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1
Glithero, Ann. "Presentation of glycopeptides by major histocompatibility complex (MHC) class I." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267901.
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Godinez, Ricardo. "Comparative Genomics of the Major Histocompatibility Complex in Amniotes." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10685.
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The major histocompatibility complex region (MHC) is a multi gene family present in all jawed vertebrates, with a fundamental role in vertebrate immunity. More than two decades of studies have resulted in the characterization of over a dozen MHC regions, and models of evolution explaining that the MHC has gradually increased in size and gene content since its origins without addressing their genomic context or the environmental selective forces. Furthermore, a compelling reconstruction of the evolutionary history of the MHC has been hampered due to phylogenetic gaps and the absence of comparative phylogenetic methods applied to comparative genomics. Here I reconstruct 320 MY of MHC evolution using 42 amniote genomes using improved gene annotations, genomic alignments and phylogenetic algorithms to reconstruct the evolution of the MHC at three levels of phylogenetic resolution. The first one describes 25 MY of evolution of the primate MHC using eight Human and four non-Human primate MHC haplotypes. Results suggests that highly dense gene segments have a strikingly conserved gene organization, and six conserved and highly rearranging segments overlap genes that are most commonly associated to disease. Phylogenomic analysis implies that the MHC has remained stable in gene content and size, with significantly increased duplication rates in the primate ancestors. The second one describes 280 MY of MHC evolution through the first characterization of reptilian MHC region, which combines mammalian, reptilian, Bird and amphibian characteristics, which favors the hypothesis of the existence of a primordial MHC in which natural killer receptors, CD1 and lectin genes co-exist. The Anolis MHC expands our understanding of the origins of the exceptionally small Bird MHC regions and provides further information about the organization and size of the ancestral amniote MHC. The third one compares 42 amniote MHC regions and map gene duplications and losses to further evaluate the mode and tempo of the evolution of the region. Comparative phylogenetic methods imply that the genomic and environmental factors affect the diversification of MHC during 320 My of evolution.
3
Qin, Jinyi. "Characterisation of the central region of the sheep major histocompatibility complex." Thesis, Curtin University, 2008. http://hdl.handle.net/20.500.11937/375.
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The major histocompatibility complex (MHC) is a chromosomal region encoding molecules controlling adaptive immune response in vertebrates. In farm animals, many associations between MHC loci and productivity traits including disease susceptibility have been described. However, current knowledge about the structure and function of the MHC in domestic animals, especially sheep, is very limited. Characterization of the sheep MHC may potentially facilitate breeding for enhanced disease-resistant animals through use of marker assisted selection. The main aim of this project has been to provide insights into the organization of the genomic content of the central region of the sheep MHC. The work described herein has utilized subcloning of a sheep BAC genomic library in conjunction with DNA sequencing to generate a map of the central region of the sheep MHC covering ≈700 kbp. Within this map the relative order and identity of twenty five recognized loci were established. For some loci the intergenic distances were also determined. The final map is the most accurate map of this region reported to date and shows a high degree of similarity to the analogous region of the human MHC. This work has been published and a copy of the paper is included in Appendix 1. During the course of this work detailed genomic sequences were obtained for several sheep central region loci. Complete nucleotide sequences were generated for the complement factor B locus (CFB) and the TNFα locus and a comparative analysis of these sequences confirmed their homology with other vertebrate orthologues. Extensive partial sequences for complement components C2 and C4 were also obtained and reported to GenBank.In addition, a previously identified short tandem repeat locus designated BfMs believed to be in the CFB locus was mapped to an intron within the adjacent SKI2VL locus. Single nucleotide polymorphisms (SNPs) were identified by analysing homologous sequences from a minimum of five individual sheep. In total 33 SNPs were discovered distributed over eleven distinct loci. Allele frequencies for SNPs from ten of these loci were determined and reported for a panel of 71 sheep