Tesis: "Human Major Histocompatibility Complex Selection"

1

Bubb, Kerry Leigh. "The role of balancing selection in maintenance of natural genetic variation /". Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/10258.

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2

Lie, Hanne Cathrine. "The role of genetic diversity in human sexual selection : is the MHC special?" University of Western Australia. School of Psychology, 2009. http://theses.library.uwa.edu.au/adt-WU2010.0053.

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[Truncated abstract] The assumption that facial attractiveness signals mate quality is central to current evolutionary theories of human sexual selection. Evidence for direct links between attractiveness and mate quality is, however, scarce, and the exact nature of mate quality remains the subject of debate. Mate quality may include genetic diversity, because genome-wide diversity has been linked to individual fitness, and diversity within the Major Histocompatibility Complex (MHC) has been associated with immunocompetence and health in many species. This thesis investigates whether individual genetic diversity plays a role in human sexual selection. The main aim is to examine whether MHC diversity, compared to genetic diversity in general, is especially important for mate preferences, health and mating success. The four studies herein are based on data collected from a large sample of heterosexual, Caucasian males and females. Participants were photographed, provided a DNA sample, and completed questionnaires regarding sexual history and health. Genetic diversity was calculated as both mean heterozygosity (H) and standardised mean-d2 (d2), separately for 12 MHC microsatellite loci and 11 nonMHC loci. The photographs were rated for various attractive features by opposite-sex raters. The first study investigated whether MHC diversity influences preferences for facial appearance in a potential mate, and if so, are they specific to the MHC and are they mediated by specific facial characteristics? I found that MHC-H, but not nonMHCH, positively predicted male facial attractiveness, and that this relationship was mediated by facial averageness. For females, nonMHC-d2 predicted facial symmetry, and potentially attractiveness. These findings indicate that faces contain visual cues to mate quality in both males and females, providing support for evolutionary theories that our preferences are adaptations for identifying mates of high quality. ... Measuring them both allowed me to tease apart their effects on mate preferences, and on health and mating success. Indeed, the MHC appears to be especially important in sexual selection as MHC diversity predicted female mate preferences after controlling for nonMHC diversity, and MHC dissimilarity predicted male mate preferences after controlling for nonMHC dissimilarity. Moreover, although MHC diversity did not appear to influence males preference for females, it did predict female mating success, suggesting that males also attend to MHC-related cues, although perhaps non-facial cues, when seeking mates. Additionally, nonMHC diversity predicted both male preferences for female faces and health, suggesting that such preferences are adaptive. Importantly, by providing direct links between facial attractiveness and biological markers of individual quality, genetic diversity, these results support the commonly held assumption that facial attractiveness signals mate quality.

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3

Kendall, Elaine. "Molecular characterisation of the human major histocompatibility complex". Thesis, University of Oxford, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333402.

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4

Takousis, Petrus. "DNA replication in the human major histocompatibility complex". Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1445119/.

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DNA replication is a vital component of the eukaryotic cell cycle. During the course of S-phase, numerous origins of replication become activated along each chromosome. Several adjacent origins fire synchronously to replicate large sections of a chromosome at specific times. Early studies identified a relationship between cytogenetic bands and replication timing: GC-rich R-bands replicate early while AT-rich and gene poor G-bands replicate late, apparently regardless of differentiation and developmental status. Subsequent studies revealed that other factors such as transcriptional status also influence the replication programme. The aim of this thesis is to examine the organisation of DNA replication in the human Major Histocompatibility Complex (MHC) on chromosome 6, and understand how it relates to gene expression and inherent genomic properties. A previous investigation from the Human Cytogenetics Laboratory using fluorescence in situ hybridisation (FISH) suggested that replication timing of the MHC is organised into distinct zones, with the MHC class II region, an AT-rich isochore, replicating later than neighbouring regions. Using a biochemical approach, the entire MHC was found to replicate within the first half of S-phase in cell lines derived from different tissues. Subsequent analysis of a B-lymphoblastoid cell line using a high resolution tiling path array for the MHC confirmed that a large proportion of the MHC class II replicates later than its neighbours. The data suggested the existence within the MHC of replication origins that fire at distinct times in S-phase. An investigation of replication initiation in the MHC revealed the presence of several potential initiation sites, which were further analysed by quantitative PCR. The gene-rich MHC class III was found to have a relatively large number of replication initiation sites. Overall, these results suggest that either specific origins of replication or zones of initiation can fulfill the replication requirements of a region.

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5

Dunham, Ian. "Molecular mapping of the human major histocompatibility complex". Thesis, University of Oxford, 1988. http://ora.ox.ac.uk/objects/uuid:61559181-d77f-479e-8bfe-2e324d8806bd.

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2. The long range DNA organisation of the class II and class III regions in eight HLA homozygous cell lines has been analysed using PFGE. Comparison of the size of the BssHII restriction fragment observed for these cell lines and five individuals possessing one to three C4 genes, shows that the organisation of the C4 genes on each chromosome can be deduced from a single PFGE experiment. Outside of the C4 and 21-OHase loci the class III region shows a highly invariant structure, with no detectable differences in the amount of DNA present. Moreover the class III region is rich in CpG-islands, one of which has been characterised, and contains at least thirteen new genes. However, in the class II region, two differences between common haplotypes have been found. The DRw52-related haplotypes have the same DNA organisation. DR2 haplotypes possess 20-30 kb more DNA in the DRB region. DRw53 haplotypes have 100-130 kb more DNA than DRw52-related haplotypes in the region containing the DRB and DQA genes.

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6

Ottaviani, D. "The genomic anchors of the human major histocompatibility complex". Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/16303/.

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Eukaryotic chromatin is organised into a hierarchy of topologically constrained loop structures. Matrix Attachment Regions (MARs) are genomic sequences that mediate the anchoring of chromatin to the insoluble proteinaceous fraction of the nucleus known as the nuclear matrix. Since only a few MARs have been characterised so far, their role in genomic structure and function is not well understood. The aim of this thesis is to use the human Major Histocompatibility Complex (MHC) as model region to provide novel insights into the relationship between chromatin folding mediated by MARs and gene expression. This large locus contains critical genes for immunity and is associated with more diseases than any other genomic region. Classical MHC genes are expressed in a cell type specific pattern, and can be induced by cytokines such as IFN-γ. MARs were identified across the entire MHC in uninduced fibroblasts, IFN-γ induced fibroblasts and B lymphoblastoid cells. Expression array analysis showed that these cell types exhibit different MHC expression profiles. MARs were first isolated treating nuclei with hypertonic buffers followed by nuclease digestion and then mapped by hybridizing them onto a novel tiling path array for the MHC. The suitability of this array platform to study DNA-protein interactions was verified using hybridisations of CIITA-enriched DNA and DNA enriched in H3-K9/K14 acetylation. The findings reveal that MARs are unevenly distributed across the MHC, and that they can be classified into three classes: constitutive, cell type specific and transcriptiondependent. These sequences are mainly positioned in intergenic regions and in close proximity to the MHC class boundaries, subdividing the locus into physical domains. By comparing the position of MARs in uninduced fibroblasts, IFN-γ induced fibroblasts and B lymphoblastoid cells, transcriptional activation of the MHC was found to be associated with a reconfiguration of chromatin architecture resulting from the formation of additional genomic anchors. These results suggest that the dynamic tethering of chromatin is linked to transcriptional regulation.

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7

Plant, Katharine. "Allele specific gene expression in the major histocompatibility complex". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:f565a41c-4699-4416-b1be-150b6a87dd0f.

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The Major Histocompatibility Complex (MHC) is a highly polymorphic region of the genome located on chromosome 6p21 in which genetic diversity has been associated with susceptibility to many autoimmune, infectious and other common diseases. Despite strong associations between disease and variation in the MHC that have been identified initially from serological testing and more recently by genome-wide association studies, functional insights into how specific variants may be altering disease susceptibility remain poorly understood in most cases. It is predicted that gene expression will play a significant role in the modulation of disease susceptibility and so further understanding of allele specific gene expression in the MHC will be necessary to help define the function of disease associated variants in this region. This thesis aimed to define allele specific gene expression in the MHC by characterising specific candidate genes together locus-wide approaches in order to try and resolve functional variants. Gene expression was analysed in both lymphoblastoid cell lines (LCLs) and primary human peripheral blood mononuclear cells (PBMCs). Data is presented validating a novel haplotype-specific MHC microarray and fine mapping putative local, likely cis-acting, regulatory variants. This was done by expression quantitative trait mapping for two cohorts of healthy volunteers. A transcription factor ZFP57, encoded in the MHC, was found to show significant differential allelic expression relating to specific single nucleotide polymorphisms (SNPs) and possession of HLA-type. This provided new insights into reported disease associations, notably HIV-1 infection and cancer. The function of ZFP57 was further investigated in terms of genome-wide DNA binding sites by ChIP-seq together with its binding co-factor KAP1. Allele-specific gene expression was also demonstrated for several classical HLA genes including the HLA-C and HLA-DQ genes, fine mapping specific putative regulatory variants. This provided new insights into disease association, notably variants of HLA-DQB1 and susceptibility to leprosy. The applicability and sensitivity of the technique of RNA sequencing (mRNA-seq) for allele-specific quantification of gene expression was investigated for different allelic ratios of RNA from LCLs homozygous for sequence across the MHC. Significant challenges were identified in successful application of this technique to MHC genes while high levels of accuracy were observed dependent on read depth in non-MHC genes. This thesis provides new insights into the extent and nature of allele-specific gene expression in the MHC, experimental approaches that can be used and insights gained into disease susceptibility for this important genomic region.

