. Roberts, Roger Horton, Marcos Mateo Miretti, John A. Todd, Penny Coggill, Mary Carrington, Alexey Atrazhev, Pieter J. de Jong, Matthew E. Hurles, J P Almeida, Laurens G. Wilming, Sophie Palmer, and John F. Elliott
- Subjects
Chromosomes, Artificial, Bacterial ,Cancer Research ,lcsh:QH426-470 ,Evolution ,Sequence analysis ,Genetics/Genetics of Disease ,Single-nucleotide polymorphism ,Human leukocyte antigen ,Biology ,Major histocompatibility complex ,Polymorphism, Single Nucleotide ,Evolution, Molecular ,Major Histocompatibility Complex ,03 medical and health sciences ,HLA-C ,0302 clinical medicine ,Homo (Human) ,Genetic variation ,Genetics ,Humans ,Cloning, Molecular ,Molecular Biology ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics ,Genetics/Population Genetics ,030304 developmental biology ,Genetics/Gene Discovery ,Recombination, Genetic ,0303 health sciences ,Genetics/Genome Projects ,Polymorphism, Genetic ,Allergy - Immunology ,Haplotype ,Chromosome Mapping ,Genetic Variation ,HLA-DR Antigens ,Sequence Analysis, DNA ,Genetics/Chromosome Biology ,Genetics/Disease Models ,Genetics/Complex Traits ,lcsh:Genetics ,Haplotypes ,biology.protein ,Diabetes - Endocrinology - Metabolism ,Human genome ,Research Article ,030215 immunology - Abstract
The major histocompatibility complex (MHC) is recognised as one of the most important genetic regions in relation to common human disease. Advancement in identification of MHC genes that confer susceptibility to disease requires greater knowledge of sequence variation across the complex. Highly duplicated and polymorphic regions of the human genome such as the MHC are, however, somewhat refractory to some whole-genome analysis methods. To address this issue, we are employing a bacterial artificial chromosome (BAC) cloning strategy to sequence entire MHC haplotypes from consanguineous cell lines as part of the MHC Haplotype Project. Here we present 4.25 Mb of the human haplotype QBL (HLA-A26-B18-Cw5-DR3-DQ2) and compare it with the MHC reference haplotype and with a second haplotype, COX (HLA-A1-B8-Cw7-DR3-DQ2), that shares the same HLA-DRB1, -DQA1, and -DQB1 alleles. We have defined the complete gene, splice variant, and sequence variation contents of all three haplotypes, comprising over 259 annotated loci and over 20,000 single nucleotide polymorphisms (SNPs). Certain coding sequences vary significantly between different haplotypes, making them candidates for functional and disease-association studies. Analysis of the two DR3 haplotypes allowed delineation of the shared sequence between two HLA class II–related haplotypes differing in disease associations and the identification of at least one of the sites that mediated the original recombination event. The levels of variation across the MHC were similar to those seen for other HLA-disparate haplotypes, except for a 158-kb segment that contained the HLA-DRB1, -DQA1, and -DQB1 genes and showed very limited polymorphism compatible with identity-by-descent and relatively recent common ancestry (, Synopsis A group of genes involved in the human immune system are contained within a surprisingly short section of Chromosome 6 that has long been recognised as the most important genomic region in relation to disease susceptibility. Discerning the actual genes playing a role in disease has proved difficult mainly because the region contains numerous genes and is also the most genetically variable in the genome. Within this jungle of variation, the research reported here has identified and characterised a discrete segment shared by two individuals that is virtually devoid of variation—a polymorphism desert. The conservation of this segment amongst a background of extreme variation suggests both an ancient origin and genetic exchange in early human history. These observations are important in evolutionary terms as they reveal a potential mechanism whereby certain genetic segments associated with favourable immune functions have spread across human populations. Within medical terms this may also explain contrasting disease risks in people from different ethnic backgrounds. Public access to these data will help researchers find specific variants conferring disease susceptibility or resistance and, as in this report, rule out regions for conveying specificity to certain diseases.
- Published
- 2006
29. [Untitled]
- Author
-
Stephan Beck, D J Lehmann, Roger Horton, Donald Warden, L. Barnetson, Andrew I Sutherland, A. David Smith, Martin C N M Barnardo, Isabel Quiroga, and Susan V. Fuggle
- Subjects
Genetics ,0303 health sciences ,medicine.medical_specialty ,Neurology ,General Neuroscience ,Immunology ,Human leukocyte antigen ,Disease ,Biology ,medicine.disease ,Loss of heterozygosity ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,medicine ,Dementia ,Allele ,Association (psychology) ,Gene ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Background There are reasons to expect an association with Alzheimer's disease (AD) within the HLA region. The HLA-B & C genes have, however, been relatively understudied. A geographically specific association with HLA-B7 & HLA-Cw*0702 had been suggested by our previous, small study.
- Published
- 2006
30. Association of Smoking Behavior with an Odorant Receptor Allele Telomeric to the Human Major Histocompatibility Complex.
- Author
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Pablo Sandro Carvalho Santos, George Füst, Zoltán Prohászka, Armin Volz, Roger Horton, Marcos Miretti, Chack-Yung Yu, Stephan Beck, Barbara Uchanska-Ziegler, and Andreas Ziegler
- Published
- 2008
- Full Text
- View/download PDF
31. A second major histocompatibility complex susceptibility locus for multiple sclerosis.
- Author
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Tai Wai Yeo, Philip L. De Jager, Simon G. Gregory, Lisa F. Barcellos, Amie Walton, An Goris, Chiara Fenoglio, Maria Ban, Craig J. Taylor, Reyna S. Goodman, Emily Walsh, Cara S. Wolfish, Roger Horton, James Traherne, Stephan Beck, John Trowsdale, Stacy J. Caillier, Adrian J. Ivinson, Todd Green, and Susan Pobywajlo
- Abstract
Variation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLAâDRB1 gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed.Using a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DRB1*1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects.Screening confirmed the presence of residual association and suggested that this was maximal in the region of the HLAâC gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLAâDRB1 locus, but also reflects an independent effect from the HLAâC gene. Specifically, the HLAâC*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 Ã 10â5).Variation in the HLAâC gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLAâDRB1 gene. Ann Neurol 2007 [ABSTRACT FROM AUTHOR]
- Published
- 2007
32. Evidence for an accumbens-pallidal pathway in the rat and its possible gabaminergic control
- Author
-
Roger Horton and Chris Pycock
- Subjects
Cerebral Cortex ,Dose-Response Relationship, Drug ,Chemistry ,Aminobutyrates ,Dopamine ,General Neuroscience ,Motor Activity ,Globus Pallidus ,Olfactory Bulb ,Rats ,Ethanolamines ,Cerebellum ,Neural Pathways ,Synapses ,Limbic System ,Animals ,Female ,Neurology (clinical) ,Control (linguistics) ,Molecular Biology ,Neuroscience ,gamma-Aminobutyric Acid ,Developmental Biology - Published
- 1976
33. The relationship of teachers' level of dogmatism and sense of power to their receptivity to change /
- Author
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Peck, Roger Horton
- Subjects
- Education, Teachers, Educational innovations
- Published
- 1969
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