comprising 58 unrelated sheep from the Rylington Merino flock plus a further 13 unrelated parental animals from a three generation half sibling sheep pedigree. The availability of an independently confirmed pedigree constructed from a three generation half sibling sheep family permitted the identification by deduction of central region MHC haplotypes based on a panel of SNPs derived from 10 loci. This is the first reporting of haplotypes covering this region of the sheep MHC. Analysis of SNP panel genotypes in the cohort of 71 unrelated sheep using the expectation maximization algorithm permitted the prediction of a group of approximately 20 haplotypes, which accounted for more than 90% of the expected haplotype distribution. Four of these predicted haplotypes were also present in the known haplotype cohort deduced from the sheep pedigree. Analysis of pairwise linkage disequilibrium between SNP loci in the cohort of 71 unrelated sheep showed a centre-most region displaying relatively high levels of linkage disequilibrium which was bounded by two regions displaying more variable linkage disequilibrium.It is hypothesised that this mid region of the central region of the sheep MHC may be a block like structure characterized by low recombination similar to those that have been widely described in the human and mouse genomes. The discoveries reported in this thesis provide a more accurate and detailed description of the central region of the sheep MHC together with a panel of SNPs, which reflect the diversity of this important genomic region which is known to be associated with immune responsiveness. The description, for the first time, of central region haplotypes provides a practical means of seeking candidate loci associated with disease resistance and productivity traits. The application of molecular techniques will enhance the rate at which the genomic composition of this region is elucidated and the work described in this thesis will contribute to final characterization of this important complex in health and disease.
4
Feichtlbauer-Huber, Petra. "Einfluss des major histocompatibility complex (MHC) auf die Nematodenanfälligkeit beim Schaf." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=964457458.
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5
Miltiadou, Despoin. "Characterization of the ovine Major Histocompatibility Complex (MHC) class I genes." Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/29891.
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To develop cellular and molecular tools to support development of vaccines against intracellular pathogens of sheep, a molecular genetic analysis of four distinct ovine MHC haplotypes carried by two heterozygous Blackface rams (501 and 504) was conducted. A total of 17 novel sequences was identified, 11 of which were obtained full length. Phylogenetic analysis using the identified transcripts and published ovine, bovine and other ruminant class I sequences belonging to the Bovidae family indicated that there are at least six ovine MHC class I loci (chapter 6). Sequence N1 and N2 are closer to the non classical bovine MHC class I sequence HD15 than to the remaining ovine class I transcripts. Seven out of eight full length transcripts subcloned into a mammalian expression vector expressed detectable class I cell surface glycoproteins in COS-7 cells (chapter 7). The combination of phylogenetic analysis, haplotype, transcription and expression data suggest that there are at least four distinct polymorphic ovine MHC class I loci, three of which appear to be expressed in a number of combinations in individual haplotypes, a couple of non polymorphic poorly transcribed class I like sequences and at least one additional diverged non classical class I locus (chapter 8). Similarities and differences of the ovine MHC class I region with that of other species and implications in immune response and sustainable control of intracellular sheep pathogens are discussed. Using the data generated here, an MHC defined sheep flock, which includes animals homozygous for each of the four MHC haplotypes, is currently under development. The MHC defined resource population, along with the transfected cell lines expressing each of the full length ovine MHC class I sequences, comprise tools for immunization and disease association experiments studying the protective immunity to intracellular pathogens of sheep.
6
Lim, Elaine Hsuen. "Study of Fugu orthologues of mammalian MHC class III genes." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266288.
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7
Lo, Yun-hua. "A preliminary survey of MHC class I sequences in mandrills." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648208.
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8
Qin, Jinyi. "Characterisation of the central region of the sheep major histocompatibility complex." Curtin University of Technology, School of Biomedical Sciences, 2008. http://espace.library.curtin.edu.au:80/R/?func=dbin-jump-full&object_id=118317.