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8

Sherborne, Amy Louise. "Balancing selection at the major histocompatibility complex (MHC) : sequence diversity and inbreeding avoidance". Thesis, University of Liverpool, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501605.

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The major histocompatibility complex (MHC) is a much studied region of the mammalian genome because of its uniquely high level of polymorphism. Both natural and sexual selection have been implicated in the maintenance of MHC diversity. The elevated heterozygosity observed at the MHC could reflect overdominant heterozygote advantage against pathogenic infection. Equally, MHC disassortative mating would lead to an excess of heterozygotes.

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9

au, ddunn@cbbc murdoch edu y David Suliman Dunn. "Studies on polymorphic alu insertions and genomic diversity within the major histocompatibility complex". Murdoch University, 2005. http://wwwlib.murdoch.edu.au/adt/browse/view/adt-MU20061121.94752.

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After the initiation of the human genome sequencing project and the introduction of the field of bioinformatics, interest in human genetic diversity studies has been increased. Sequence diversity has helped define differences between genes and genomic regions that were previously unknown or difficult to determine. In this thesis I have undertaken to study sequence diversity in the human genome in three areas; 1) investigated diversity in the MHC as represented by the MICA alleles with respect to the known HLA alleles, 2) investigated the structure and diversity in the intergenic region from an MHC related (paralogous) genomic region and related the structural and diversity findings to the knowledge available on the MHC and the wider genome, and 3) described the identification of three and characterization of five new MHC class I polymorphic markers (Alu) and their polymorphic characteristics in worldwide populations and their associations with skin cancer. 1. Phylogenetic analysis of MICA alpha-domain (extracellular) sequences demonstrated relationships with HLA-B cross-reactive serogroups. The HLA-B and MICA loci are in linkage disequilibrium. The data indicated that MICA and HLA-B have evolved in concert from their common ancestors and that the transmembrane polymorphisms have arisen independently and more recently. 2. Sequence analysis of the CD1 genomic region confirmed the presence of five CD1 genes and revealed that there are four unrelated intergenic regions (IGRs). The IGRs are composed mostly of retroelements including five full-length L1 PA sequences and various pseudogenes. Genomic and phylogenetic analyses support the view that the human CD1 gene copies were duplicated prior to the evolution of primates and the bulk of the HLA class I genes found in humans. 3. Five polymorphic Alu insertions (POALINs) were identified (two from previous studies) and located within the 1.8 megabase of the MHC class I genomic region. All five POALINs are polymorphic, and are positively associated with the HLA-A and HLA-B alleles. The AluyHJ insertion was found most frequently associated with HLA-A1 or A24, AluyHG with HLA-A2, AluyHF with HLA-A2, A-10 or -A26 and AluyTF showed a marginal association with HLA-A29. The AluyMICB insertion was strongly associated with HLA-B17 (HLA-B57, HLA-B58) and HLA-B13. The presence of three Alu insertions (AluyHJ, AluyHG and AluyHF) was found in only one HLA class I haplotype (HLA-A1, -B57, -Cw6) in the 10th IHW cell lines. A novel positive association between the presence of AluyMICB and the MICAdel/MICBnull/HLA-B48 haplotype was determined. The AluyMICB insertion was also associated with at least three different MICB alleles (*0102, *0107N and *0105) and three different HLA-B alleles (B13, B48 and B57). Based on the analysis of associations between different polymorphic markers within the beta block, the MICB*0102 allele was inferred to be the ancestral form of the MICB*0105 and MICB*0107N alleles. The AluyMICB polymorphism can be used to further investigate haplotype relationship and consequently their lineage origins. Some of the MHC POALINs are haplospecific and associate strongly with certain groups of HLA class I alleles and MHC ancestral haplotypes. The AluyTF frequency was significantly associated with skin cancer (p<0.005). MICA gene diversity is derived from two different evolving paths, therefore one or the other alone cannot reliably mark an ancestral haplotype. The CD1 duplicons originated well before the HLA class I duplicons. The MHC POALINs provide new lineage and linkage markers for the fine mapping study of different haplotypes and variations in linkage groups across 1.8 Mb of the MHC class I region. The POALINs may also prove useful in investigating the origins and history of human populations and in determining the role of human genetic diversity in disease risk.

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10

Dunn, David Suliman. "Studies on polymorphic alu insertions and genomic diversity within the major histocompatibility complex". Dunn, David Suliman (2005) Studies on polymorphic alu insertions and genomic diversity within the major histocompatibility complex. PhD thesis, Murdoch University, 2005. http://researchrepository.murdoch.edu.au/28/.

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After the initiation of the human genome sequencing project and the introduction of the field of 'bioinformatics', interest in human genetic diversity studies has been increased. Sequence diversity has helped define differences between genes and genomic regions that were previously unknown or difficult to determine. In this thesis I have undertaken to study sequence diversity in the human genome in three areas; 1) investigated diversity in the MHC as represented by the MICA alleles with respect to the known HLA alleles, 2) investigated the structure and diversity in the intergenic region from an MHC related (paralogous) genomic region and related the structural and diversity findings to the knowledge available on the MHC and the wider genome, and 3) described the identification of three and characterization of five new MHC class I polymorphic markers (Alu) and their polymorphic characteristics in worldwide populations and their associations with skin cancer. 1. Phylogenetic analysis of MICA alpha-domain (extracellular) sequences demonstrated relationships with HLA-B cross-reactive serogroups. The HLA-B and MICA loci are in linkage disequilibrium. The data indicated that MICA and HLA-B have evolved in concert from their common ancestors and that the transmembrane polymorphisms have arisen independently and more recently. 2. Sequence analysis of the CD1 genomic region confirmed the presence of five CD1 genes and revealed that there are four unrelated intergenic regions (IGRs). The IGRs are composed mostly of retroelements including five full-length L1 PA sequences and various pseudogenes. Genomic and phylogenetic analyses support the view that the human CD1 gene copies were duplicated prior to the evolution of primates and the bulk of the HLA class I genes found in humans. 3. Five polymorphic Alu insertions (POALINs) were identified (two from previous studies) and located within the 1.8 megabase of the MHC class I genomic region. All five POALINs are polymorphic, and are positively associated with the HLA-A and HLA-B alleles. The AluyHJ insertion was found most frequently associated with HLA-A1 or A24, AluyHG with HLA-A2, AluyHF with HLA-A2, A-10 or -A26 and AluyTF showed a marginal association with HLA-A29. The AluyMICB insertion was strongly associated with HLA-B17 (HLA-B57, HLA-B58) and HLA-B13. The presence of three Alu insertions (AluyHJ, AluyHG and AluyHF) was found in only one HLA class I haplotype (HLA-A1, -B57, -Cw6) in the 10th IHW cell lines. A novel positive association between the presence of AluyMICB and the 'MICAdel/MICBnull/HLA-B48' haplotype was determined. The AluyMICB insertion was also associated with at least three different MICB alleles (*0102, *0107N and *0105) and three different HLA-B alleles (B13, B48 and B57). Based on the analysis of associations between different polymorphic markers within the beta block, the MICB*0102 allele was inferred to be the ancestral form of the MICB*0105 and MICB*0107N alleles. The AluyMICB polymorphism can be used to further investigate haplotype relationship and consequently their lineage origins. Some of the MHC POALINs are haplospecific and associate strongly with certain groups of HLA class I alleles and MHC ancestral haplotypes. The AluyTF frequency was significantly associated with skin cancer (p<0.005). MICA gene diversity is derived from two different evolving paths, therefore one or the other alone cannot reliably mark an ancestral haplotype. The CD1 duplicons originated well before the HLA class I duplicons. The MHC POALINs provide new lineage and linkage markers for the fine mapping study of different haplotypes and variations in linkage groups across 1.8 Mb of the MHC class I region. The POALINs may also prove useful in investigating the origins and history of human populations and in determining the role of human genetic diversity in disease risk.

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11

Rosenberg, William. "Immunogenetic studies of the human major histocompatibility complex and T cell receptor". Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315822.

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12

Johonnett, Peter. "Replication timing analysis of the major histocompatibility complex on human chromosome 6". Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395158.

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13

Niskanen, A. (Alina). "Selection and genetic diversity in the major histocompatibility complex genes of wolves and dogs". Doctoral thesis, Oulun yliopisto, 2014. http://urn.fi/urn:isbn:9789526205960.

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Abstract Hosts and pathogens are involved in a continuous evolutionary arms race, where pathogens attack and hosts defend themselves. The main tools for winning the race are natural selection and the genetic diversity that selection acts on. However, in small populations natural selection may be ineffective. Therefore, the genes taking part in immune defense may lack adaptability to new or changing pathogens. Major histocompatibility complex (MHC) is an important genomic region that includes highly polymorphic immune defense genes. In this doctoral thesis, I studied the natural selection and genetic diversity of MHC class II genes in dogs and Finnish wolves. I also used dog MHC diversity to estimate the number of founding wolves in dog domestication. The Finnish wolf population declined rapidly in size due to excessive hunting from the late 19th century until the early 20th century. After decades of a very small population size, the population started recovering in the mid-1990s. This study shows that, despite the fluctuations in population size, the diversity of the MHC loci in the Finnish wolf has remained high and comparable to the larger neighboring Russian Karelian wolf population. Unlike the neutral genetic markers, the MHC loci of the Finnish and Russian Karelian populations have not differentiated. These results indicate similar balancing selection acting on the MHC loci of the two wolf populations. In dogs, the strength of natural selection is likely weakened by artificial selection and veterinary care. The potential phases of natural selection would be during embryogenesis and fetal development. However, no strong signs of prenatal selection were found in this study. MHC diversity was estimated to be higher in Asian dogs than in dogs from Europe. A simulation study indicated a minimum of 500 founding wolves for the modern dog population. Dog MHC diversity implies an Asian origin for domestication from a large and diverse wolf population. Both natural selection and demography have an influence on the genetic diversity of a species. In small populations, random genetic drift is enforced. However, in loci with important fitness impacts, selection may be particularly strong and outweigh drift, as demonstrated in the MHC loci of a small wolf population in this study
Tiivistelmä Isäntä ja taudinaiheuttajat käyvät jatkuvaa kaksinkamppailua, jossa taudinaiheuttajat hyökkäävät ja isäntä puolustautuu. Kamppailussa menestymiseen tarvitaan geneettistä monimuotoisuutta sekä sen pohjalta toimivaa luonnonvalintaa. Pienissä populaatioissa luonnonvalinnan teho voi kuitenkin heikentyä, jolloin immuunipuolustukseen osallistuvat geenit eivät kykene sopeutumaan uusiin tai muuttuneisiin taudinaiheuttajiin. MHC-alueella (major histocompatibility complex) sijaitsee suuri joukko monimuotoisia immuunipuolustukseen osallistuvia geenejä. Väitöskirjassani tutkin luokan II MHC-geeneihin kohdistuvaa luonnonvalintaa ja niiden geneettistä monimuotoisuutta koirilla ja Suomen susilla. Arvioin myös koiran kesyttämisprosessiin osallistuneiden susien määrää nykykoiran MHC-monimuotoisuuden pohjalta. Suomen susipopulaation koko pieneni nopeasti voimakkaan metsästyksen vuoksi 1800-luvun lopulta 1900-luvun alkuun. Populaatio pysyi hyvin pienenä useita vuosikymmeniä, kunnes se alkoi elpyä 1990-luvun puolivälissä. Tutkimus osoitti, että populaatiokoon vaihteluista huolimatta Suomen susien MHC-geenien monimuotoisuus on säilynyt korkeana ja on vastaavalla tasolla kuin Venäjän Karjalan susipopulaatiossa. Suomen ja Venäjän Karjalan susipopulaatioiden MHC-geenit eivät ole erilaistuneet, vaikka populaatiot poikkeavat toisistaan neutraalien geenimerkkien suhteen. Samanlainen tasapainottava valinta näyttäisi kohdistuvan näiden susipopulaatioiden MHC-geeneihin. Keinotekoinen valinta ja eläinlääketieteellinen hoito todennäköisesti heikentävät koirien MHC-geeneihin kohdistuvaa luonnonvalintaa. Luonnonvalinta voisi yhä vaikuttaa alkion- ja sikiönkehityksen aikana, mutta tästä ei tutkimuksessa löytynyt todisteita. MHC-muuntelun määrän arvioitiin olevan suurempaa aasialaisissa kuin eurooppalaisissa koirissa. Simulaatiotutkimuksen mukaan nykyisen koirapopulaation perustamiseen olisi tarvittu vähintään 500 sutta. Tulokset viittaavat koiran kesyttämisen tapahtuneen Aasiassa suuresta ja monimuotoisesta susipopulaatiosta. Sekä luonnonvalinta että demografia vaikuttavat lajien geneettiseen monimuotoisuuteen. Pienissä populaatioissa satunnaisajautuminen voimistuu. Valinta voi kuitenkin olla erityisen voimakasta ja voittaa satunnaisajautumisen geeneissä, joilla on erityisen tärkeä vaikutus yksilön kelpoisuuteen, kuten tutkimuksessa osoitettiin pienen susipopulaation MHC-geenien kohdalla

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14

Scott, William Reid. "Structures of the human major histocompatibility complex (MHC) class I molecule, HLA B8". Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318852.

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15

Albertella, Mark Robert. "The isolation and characterisation of new genes in the human Major Histocompatibility Complex". Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364146.

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16

Zavala-Ruiz, Zarixia 1977. "Structure studies of the human class II major histocompatibility complex protein HLA-DR1". Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/17842.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2004.
Vita.
Includes bibliographical references (leaves 149-162).
Major Histocompatibility Complex (MHC) proteins are heterodimeric membrane glycoproteins that bind antigens in the form of short peptides within the cell and present them to the T cell receptors on the surface T cells. In this thesis work, the structural aspects of the human class II MHC protein HLA-DR1 in complex with different peptides and also in the peptide-free form were investigated. Biochemical, crystallographic, and immunological analyses of an unusually long peptide antigen derived from HIV-gag (p24) and its interaction with HLA-DR1 and a HIV-specific CD4+ T cell clone were studied. The HIV-gag (p24) peptide binds in an unexpected conformation, with its C- terminal region making a hairpin turn that bends back over the groove. The residues at the C-terminus are critical for T-cell recognition, and disruption of the hairpin turn abrogates the immune response. The results suggest a new mode of MHC-peptide-TCR interaction. A set of viral peptide analogs designed to increase binding affinity for HLA-DR while maintaining antigenic interactions with a virus-specific T cell receptor were designed, tested and analyzed. Ultimately, a N-methyl substitution at position 7 is shown to increase binding affinity by displacement of one of three water molecules bound between the MHC and peptide. The results have implications for design of peptido-mimetic vaccines, and are discussed in the broad context of other attempts to increase protein-ligand interaction through displacement of tightly bound water molecules. The role for the P10 shelf in peptide binding site was investigated. Crystallographic studies confirm the formation of a P10 shelf that is lined with highly polymorphic residues. Biochemical studies were conducted
(cont.) on a series of peptides different at the P10 position on four HLA-DRl(P10) mutants showing that this shelf has some specificity and can be involved in the discrimination of peptides that bind to class II MHC proteins. Studies of the empty, peptide-free form of HLA-DR1 were conducted by NMR spectroscopy showing that the conformation of this empty form is not in a molten globule-like state and that in general is similar to that of the peptide-loaded form but with several differences. Preliminary characterization of the peptide-receptive and peptide-averse forms of the empty HLA-DR1 is described.
by Zarixia Zavala-Ruiz.
Ph.D.

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17

Tomazou, Eleni-Marina. "Identification and characterisation of differentially methylated regions within the human Major Histocompatibility Complex". Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612460.

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18

Olavesen, Mark G. "Characterisation of a cluster of novel genes in the human major histocompatibility complex". Thesis, University of Oxford, 1993. https://ora.ox.ac.uk/objects/uuid:3340fd57-26ca-4172-8f85-0fb07f2d7d24.