Full textAbstract:
The major histocompatibility complex (MHC) is a chromosomal region encoding molecules controlling adaptive immune response in vertebrates. In farm animals, many associations between MHC loci and productivity traits including disease susceptibility have been described. However, current knowledge about the structure and function of the MHC in domestic animals, especially sheep, is very limited. Characterization of the sheep MHC may potentially facilitate breeding for enhanced disease-resistant animals through use of marker assisted selection. The main aim of this project has been to provide insights into the organization of the genomic content of the central region of the sheep MHC. The work described herein has utilized subcloning of a sheep BAC genomic library in conjunction with DNA sequencing to generate a map of the central region of the sheep MHC covering ≈700 kbp. Within this map the relative order and identity of twenty five recognized loci were established. For some loci the intergenic distances were also determined. The final map is the most accurate map of this region reported to date and shows a high degree of similarity to the analogous region of the human MHC. This work has been published and a copy of the paper is included in Appendix 1. During the course of this work detailed genomic sequences were obtained for several sheep central region loci. Complete nucleotide sequences were generated for the complement factor B locus (CFB) and the TNFα locus and a comparative analysis of these sequences confirmed their homology with other vertebrate orthologues. Extensive partial sequences for complement components C2 and C4 were also obtained and reported to GenBank.In addition, a previously identified short tandem repeat locus designated BfMs believed to be in the CFB locus was mapped to an intron within the adjacent SKI2VL locus. Single nucleotide polymorphisms (SNPs) were identified by analysing homologous sequences from a minimum of five individual sheep. In total 33 SNPs were discovered distributed over eleven distinct loci. Allele frequencies for SNPs from ten of these loci were determined and reported for a panel of 71 sheep comprising 58 unrelated sheep from the Rylington Merino flock plus a further 13 unrelated parental animals from a three generation half sibling sheep pedigree. The availability of an independently confirmed pedigree constructed from a three generation half sibling sheep family permitted the identification by deduction of central region MHC haplotypes based on a panel of SNPs derived from 10 loci. This is the first reporting of haplotypes covering this region of the sheep MHC. Analysis of SNP panel genotypes in the cohort of 71 unrelated sheep using the expectation maximization algorithm permitted the prediction of a group of approximately 20 haplotypes, which accounted for more than 90% of the expected haplotype distribution. Four of these predicted haplotypes were also present in the known haplotype cohort deduced from the sheep pedigree. Analysis of pairwise linkage disequilibrium between SNP loci in the cohort of 71 unrelated sheep showed a centre-most region displaying relatively high levels of linkage disequilibrium which was bounded by two regions displaying more variable linkage disequilibrium.
It is hypothesised that this mid region of the central region of the sheep MHC may be a block like structure characterized by low recombination similar to those that have been widely described in the human and mouse genomes. The discoveries reported in this thesis provide a more accurate and detailed description of the central region of the sheep MHC together with a panel of SNPs, which reflect the diversity of this important genomic region which is known to be associated with immune responsiveness. The description, for the first time, of central region haplotypes provides a practical means of seeking candidate loci associated with disease resistance and productivity traits. The application of molecular techniques will enhance the rate at which the genomic composition of this region is elucidated and the work described in this thesis will contribute to final characterization of this important complex in health and disease.
9
Parker, Kay Elizabeth. "Genetic and immunological studies on class I MHC antigens of the rat." Thesis, Open University, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278511.
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Rogers, Sarah Louise. "Characterisation of C-type lectin-like receptor genes in the chicken MHC." Thesis, University of Bristol, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271871.
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11
Mawas, Fatme Omar. "Expession of MHC molecules on rat cardiac cells : its effect on their immunogenicity in vitro." Thesis, King's College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283719.
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12
Lill, Jennie Rebecca. "Characterisation of MHC class I tumour antigens." Thesis, Nottingham Trent University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366082.
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13
Lee, Chee Yang. "Characterisation of the ovine major histocompatibility complex class II region." Thesis, Curtin University, 2009. http://hdl.handle.net/20.500.11937/1849.
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The main aim of this project has been to provide insights into the genomic organization of the class II region of the ovine major histocompatibility complex (MHC), a chromosomal region containing genes that control adaptive immune responses in vertebrate species. Assessment of the potential of measuring resting serum IgA levels as a predictor of the resistance of sheep to gastrointestinal parasites was also undertaken.Loci within the ovine MHC class II region were identified and sequenced either by direct sequencing of known class II genes using ovine specific primers or from sub-clones constructed from bacterial artificial chromosome (BAC) clones containing the class II region. The loci were apportioned into two groups (IIa and IIb) based on analogy with the class II region in the cattle MHC where it is known that a chromosomal inversion has divided and separated the region into two subregions ≈15 cM apart. All sequences obtained have been deposited in GenBank. A relative map of the ovine class IIa and IIb subregions was constructed based on comparative information from the human and cattle MHCs. Additionally, complete nucleotide sequences were obtained for the protein folding chaperone gene PFDN6; phylogenetic analysis confirmed its homology and impressive conservation with orthologues from other vertebrate. Partial sequences were also generated for several other loci including WDR46 and DRA.Single nucleotide polymorphisms (SNPs) were identified by analysing homologous sequences from a minimum of five individual sheep. In total, 103 SNPs were discovered that were distributed over 20 distinct loci spanning both the putative class IIa and IIb regions. Genotypes were typed for panels of 10 SNPs across each of the ovine class IIa, IIb subregions, plus 10 published SNP loci for the class III region, in a total of 261 sheep. The sheep comprised 68 unrelated parental animals and 193 sheep from nine different family groups for which worm egg count (WEC) data and estimated breeding values (EBV) were available. Allele frequencies for each SNP locus were estimated and determined to be in Hardy Weinberg proportions. Analysis of SNP heterozygosity in sheep revealed a region within the class IIa subregion where heterozygosity was reduced. This region is similar to a corresponding region within the human MHC manifesting a reduced frequency of SNPs. Analysis of linkage disequilibrium (LD) across the panel of 30 SNP loci showed regions of high and low LD. The region of low heterozygosity within the putative sheep class IIa subregion was characterised by low LD.The availability of independently confirmed pedigrees permitted identification of 54 Mendelian inherited haplotypes across the class IIa, IIb and III subregions for all 30 loci. Haplotypes for other sheep were inferred using the EM algorithm as implemented in the SNPstats software package. Analysis of the deduced haplotypes showed evidence for the presence of conserved allele groupings or ‘blocks’ corresponding to each subregion. These ‘blocks’ seemed to occur more frequently than expected despite some SNP loci being homozygous (especially in the sires). Similar blocks were predicted by haplotype function in SNPstats. This result suggests that conserved subregion haplotypes may be present in the sheep MHC as are known to exist in the human MHC. Further analysis of the sheep pedigrees showed four haplotypic crossovers between the class IIb and class IIa subregions. Four sire derived crossovers in 21 meioses is consistent with a physical separation between these two subregions similar to that observed in cattle. No crossovers were observed between the class IIa and class III subregions.Total and parasite-specific IgA levels were measured in serum collected post weaning from 171 unchallenged sheep for which WEC data was available. There were no significant correlations between either total or parasite specific IgA serum levels and post natal WEC or WEC at weaning Hence, this parameter is not a useful predictor of worm immunity and cannot replace the more difficult to measure WEC values. Multiple regression analysis of the data did suggest however that IgA synthesis may have a role in the humoral immune responses of sheep to gastrointestinal parasites.The discoveries reported in this thesis provide a more detailed description of the ovine MHC class II region, evidence of its division into two separated subregions, and the description of haplotypes based on newly discovered SNPs. Haplotypic associations with breeding values based on WEC were identified, but these did not permit speculation concerning the identity of candidate loci for parasite immunity probably due to the relatively small populations studied. These findings will contribute to association and linkage studies in larger sheep populations and between breeds in the search for genetic determinants of immunity to gastrointestinal worms. It is expected that such determinants in turn will facilitate breeding for more disease-resistant sheep by marker-assisted selection with consequent increases in industry productivity.