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The human MHC has been shown to be associated with susceptibility to a large number of diseases. Within the MHC class III region, which consists of a ~1,100kb segment of DNA located between the class I and class II multigene families, at least 38 genes have been identified, some of which could be involved in disease susceptibility. Analyses of the homologous mouse H-2S region have localised two loci responsible for susceptibility to experimental autoimmune orchitis, Orch-1, and corticosteroid-induced cleft palate, Cps-1, to an ~100kb segment of DNA. The characterisation of four genes located within the homologous region of the human MHC class III region is described here. The G7 gene is a novel gene located 58kb telomeric of the HSP70-Hom locus. G7 has been sequenced at the cDNA and genomic levels. The G7 gene, which contains 27 exons that span ~22kb of DNA, is expressed as an ~3kb mRNA. This mRNA was shown to be present at low levels in all of the cell types analysed, and was most abundant in monocytes and macrophages. Sequence analysis of cDNA clones revealed that the G7 mRNA contains two alternatively spliced exons which alter the putative G7 protein at the C-terminus. The different mRNA species encode putative protein products of 747 and 788 amino acids. The putative G7 proteins appear to be intracellular although their function remains to be determined. However, the putative G7 protein sequences do share significant similarity with bacterial DNA mismatch repair proteins and other similar proteins in yeast, mouse and man. A Pvull RFLP associated with the G7 gene was shown to result in a potential Thr â Ala amino acid substitution in ~25% of the haplotypes analysed. The G7b gene is another novel gene which is located between the HSP70-Hom and valyl-tRNA synthetase (VARS2) genes and may be homologous to other genes elsewhere in the human genome. G7b has been sequenced at the cDNA and genomic levels. The G7b gene contains 5 exons that span ~10kb. The G7b gene expressed an ~0.9kb mRNA that was present in all of the cell types analysed and was most abundant in monocytes and macrophages. The G7b cDNA clones encode a putative G7b protein of 95 amino acids. Polyclonal antisera have been raised against the putative G7b protein which detected an ~5kDa protein in U937 cell lysates. Therefore, the putative G7b protein appears to be an intracellular protein for which the function remains to be determined. However, the putative G7b protein shares significant sequence similarity to the human small ribonucleoprotein Sm-D for which autoantibodies are present in patients with SLE. A new gene G7c located between the G7 and valyl-tRNA synthetase (VARS2) genes has been identified as a result of the presence of non-repetitive sequence in the intergenic region that were shown to be conserved between species. Exon trapping analysis has identified two discrete exons from within this region. The mouse homologue of the human HSP70-Hom gene, Hsc70t, is a potential candidate gene for the Orch-1 locus. As a result it was been sequenced in H-2 congenic mouse strains known to be resistant and susceptible to experimental autoimmune orchitis. Sequence polymorphism was detected although this did not correlate with resistance or susceptibility to the disease.

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19

Houlihan, James Michael. "A study of major histocompatibility complex class I molecules in the developing human liver". Thesis, University of Bristol, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.357972.

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20

Milner, Caroline M. "Characterisation of novel genes in the human major histocompatibility complex : the HSP70 & G9a genes". Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302867.

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Hsieh, Shie-Liang. "Characterisation of novel genes and mapping of polymorphic markers in the human major histocompatibility complex". Thesis, University of Oxford, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315942.

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Ore, Begona Aguado. "Sequence analysis and functional characterisation of three novel genes located in the human major histocompatibility complex". Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390471.

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Jackson, Amanda. "Genomic organisation and transcript identification in the class II region of the human major histocompatibility complex". Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309171.

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Sambrook, Jennifer Gwyneth. "Comparative analyses of the human Major Histocompatibility Complex class III region in the pufferfish Fugu rubripes". Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619965.

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Qutob, Nouar. "Worldwide MHC class I and II diversity in humans". Thesis, University of Cambridge, 2011. https://www.repository.cam.ac.uk/handle/1810/252242.

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Ferrandiz-Rovira, Mariona. "The role of the major histocompatibility complex in the wild : the case of the Alpine marmot (Marmota marmota)". Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10089/document.

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La diversité génétique intra-spécifique constitue le potentiel adaptatif des espèces et, à ce titre, elle est donc indispensable pour l'évolution de celles-ci. Chez les vertébrés, les gènes du complexe majeur d'histocompatibilité (CMH) sont une composante essentielle de quoi permet de faire face aux parasites en initiant une réponse immunitaire. La pression de sélection exercée par les parasites et la sélection sexuelle via le choix du partenaire devraient donc agir sur la diversité génétique du CMH. Cependant, la distinction empirique des pressions sélectives agissant sur la diversité génétique du CMH en milieu naturel nécessite de suivre un grand nombre individus tout au long de leur vie et d'effectuer leur génotypage. Le premier objectif de cette thèse a donc été développer et appliquer un protocole de génotypage chez la marmotte Alpine (Marmota marmota), sur quatre loci du CMH décrits précédemment. Ceci permet par la suite d'étudier, dans une population de marmottes Alpines vivant en milieu naturel, si les caractéristiques génétiques du CMH influencent (1) le choix de partenaire, (2) la présence et/ou l'abondance de trois espèces de parasites intestinaux et (3) leur survie juvénile. Ce travail a fourni une méthode appropriée pour la détermination de génotypes fiables sur un grand nombre d'échantillons en utilisant des techniques de séquençage de nouvelle génération. Ensuite, nous avons constaté l'existence d'un choix de partenaire basé sur le CMH mais aussi sur les caractéristiques de l'ensemble du génome. Par la suite, nous avons mis en évidence le faible rôle du CMH sur la présence et abondance de trois espèces de parasites intestinaux. Finalement, nous avons constaté que l'association entre la survie juvénile et les caractéristiques génétiques du CMH et de l'ensemble du génome ont changé au cours des vingt-trois ans de suivi de la population. Dans l'ensemble, cette thèse présente une approche intégrée de l'étude des rôles du CMH sur une population contemporaine de marmottes Alpines
Intra-specific genetic diversity represents the true potential of adaptation of species and is thus essential for evolutionary change. In vertebrates, the genes of the major histocompatibility complex (MHC) play a critical role in vertebrate disease resistance by initiating immune response. The selective pressure carried out by parasites and sexual selection via mate choice are supposed to maintain the extreme diversity found in the MHC. Yet, empirical differentiation of selective pressures acting on MHC in the wild requires individually based monitoring of a large number of individuals and genotyping them. The aim of this thesis was firstly to develop and apply a genotyping protocol in Alpine marmots (Marmota marmota) to genotype four previously described MHC loci. This allows subsequently to evaluate, in a wild population of Alpine marmots, if MHC characteristics play a role (1) on mate choice, (2) on the presence and/or abundance of three intestinal parasite species and (3) on juvenile survival. This work provided a suitable method to reliably genotype large number of individuals using next-generation sequencing techniques. Then, we found evidences for female mate choice based on MHC but also on neutral genetic characteristics. Subsequently, we evidenced the weak role of MHC characteristics on the presence and abundance of three intestinal parasites. Finally, we found evidences for a change of the effect of genetic diversity at both MHC and neutral loci on juvenile survival during the 23-year monitoring study. Overall, this thesis comprises an integrated approach for the study of the roles of MHC in a contemporaneous population of Alpine marmots

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27

Burfoot, Mark S. "Cloning of genes in the human major histocompatibility complex class III region by use of novel techniques". Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308669.

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28

Robinson, Keira. "Polymorphisms in the major histocompatibility complex and cervical human papillomavirus infection in a cohort of Montreal university students". Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=81428.

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Only a minority of women with a human papillomavirus (HPV) infection eventually develop cervical cancer. This suggests a role for immune mechanisms in viral acquisition and clearance, most notably presentation of HPV antigens as mediated by gene products of the human leukocyte antigen (HLA) complex.
A longitudinal cohort investigation of cervical HPV infections was utilized to examine the role of selected HLA class I and II alleles in determining risk of HPV positivity and persistence for students attending McGill and Concordia universities in Montreal. HPV positivity was measured at baseline and then once every six months for a period of two years. Five hundred and fifty-nine women were identified for analysis. Five HLA alleles: B*07, DQB1*03, DQB1*0602, DRB1*13, and DRB1*1501 were typed using DNA extracted from cervical specimens sampled at enrollment.
In multivariate logistic regression analyses DRB1*13 (odds ratio [OR]: 2.0; 95% confidence interval [CI]: 1.0-4.0) and DRB1*1501 (OR: 2.1; CI: 1.1-4.1) were associated with HPV 16 positivity. Women with DRB1*13 were also more likely to be positive for high-risk (HR) HPV infections (OR: 1.7; CI: 1.0-2.9), or H PV infection of any type (OR: 1.7; CI: 1.0-2.8). Most associations became stronger in the subset of women restricted on the basis of high likelihood to prior HPV exposure.
These results support the hypothesis that certain HLA class II polymorphisms mediate genetic susceptibility to HPV infection in young women.

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29

Grenier, Yannick. "In vitro systems for the study of major histocompatibility complex antigens on the surface of adult human astrocytes". Thesis, McGill University, 1989. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=61787.

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30

Sepil, Irem. "The secret in their MHC : variation and selection in a free living population of great tits". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:dd753cf0-9ec5-4d63-b318-57f037d73ee5.

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Understanding the genetic basis of fitness differences has been a major goal for evolutionary biologists over the last two decades. Although there are many studies investigating how natural selection can promote local adaptation, few have succeeded to find the link between genotype and fitness of the phenotype. Polymorphic genes of the major histocompatibility complex (Mhc) are excellent candidates for such associations as they are a central component of the vertebrate immune system, playing an important role in parasite resistance, and hence can have direct effects on survival of their bearers. Although associations between Mhc and disease resistance are frequently documented, the epidemiological basis of the host-parasite interaction is often lacking and few studies have investigated the role that Mhc genes play in individual variation in fitness; thus comparatively little is known about the fitness consequences of Mhc in wild populations. Furthermore, the majority of work to date has involved testing associations between Mhc genotypes and disease. However, the mechanism by which any direct selection on the Mhc acts, depends on how genotypes map to the functional properties of Mhc molecules. The aim of this thesis was to characterize Mhc alleles in terms of their predicted functional properties and to investigate whether and how selection operates on Mhc class I functional variation using the great tit (Parus major) population at Wytham Woods as a model host species. Through a comprehensive characterization effort and the use of 454 pyrosequencing platform, I performed a detailed analysis of genetic variation at Mhc class I exon 3 and grouped alleles with similar antigen-binding affinities into supertypes to classify functionally distinct Mhc types. There was extreme complexity at the Mhc class I of the great tit both in terms of allelic diversity and gene number. A total of 862 alleles were detected from 857 individuals; the highest number yet characterized in a wild bird species. The functional alleles were clustered into 17 supertypes; there was clear evidence that functional alleles were under strong balancing selection. To understand the role of Mhc in disease resistance, I examined the linkage between Mhc supertypes, Plasmodium infection and great tit survival, and showed that certain functional variants of Mhc confer resistance to two divergent Plasmodium parasite species that are common in the environment. I further investigated the fitness consequences of functional variation at Mhc, using mark-recapture methods and long-term breeding data; and tested the hypotheses that selection: (i) maximizes Mhc diversity; (ii) optimizes Mhc diversity, or (iii) favours specific functional variants. I found that the presence of three different supertypes was associated with three different components of individual fitness: adult survival, annual recruitment probabilities and lifetime reproductive success. In contrast, there was no evidence for a selective advantage of Mhc functional diversity, either in terms of maximal or optimal supertype diversity. Finally, I explored the role that Mhc plays in female mate choice decisions and examined the reproductive fitness consequences of Mhc-dependent mating patterns. There was little evidence to suggest that functional dissimilarity at Mhc has any influence on female mate choice decisions or that dissimilarity at Mhc affects the reproductive output of the social pair. Overall, this thesis provides strong support for the suggestion that selection favours specific functional variants of Mhc, possibly as a result of supertype-specific resistance or susceptibility to parasites that exert strong selective pressures on their hosts; whereas there is no support for selection favouring maximal or optimal Mhc diversity. More importantly it demonstrates that functional variants of Mhc class I loci are an important determinant of individual fitness in natural populations.

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31

Halvarsson, Peter. "Host-Parasite Interactions in Natural Populations". Doctoral thesis, Uppsala, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-300023.

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Parasitism is one of the most common ways of living and it has arised in many taxa. Parasites feed and live inside or on their hosts resulting in both long and short term consequences for the host. This thesis is exploring the phenotypic and genotypic effects of animals living with parasitic infections. I have been studying three different parasite groups and their associated host species: the great snipe, a lekking freshwater wader bird that migrates between Africa and Northern Europe; the tree sparrow, a stationary passerine found close to human settlements and lastly the water vole, a large rodent living in riparian habitats. Avian malaria is one of the most commonly studied parasites affecting birds. Atoxoplasma, an intestinal protozoan parasite is less studied but is thought to be endemic in free-ranging birds. Given the freshwater habitat great snipes inhabit, a prevalence of 30% avian malaria infections is not high and that the prevalence fluctuated among years. Sequencing of the avian malaria cytochrome b gene revealed that parasites are similar to avian malaria parasites found in African birds suggesting that they were infected on the wintering grounds in Africa. Tree sparrows had few malaria infected individuals, a result that is consistent with other studies of stationary birds at high latitudes. Atoxoplasma infections were common in tree sparrows and capture-recapture analyses show decreased survival in infected compared to uninfected birds and signs of lower mating success among infected. Genetic analyses comparing the transcriptome between mated and unmated great snipe males revealed that the genotype is important for mating success and health status for some of the expressed genes. That variations in some of these genes are involved in maintaining a good health status and mating success supports handicap models for sexual selection in this lek mating system. The major histocompatibility complex (MHC) is a part of the immune system and it contains genes involved in immune response. In water voles, a number of new MHC alleles were identified. Based on their in silico phenotype they were grouped into supertypes to facilitate studies on how helminth infections affect the MHC diversity in the water voles. Some of these MHC supertypes provided resistance to one helminth species, but the same supertype caused the opposite effect for other helminth parasites. Overall, parasites are a driving force for maintaining genetic diversity and parasite infections lowers survival rate, which would lead to a lower lifetime breeding success.

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32

Gomez-Escobar, Natalia. "Functional characterisation of a novel serine/threonine protein kinase encoded by a gene in the human major histocompatibility complex". Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320656.

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33

Hanchard, Neil A. "Patterns of linkage disequilibrium and transmission ratio distortion in the class III region of the human major histocompatibility complex". Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409032.

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34

Salie, Muneeb. "The role of the major histocompatibility complex and the Leukocyte receptor complex genes in susceptibility to tuberculosis in a South African population". Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/86715.