14
Ramsay, Joshua David. "Development of a DNA microarray for detection of expressed equine classical MHC class I alleles in a defined population." Pullman, Wash. : Washington State University, 2009. http://www.dissertations.wsu.edu/Thesis/Fall2009/j_ramsay_112309.pdf.
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Thesis (M.S. in veterinary science)--Washington State University, December 2009.Title from PDF title page (viewed on Jan. 14, 2010). "College of Veterinary Medicine." Includes bibliographical references (p. 12-13).
15
Scott, Adrian Phillip. "Investigation of major histocompatibility complex (MHC) associations in sporadic inclusion body myositis." University of Western Australia. School of Pathology and Laboratory Medicine, 2009. http://theses.library.uwa.edu.au/adt-WU2009.0153.
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[Truncated abstract] Sporadic inclusion body myositis (sIBM) is a chronic inflammatory disease that is the most common myopathy in individuals above the age of 50 in the Caucasian population. sIBM is characterised by cytotoxic immune infiltration of skeletal muscle, consisting primarily of CD8+ T-cells and macrophages, as well as a degenerative process, with muscle fibre vacuolation and intracellular filamentous inclusions. The pathogenesis of sIBM is likely to involve a complex interaction between genetic and environmental factors. Whilst the physiological and pathological characteristics of sIBM have been clearly identified, the exact origin and genetic basis of the disease remains unknown. A number of studies show that sIBM is associated with alleles of the major histocompatibility complex (MHC) on chromosome 6p21.3 and specifically with two ancestral haplotypes (AH) in Caucasians the 8.1AH, defined by HLA-B*0801, HLA-DRB1*0301 and the 35.2AH, defined by HLA-B*3501, HLA-DRB1*0101. Mapping studies subsequently showed that sIBM susceptibility likely originates from a 389kb region of the MHC, spanning from centromeric of PBX2 to telomeric of HLA-DRB1. The central hypothesis of this thesis was that susceptibility to sIBM is conferred by a single allele found within a region defined using the 8.1AH, which is also carried by other haplotypes associated with sIBM. Three patient cohorts from Australia, the U.S.A and Japan were studied. ... Of the 32 alleles genotyped, none were found in all susceptibility haplotypes and one was common, but not unique, to the 8.1AH, 7.2AH and 52.1AH. Five SNPs were also found in two of the three haplotypes, although none were specific to the sIBM susceptibility haplotypes. These data suggest that the 8.1AH is likely to carry an sIBM susceptibility allele independent of the 35.2AH, 7.2AH and 52.1AH. Based on the possible mechanism of action in cellular differentiation and its location within the 8.1AH-defined sIBM susceptibility region reported in 2004, NOTCH4 was a strong candidate for conferring sIBM susceptibility. NOTCH4 coding region polymorphisms were thus investigated in a Caucasian patient cohort to assess any possible role in sIBM susceptibility. While the frequency of some alleles were increased in sIBM patients, the strong linkage disequilibrium throughout the MHC prevented confirmation of any alleles as playing a direct role in sIBM. The 8.1AH-derived sIBM susceptibility region was further refined using recombination mapping. This approach used markers characterised against multiple haplotypes to genotype patients carrying part of the 8.1AH to locate a common, overlapping susceptibility region. Recombination mapping of patients revealed a common overlapping region of the 8.1AH, extending from BTNL2 to HLA-DRB3. The results of the study indicate that 8.1AH-derived susceptibility for sIBM is likely to originate from a 172kb region encompassing HLA-DRA, HLA-DRB3 and part of BTNL2. These genes warrant further investigation in future studies.
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Siva, Subramaniam Nitthiya. "An analysis of the Class 1 Gene region in sheep major histocompatibility complex." Thesis, Curtin University, 2012. http://hdl.handle.net/20.500.11937/773.