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Thesis (PhD)--Stellenbosch University, 2014.
ENGLISH ABSTRACT: Tuberculosis (TB) disease results in approximately 2 million deaths annually and is the leading cause of death due to a single infectious agent. Previous studies have indicated that host genetics play an important role in the development of TB. This together with pathogen and environmental factors intensifies the complexity of this disease. The Major Histocompatibility Complex (MHC) and Leukocyte Receptor Complex (LRC) comprise several genes which are known to be important modulators of the host immune response. The human leukocyte antigen (HLA) class-I genes of the MHC are involved in the presentation of pathogenic antigens on the surfaces of infected cells, while the killer cell immunoglobulin-like receptors (KIRs) of the LRC are involved in the recognition of self and non-self cells. Natural Killer (NK) cells through their KIRs are thus able to kill non-self cells through recognition of the class-I molecules expressed. Additionally, HLAs and KIRs are extremely polymorphic and differ markedly across populations of different ethnicities. Here we studied these genes and their polymorphisms in the South African Coloured (SAC) population to determine their involvement in susceptibility to TB, susceptibility to disease caused by specific Mycobacterium tuberculosis subtypes, and understanding their ancestral contribution to the SAC with regards to the development of TB. We showed that the KIR3DS1 gene and KIR genotypes with five or more activating KIRs, and the presence of 3DS1, protected against the development of active TB in the SAC population. Several HLA class-I alleles were identified as susceptibility factors for TB disease. With regards to genes of the MHC and LRC, several loci were found to alter susceptibility to TB in the SAC population, including MDC1, BTNL2, HLA-DOA, HLA-DOB, C6orf10, TAP2, LILRA5, NCR1, NLRP7 and the intergenic regions between HLA-C/WASF5P and LAIR1/TTYH1. We showed that the Beijing strain occurred more frequently in individuals with multiple disease episodes, with the HLA-B27 allele lowering the odds of having an additional episode. Associations were identified for specific HLA types and disease caused by the Beijing, Latin America-Mediterranean (LAM), Low-Copy Clade (LCC), and Quebec strains. HLA types were associated with disease caused by strains from the Euro-American or East Asian lineages, and the frequencies of these alleles in their sympatric human populations identified potential co-evolutionary events between host and pathogen. Finally, we showed that the SAC population is the most diverse SA population with regards to HLA alleles and KIR genotypes, as would be expected given the admixture of the SAC. Based on the HLA allele class-I profiles across SA populations, we noted that the Ag85BESAT- 6, Ag85B-TB10.4 and Mtb72f vaccines currently undergoing clinical trials would have low efficacy across most SA populations. We showed that the MHC and LRC regions in SAC healthy controls are predominantly of European ancestry, and that SAC TB cases are more closely related to Khoisan and black SA population groups. Our work highlights the importance of investigating both host and pathogen genetics when studying TB disease development and that understanding the genetic ancestral contributions to the SAC population can contribute to the identification of true and novel TB causing variants.
AFRIKAANSE OPSOMMING: Tuberkulose (TB) is jaarliks verantwoordelik vir ongeveer 2 miljoen sterftes en is die hoofoorsaak van dood as gevolg van „n aansteeklike siekte. Vorige navorsingstudies het aangedui dat die genetiese samestelling van die gasheer „n beduidende rol speel in die ontwikkeling van TB. Die kompleksiteit van hierdie siekte word vererger deur die betrokkenheid van die gasheer genoom sowel as bakteriële en omgewings faktore. Die Major Histocompatibility Complex (MHC) en Leukocyte Receptor Complex (LRC) bestaan uit verskeie gene wat die gasheer immuunrespons verstel. Die human leukocyte antigen (HLA) klas I gene van die MHC is betrokke by die aanbieding van patogeniese antigene op die oppervlak van geïnfekteerde selle, terwyl die killer cell immunoglobulin-like receptors (KIRs), geleë in die LRC, betrokke is by die herkenning van eie en vreemde selle. NK selle, deur middel van hul KIRs, kan dus vreemde selle uitwis aangesien hulle die uitgedrukte klas I molekules kan herken. Beide HLA en KIRs is hoogs polimorfies en verskil beduidend tussen etniese groepe. In hierdie studie is die bogenoemde gene en hul polimorfismes in die Suid Afrikaanse Kleurling bevolking (SAC) ondersoek om vas te stel tot watter mate dit genetiese vatbaarheid vir TB, asook vatbaarheid vir TB wat deur spesifieke Mycobacterium tuberculosis subtipes veroorsaak word, beïnvloed. Daar is ook gepoog om te verstaan hoe die voorouerlike bydrae van hierdie gene die SAC met betrekking tot TB vatbaarheid affekteer. Die resultate van die studie het aangedui dat die KIR3DS1 geen en KIR genotipes met vyf of meer aktiewe KIRs en die teenwoordigheid van 3DS1, die SAC bevolking beskerm teen die ontwikkeling van aktiewe TB. Verskeie HLA klas I allele is geïdentifiseer as vatbaarheidsfaktore vir TB. Talle lokusse van die MHC en LRC gene is ook as vatbaarheidsfaktore vir TB in die SAC bevolking geïdentifiseer, insluitende MDC1, BTNL2, HLA-DOA, HLA-DOB, C6orf10, TAP2, LILRA5, NCR1, NLRP7 en die intergeniese areas tussen HLA-C/WASF5P en LAIR1/TTYH1. Die studie het aangedui dat die Beijing stam meer voorkom in individue wat verskeie kere TB gehad het en dat die HLA-B27 alleel die kanse om „n verdere episode te hê, verlaag het. Assosiasies is geïdentifiseer tussen spesifieke HLA tipes en siekte veroorsaak deur die Beijing, LAM, LCC, en Quebec TB stamme. HLA tipes was geassosieer met siekte veroorsaak deur TB stamme van Euro-Amerikaanse en Oos-Asiëse afkoms. Die frekwensies van hierdie allele, in hul ooreenstemmende mensbevolkings, dui op „n potensïele koevolusionêre gebeurtenis tussen die gasheer en patogeen. Die studie het ook vasgestel dat die SAC populasie die mees diverse SA bevolking is met betrekking tot die HLA allele en KIR genotipes, soos verwag sou word gegewe die gemengde genetiese herkoms van die SAC. Gebaseer op die HLA allele klas I profiel van verskillende SA bevolkings merk ons op dat die Ag85B-ESAT-6, Ag85B-TB10.4 en Mtb72f vaksiene, wat huidiglik kliniese toetsing ondergaan, nie so effektief in die meeste SA bevolkings sal wees nie. Die studie het ook bewys dat die MHC en LRC streke in gesonde SAC kontroles, grootliks afkomstig was van „n Europese nalatenskap en dat die SAC TB gevalle meer verwant is aan die Khoisan en swart SA bevolkings. Hierdie studie beklemtoon die noodsaaklikheid om beide gasheer en patogeen genetika te bestudeer wanneer die ontwikkeling van TB ondersoek word en dat die verstaan van die genetiese voorouerlike bydrae van die SAC bevolking kan bydra tot die identifisering van ware en nuwe TB-veroorsakende variante.

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35

Neville, Matt J. "Characterisation of the genomic region around the TNF locus within the human major histocompatibility complex in the chromosome band 6p21.3". Thesis, University of Oxford, 2000. http://ora.ox.ac.uk/objects/uuid:1fcb0019-0b54-418a-a44c-b1b4a7d5a51e.

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It is becoming increasingly apparent that many of the genes in the class III region of the human Major Histocompatibility Complex encode proteins involved in the immune and inflammatory responses. Furthermore, genetic studies have indicated that genes within the class III region, particularly the telomeric segment containing the TNF gene, could contribute to susceptibility to diseases of immune-related aetiology. To further characterise this region and to identify candidate disease susceptibility genes, two overlapping cosmids, TN62 and TN82, covering an ~82kb segment of DNA around the TNF gene were selected for sequence analysis. The eight known genes in this region have been precisely positioned with the order: Gl/AIF-1, 1C7, LST1 (B144), LTB, TNF, LTA, IKBL, BAT1 (centromere to telomere) and their genomic structures have been defined. Comparison of the Gl genomic region with previously described cDNA and genomic sequences, together with the results of RT-PCR, indicates that three alternative transcripts, Gl, Allograft Inflammatory Factor-1 and Interferon-γ Responsive Transcript-1, are all derived from this gene. The completion of the sequence of 1C7 (D6S2570) has revealed that this gene encodes a putative novel member of the immunoglobulin superfamily. A number of alternatively spliced transcripts of 1C7 were identified by RT-PCR, all of which are expressed in immune-related cell lines. Alternative splicing within the immunoglobulin domain- encoding region was seen to result in possible set switching between an IgV domain and an IgC2 domain. In addition to this, a previously unidentified gene, homologous to a number of V- ATPase G-subunits, has been located 1kb telomeric of IKBL. Lastly, the pseudogene UCRH-L and an AIF-1 gene fragment have been identified in the intergenic region between AIF-1 and 1C7. In order to assess the contribution of loci in this region to disease susceptibility, the genes AIF-1, 1C7, ATP6G and the BAT1 promoter region were subjected to mutation analysis. A total of 28 polymorphisms have been identified, 8 in AIF-1, 10 in 1C7, 7 in ATP6G and 3 in the BAT1 promoter region. Work is at present underway to genotype a number of the identified polymorphisms in control DNAs and in DNA samples from patients with combined variable immunodeficiency (CVID). The information generated from this analysis will bring us closer to explaining the reported linkage of CVID with the telomeric end of the human MHC class III region.

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36

Newland, Stephen Alexander. "Functional characterisation of LY6G6C, LY6G6D, G6B and G6F, cell surface receptors encoded by genes within the Human Major Histocompatibility Complex". Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613107.

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Miller, Roseanne. "Mating plasticity within a natural population of sea trout (Salmo trutta) and the effects of the Major Histocompatibility Complex on mate choice and survival". Thesis, University of Aberdeen, 2014. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=229730.

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The genes of the Major Histocompatibility Complex (MHC) represent the most diverse genomic region in vertebrates, and has become a paradigm both for adaptively important genetic variation and how balancing selection can act to retain diversity in the face of gene flow. Within this thesis I examined how the natural mating system of a population of sea trout (Salmo trutta) located in a stream in N E Scotland, affected levels of genetic diversity at both neutral microsatellite loci and at the MHC. High levels of multiple mating were observed for both males and females whereby females mated with as many as nine males during one spawning event and often spawned at multiple nests and males mated with as many as nine females. Repeat spawning events including the same mate pairs was common, perhaps indicating mate choice. Indeed majority males (those which sired the highest number of offspring within a nest) sired more MHC divergent offspring than expected under random mating i.e. individual offspring's maternally and paternally inherited MHC sequences contained a higher number of polymorphic sites than expected under random mating. This may indicate a mating strategy whereby disassortative MHC mate choice increases offspring diversity. Although, MHC played a significant role in mate selection¸ no selective effect of MHC diversity or genotype was found to influence offspring survival in c.8 month old parr. However, any affect may be masked by the strong family group structure within the offspring population with clustering of highly related individuals. Selective mating resulting in high individual diversity and high diversity across the offspring cohort may act as a bet hedging mechanism maximising the chances that at least some offspring will be genetically equipped to deal with selective pressures in the environment. The findings of this thesis highlight the complexity of individual mating systems and the implications that mating practices such as multiple mating and mate choice can have on offspring genetic diversity.