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The major histocompatibility complex (MHC) is a chromosomal region associated with immune responsiveness in vertebrates. Over four decades many studies have demonstrated important associations between MHC loci and disease resistance or susceptibility in a variety of mammals, especially humans and mice. However, characterisation of the sheep MHC has not been widely studied compared to other domestic species. Since sheep provide food and fibre to many of the world’s populations, and is a major industry in Australia a better understanding of the sheep MHC will deliver many benefits when used in conjunction with the new field of genomics, such as the marker assisted selective breeding.This will be of particular benefit for traits that are difficult to improve by conventional selection - especially those that have low heritability, or are expensive to breed for by phenotypic selection. The main aims of this study are to characterise better the genomic architecture of the sheep MHC class I region and to explore structure function relationships of some of the many loci therein. Essential to these aims is the discovery of polymorphic loci, especially SNPs, and the identification of haplotypic elements for association studies and patterns of recombination within this region.Bacterial artificial chromosomes (BACs) containing sub-regions of the sheep MHC class I region were sub-cloned and sequenced. Contiguous sequences were then re-assembled to generate a physical map of MHC class I region. Single nucleotide polymorphisms (SNPs) within the sheep MHC class I region were identified by polymerase chain reaction (PCR) amplification and sequencing of specific loci in a small population of unrelated sheep. Subsequently, a panel of SNPs spanning the class I region were chosen to genotype a population of distantly related 108 animals to develop a linkage disequilibrium (LD) map, and identify possible recombination hotspots relative to the LD blocks within this region. In addition, the SNP genotypes were used to predict haplotypes within the sheep MHC class I region.In conjunction with these studies, a small population of homozygous sheep was produced by sire-daughter mating for identification of discrete immune related genes within the class I region. This strategy was considered necessary to reduce allelic variation thereby facilitating the detection of discrete class I loci within a region noted for multiple copies of classical (Ia) and non-classical (Ib) class I genes, as well as probable pseudogenes. MHC class I gene sequences derived from homozygous sheep were supplemented with published reference sequences of different breeds. The many sheep sequences obtained were subjected to multiple sequence alignments and phylogenetic analysis in order to estimate the number of discrete loci present.The SNP panel generated in this project was also used for association studies with wool production traits in sheep and class I haplotypes. In particular, intragenic genotypes and haplotypes from the skin and hair related Corneodesmosin (CDSN) gene were analysed in 107 sheep with known estimated breeding values (EBV) for clean fleece weight (CFW), fibre diameter (FD) and staple strength (SS).The work described herein produced a comprehensive physical map of the sheep MHC class I region, which includes information relating to gene location and organisation. Immune related class I genes are clustered into 3 blocks; beta, kappa and a novel block not previously identified in other organisms. The organisation of other MHC class I genes is similar to that present in the cattle MHC except for a re-arrangement of a cluster of TRIM genes. Thirty two SNPs were identified from 14 distinct loci within the MHC class I region. Linkage analysis with a selected panel of 14 SNPs spanning approximately 505 kbp of the class I region revealed four blocks characterised by high linkage disequilibrium. Genotyping of 108 animals with this SNP panel permitted the prediction of thirty four unique haplotypes, which accounted for approximately 90% of haplotype frequency.Two of these haplotypes showed associations with wool production traits, suggesting that the SNPs analysed within MHC class I could be part of an extended haplotype influencing for wool traits. Classification of MHC classical (Ia) and non-classical genes into loci resulted in identification of 14 loci in the sequences analysed. A few of the loci identified show breed specific characteristics and explains possible evolutionary history of the loci in different breeds of sheep. Analysis of SNPs within CDSN showed that the gene, which is located in the MHC class I region has an association with fineness of wool in sheep. Five SNPs within the coding region showed reduced EBV for fibre diameter when present in a homozygous state.This project has resulted therefore in an improved physical map of the class I region in the sheep MHC, the identification and annotation of several new genes, together with genotypic and haplotypic associations with productivity traits in sheep that will be of immediate interest to the wool industry. As often is the case, the resulted obtained have generated more questions that relate to the structure, function and evolution of this fascinating genomic region that is a critical modulator of the adaptive immune response in vertebrates.