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38

Molano, Alberto. "Peptide binding, TCR recognition and intrathymic positive selection : by an MHC H-2Kb class I molecule devoid of the central anchor ("c") pocket /". Access full-text from WCMC, 1998. http://proquest.umi.com/pqdweb?did=733066101&sid=11&Fmt=2&clientId=8424&RQT=309&VName=PQD.

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39

Schulz, Ruth Margaret. "Tolerance status of transgenic mice expressing a major histocompatibility complex class I molecule under the control of human CD2 regulatory elements". Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362579.

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40

Strand, Tanja. "European Black Grouse : MHC Genetic Diversity and Population Structure". Doctoral thesis, Uppsala universitet, Populationsbiologi och naturvårdsbiologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-160042.

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Black grouse Tetrao tetrix is a bird species composed of large, continuous as well as severely reduced and fragmented populations, making it an optimal species to investigate how genetic diversity is affected by habitat fragmentation. I have focused on genetic diversity in the Major Histocompatibility Complex (MHC) to measure the ability of the black grouse to respond to environmental changes. I partly characterized MHC class II in black grouse and found striking similarities with chicken MHC class II. I demonstrated that black grouse possess a similar compact MHC as chicken with few MHC class II B (BLB) and Y (YLB) loci. I did not find evidence of balancing selection in YLB so I concentrated further studies on BLB. I developed a PCR-based screening method for amplifying and separating expressed BLB alleles in European black grouse populations. Small fragmented populations had lost neutral genetic diversity (based on microsatellites and SNPs) compared to samples from the historical distribution and contemporary large populations. There was also a trend, albeit less pronounced, for reduced MHC diversity in these populations. Neutral markers in small isolated populations were affected by increased levels of genetic drift and were therefore genetically differentiated compared to other populations. MHC markers on the other hand, were not subjected to genetic drift to the same extent probably due a long historic process of balancing selection. Inferences of heterozygosity and evolutionary patterns as well as detailed correlations to reproductive success and diseases cannot be performed until MHC can be amplified in a locus-specific manner. Therefore, I developed a single locus sequence-based typing method for independently amplifying MHC class II B loci (BLB1 and BLB2). I found that BLB1 and BLB2 were duplicated in a common ancestor to chickens and black grouse and that these loci are subjected to homogenizing concerted evolution due to inter-genetic exchange between loci after species divergence. I could also verify that both BLB1 and BLB2 were transcribed in black grouse and under balancing selection. This collection of work has significance for future conservation of black grouse as well as research and management of zoonotic diseases.

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41

Arauco-Shapiro, Gabriella. "The Role of Demographic History in Shaping Genetic Diversity in the Galapagos Penguin (Spheniscus mendiculus) and the Magellanic Penguin (Spheniscus magellanicus)". Bowling Green State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1494588279161113.

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Rupert, Kristi L. "The human complement component C4 and the RP-C4-CYP21-TNX (RCCX) modules of the major histocompatibility complex in Pediatric Rehumatic Diseases /". The Ohio State University, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=osu1488192119262862.

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43

Yang, Tianyu. "Two novel mechanisms of MHC class I down-regulation in human cancer accelerated degradation of TAP-1 mRNA and disruption of TAP-1 protein function /". Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1078192113.

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Thesis (Ph. D.)--Ohio State University, 2004.
Title from first page of PDF file. Document formatted into pages; contains x, 117 p.; also includes graphics (some col.) Includes bibliographical references (p. 99-117). Available online via OhioLINK's ETD Center

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44

Admyre, Charlotte. "Exosomes in immune regulation and allergy /". Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-157-9/.

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45

Forsberg, Lars. "Genetic Aspects of Sexual Selection and Mate Choice in Salmonids". Doctoral thesis, Uppsala universitet, Populationsbiologi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8837.

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The long-term genetic consequences of supportive breeding programs are not well understood. Nevertheless, stocking populations with hatchery-produced fish to compensate for losses of natural production are common practice, for example after constructions of hydroelectric power dams. Hatcheries typically fertilize eggs using ‘mixed-milt fertilizations’, without consideration to natural reproductive behaviours, and hence, natural selective regimes would be altered. Here, a series of experiments with focus on Mhc and mate choice in a population of brown trout (Salmo trutta L.) with a history of long-term stocking are presented. The major histocompatibility complex (Mhc) constitutes of genes coding for antigen presentation in the vertebrate immune system. In addition to the immunological function, Mhc genes might also influence reproductive behaviours such as mate choice. For example, in some species individuals are able to recognize Mhc genotypes of potential mates and to some extent base their mate choice on this information. Here, I address these questions on brown trout. Can the phenomena be observed in brown trout? Could such mechanisms help individuals to avoid inbreeding, or are other mechanisms important? How does the artificial rearing of fish for enhancement of natural populations relate to these issues? The results presented here, in combination with previous work, shows that several factors are important in the process of pair formation in salmonid species. For example, females of the studied population used more than a single criterion when choosing among the available mates Mhc genes and males with certain Mhc genotypes achieved more matings, possibly an effect from increased fighting ability. Further, the population appears to contain an unnatural high level of Mhc variation, and some results indicate that the population might suffer from outbreeding depression at the Mhc. These negative effects are most likely derived from compression of sub-populations after dam-construction, in combination with supportive breeding with no consideration to natural spawning behaviour.

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46

Cartier, Anna. "Inhibition of apoptosis by the Us3 protein kinase of herpes simplex virus 1 /". Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-022-2/.

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47

Baker, Bradley J. "The evolutionarily related major histocompatibility complex and CD1 : evolution of an endogenous retrovirus responsible for a polymorphism in human C4 and the biochemical characterizations of CD1A and E /". The Ohio State University, 1998. http://rave.ohiolink.edu/etdc/view?acc_num=osu148794983620512.

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48

Schad, Julia. "Evolution of major histocompatibility complex genes in New World bats and their functional importance in parasite resistance and life-history decisions in the lesser bulldog bat (Noctilio albiventris)". Phd thesis, Universität Potsdam, 2012. http://opus.kobv.de/ubp/volltexte/2013/6351/.

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Immune genes of the major histocompatibility complex (MHC) constitute a central component of the adaptive immune system and play an essential role in parasite resistance and associated life-history strategies. In addition to pathogen-mediated selection also sexual selection mechanisms have been identified as the main drivers of the typically-observed high levels of polymorphism in functionally important parts of the MHC. The recognition of the individual MHC constitution is presumed to be mediated through olfactory cues. Indeed, MHC genes are in physical linkage with olfactory receptor genes and alter the individual body odour. Moreover, they are expressed on sperm and trophoplast cells. Thus, MHC-mediated sexual selection processes might not only act in direct mate choice decisions, but also through cryptic processes during reproduction. Bats (Chiroptera) represent the second largest mammalian order and have been identified as important vectors of newly emerging infectious diseases affecting humans and wildlife. In addition, they are interesting study subjects in evolutionary ecology in the context of olfactory communication, mate choice and associated fitness benefits. Thus, it is surprising that Chiroptera belong to the least studied mammalian taxa in terms of their MHC evolution. In my doctoral thesis I aimed to gain insights in the evolution and diversity pattern of functional MHC genes in some of the major New World bat families by establishing species-specific primers through genome-walking into unknown flanking parts of familiar sites. Further, I took a free-ranging population of the lesser bulldog bat (Noctilio albiventris) in Panama as an example to understand the functional importance of the individual MHC constitution in parasite resistance and reproduction as well as the possible underlying selective forces shaping the observed diversity. My studies indicated that the typical MHC characteristics observed in other mammalian orders, like evidence for balancing and positive selection as well as recombination and gene conversion events, are also present in bats shaping their MHC diversity. I found a wide range of copy number variation of expressed DRB loci in the investigated species. In Saccopteryx bilineata, a species with a highly developed olfactory communication system, I found an exceptionally high number of MHC loci duplications generating high levels of variability at the individual level, which has never been described for any other mammalian species so far. My studies included for the first time phylogenetic relationships of MHC genes in bats and I found signs for a family-specific independent mode of evolution of duplicated genes, regardless whether the highly variable exon 2 (coding for the antigen binding region of the molecule) or more conserved exons (3, 4; encoding protein stabilizing parts) were considered indicating a monophyletic origin of duplicated loci within families. This result questions the general assumed pattern of MHC evolution in mammals where duplicated genes of different families usually cluster together suggesting that duplication occurred before speciation took place, which implies a trans-species mode of evolution. However, I found a trans-species mode of evolution within genera (Noctilio, Myotis) based on exon 2 signified by an intermingled clustering of DRB alleles. The gained knowledge on MHC sequence evolution in major New World bat families will facilitate future MHC investigations in this order. In the N. albiventris study population, the single expressed MHC class II DRB gene showed high sequence polymorphism, moderate allelic variability and high levels of population-wide heterozygosity. Whereas demographic processes had minor relevance in shaping the diversity pattern, I found clear evidence for parasite-mediated selection. This was evident by historical positive Darwinian selection maintaining diversity in the functionally important antigen binding sites, and by specific MHC alleles which were associated with low and high ectoparasite burden according to predictions of the ‘frequency dependent selection hypothesis’. Parasite resistance has been suggested to play an important role in mediating costly life history trade-offs leading to e.g. MHC- mediated benefits in sexual selection. The ‘good genes model’ predicts that males with a genetically well-adapted immune system in defending harmful parasites have the ability to allocate more resources to reproductive effort. I found support for this prediction since non-reproductive adult N. albiventris males carried more often an allele associated with high parasite loads, which differentiated them genetically from reproductively active males as well as from subadults, indicating a reduced transmission of this allele in subsequent generations. In addition, they suffered from increased ectoparasite burden which presumably reduced resources to invest in reproduction. Another sign for sexual selection was the observation of gender-specific difference in heterozygosity, with females showing lower levels of heterozygosity than males. This signifies that the sexes differ in their selection pressures, presumably through MHC-mediated molecular processes during reproduction resulting in a male specific heterozygosity advantage. My data make clear that parasite-mediated selection and sexual selection are interactive and operate together to form diversity at the MHC. Furthermore, my thesis is one of the rare studies contributing to fill the gap between MHC-mediated effects on co-evolutionary processes in parasite-host-interactions and on aspects of life-history evolution.
Innerhalb des adaptiven Immunsystems spielen die Gene des MHC (Major Histocompatibility Complex) eine zentrale Rolle. Neben ihrer Funktion für die körpereigene Parasitenabwehr haben sie auch einen entscheidenden Einfluss auf damit verbundene ‚life-history’ Strategien. Typischerweise sind die funktional für die Pathogenerkennung wichtigen Genabschnitte hoch variabel, was evolutiv nicht nur durch die Vielfalt der Pathogene bedingt ist, sondern im Zuge der sexuellen Selektion durch entsprechende Partnerwahl gefördert wird. Dabei wird die individuelle MHC-Konstitution sehr wahrscheinlich über körpereigene Duftstoffe vermittelt, denn MHC Gene bestimmen nicht nur den individuellen Körpergeruch, sondern liegen in chromosomaler Kopplung mit olfaktorischen Rezeptorgenen. Außerdem werden sie auch auf Sperma- und Trophoplastenzellen exprimiert, so dass MHC-bedingte sexuelle Selektionsmechanismen nicht nur über die direkte Partnerwahl, sondern auch durch kryptische Mechanismen während der Fortpflanzung wirken können. Fledermäuse und Flughunde (Chiroptera) bilden die zweitgrößte Säugetiergruppe und gelten als wichtiges Reservoir und Überträger für den Menschen und andere Wildtiere hoch infektiöser Krankheiten. Innerhalb der evolutionären Ökologie sind sie außerdem auf Grund ihrer z.T. komplexen olfaktorischen Kommunikation während der Partner-wahl und den damit verbundenen fitness relevanten Vorteilen interessante Forschungsobjekte. In Anbetracht dessen ist es erstaunlich, dass bisher so gut wie nichts über den MHC in dieser Säugergruppe bekannt ist. Das Ziel meiner Dissertation war es, zum einen Einblicke in die Evolution und Diversität funktional wichtiger MHC Gene (MHC Klasse II DRB) bei Fledermäusen zu erhalten, und zum anderen zu untersuchen, inwieweit die individuelle MHC-Konstitution am Beispiel der kleinen Hasenmaulfledermaus (Noctilio albiventris) einen Einfluss auf Parasitenresistenz und Fortpflanzung hat und welche Selektionsmechanismen dabei für das entstandene genetische Diversitätsmuster verantwortlich sind. Meine Arbeit zeigt, dass Prozesse, die bei anderen Vertebratenordnungen das Diversitätsmuster am MHC hervorrufen, wie balancierende und positive Selektion, Rekombination und Genkonversion ebenfalls für Fledermäuse zutreffen. In der Anzahl exprimierter DRB loci unterscheiden sich die untersuchten Fledermausarten allerdings beträchtlich. Bemerkenswert ist die extrem hohe Anzahl DRB loci bei Saccopteryx bilineata, die in dieser Ausprägung noch bei keiner anderen Säugetierart beschrieben wurde, einer Fledermaus mit einem hoch entwickelten olfaktorischen Kommunikations-system. Die hier erstmals durchgeführten phylogenetischen Untersuchungen zeigen, dass sich anders als für die meisten anderen Säugetiergruppen beschrieben, die duplizierten DRB Loci unabhängig voneinander entwickelt haben. Dieser mono-phyletische Ursprung duplizierter Loci innerhalb von Fledermausfamilien bestätigte sich für alle Bereiche des Genes: dem hochvariablen Exon 2, das für den funktional entscheidenden Pathogen-bindenden Bereich des Proteins kodiert, sowie für Exon 3 und 4, die für die Molekülstruktur erhaltende Bereiche des Proteins kodieren. Innerhalb der Gattungen (Noctilio, Myotis), basierend auf Exon 2, fand ich das für andere Säugergruppen typische Bild eines ‚trans-species polymorphism’, bei dem MHC-Allele von verschiedenen Arten sich untereinander ähnlicher sein können als Allele der gleichen Art. Meine Ergebnisse sind ein wichtiger Beitrag zum Verständnis der MHC Evolution in der Gruppe der Fledermäuse und liefern hilfreiche Kenntnisse für zukünftige Studien zum MHC in dieser Säugetierordnung. Meine Studien an einer frei lebenden Population der kleinen Hasenmaulfledermaus zeigten dass der exprimierte DRB Locus typische Anzeichen pathogenbedingter aber auch sexueller Selektionsmechanismen zeigt. Ich fand eine ausgeprägte populations-weite Heterozygotie, positive darwinsche Selektion, die den Polymorphismus in Codons die direkt an der Pathogenerkennung beteiligt sind erhält, sowie spezifische Allele die entweder mit einer erhöhten oder einer geringen Parasitenbelastung einhergehen, entsprechend den Annahmen der ‚Frequenz-abhängigen Selektions-Hypothese’. Die individuelle Parasitenresistenz gilt als ein wichtiger Faktor um ressourceabhängige ‚life-history’ Strategien auszuloten. Vor allem Männchen mit einem effektiven Immunsystem, sollten mehr Energien für die Fortpflanzung zur Verfügung haben (‚good-genes model’). Meine Daten bestätigen diese Annahme, Männchen die stärker parasitisiert waren, waren weniger häufig reproduktiv aktiv und trugen häufiger ein DRB-Allele das mit erhöhter Parasitenbelastung einherging. Genetisch unterschieden sie sich darin nicht nur von den reproduktiv aktiven Männchen der Population sondern auch von den Jungtieren. Die Jungtiere trugen zudem häufiger ein für die Parasitenabwehr vorteilhaftes Allel. Die Ergebnisse zeigen dass die individuelle MHC-Konstitution einen nicht zu unterschätzenden Einfluss auch auf den Reproduktionserfolg eines Männchens haben kann und vorteilhafte Allele sich bereits in nachfolgenden Generationen durchsetzen. Meine Doktorarbeit gehört damit zu einer der seltenen Studien, die nicht nur zeigen konnte inwieweit der MHC an co-evolutionären Prozessen der Parasit-Wirt-Interaktion beteiligt ist, sondern dass er darüber hinaus auch direkt für die individuelle ‚life-history’ Entwicklung von Bedeutung ist.

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49

Chung, Erwin Kay Wang. "The sophisticated genetic diversities of human complement component C4 and RCCX modules in systemic lupus erythematosus and congenital adrenal hyperplasia". Connect to this title online, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1054077891.

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Thesis (Ph. D.)--Ohio State University, 2004.
Title from first page of PDF file. Document formatted into pages; contains xxxii, 311 p.; also includes graphics (some col.). Includes bibliographical references (p. 287-311). Available online via OhioLINK's ETD Center

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50

Ekblom, Robert. "Immunoecology of the Great Snipe (Gallinago media) : Mate Choice, MHC Variation, and Humoral Immunocompetence in a Lekking Bird". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4585.

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Tesis sobre el tema "Human Major Histocompatibility Complex Selection"

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