17
Dicks, Kara Leanne. "Unravelling major histocompatibility complex diversity in the Soay sheep of St Kilda." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31412.
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The major histocompatibility complex (MHC) is one of the most variable regions in the vertebrate genome. Many genes within the MHC play important roles in the development of an immune response, including the response to pathogens, by presenting pathogen fragments to T cells. Pathogen-mediated balancing selection is thought to be important in maintaining the high levels of allelic variation at these loci, though the precise mechanism remains unclear. The number of studies of MHC diversity in non-model organisms has increased dramatically in recent years as genotype data have become cheaper and easier to generate; however, key limitations in many such studies remain a lack of high quality MHC genotypes and associated phenotype data. Many studies focus on a single MHC locus, assuming that one locus will represent the full range of variation within each MHC haplotype. Alternatively, the products of different loci may co-amplify, preventing locus-specific genotypes and hence heterozygosity being accurately determined. Non-model systems are also often limited by small sample sizes and limited recording of associated host and pathogen measures, which, combined with high levels of allelic variation at MHC loci, can limit statistical power. Finally, few MHC studies control for the general effect of relatedness in explaining host traits before testing for MHC effects. With so many methodological impediments, it is challenging to identify robust associations between MHC variation and host phenotypes, such as parasite burden or fitness, and to draw conclusions about the mechanisms underpinning the maintenance of diversity at MHC loci. In this thesis, I address these problems by developing a SNP-based haplotyping system for a population of unmanaged Soay sheep (Ovis aries) on Hirta, St. Kilda, for which data is available on pedigree, phenotypic traits and fitness and its components over a 30- year study period. The ovine MHC consists of four classes of loci, within which loci are tightly clustered and show reduced recombination rates compared to the genome average. Although the mammalian MHC is usually highly variable, one would expect that the number of haplotypes within an MHC class in an island population of sheep with no immigration to be limited. The class IIa region of the ovine MHC includes the classical class II loci which are typically thought to be involved in the presentation of peptides derived from extracellular pathogens, including gastrointestinal helminths, in sheep and other mammals. In chapters 2 to 4, I describe the characterisation of class IIa haplotypic diversity in the Soay sheep using direct Sanger sequencing of PCR amplified fragments, which, in combination with cloning, revealed eight distinct haplotypes. With this knowledge of haplotypic diversity, and genotypes for a sample of Soay sheep typed on the Ovine Infinium HD chip (approximately 600K SNPs), I developed a panel of 13 SNPs which could be used to impute the class IIa haplotypes. This panel was genotyped by KASP (Kompetitive Allele Specific PCR) in 6034 samples and used to impute the class IIa haplotypes. After quality control measures, class IIa haplotypes were successfully imputed for 5349 individuals. Evidence of balancing selection was identified using the Ewens-Watterson test at different life history stages and within the standing population each year between 1985 and 2012, showing that allele frequencies were more even than would be expected under neutrality. However, there was no evidence of deviation from Hardy-Weinberg equilibrium identified at different life stages or in the standing population in any year. In chapter 5, I investigate associations between the MHC class IIa haplotypes and individual-level data on host phenotypes - body weight, plasma immunoglobulin levels (measured as anti-Teladorsagia circumcincta third larval stage IgA, IgE and IgG) and strongyle faecal egg counts (FEC). Associations were tested within mixed effects models which were used to account for repeated measures and control for fixed effects known to affect the response variables, as well as within an animal model framework to account for relatedness between individuals. Haplotype heterozygosity was unrelated to any of the traits investigated, suggesting a general heterozygote advantage is unlikely to be operating within the Soay sheep. Six of the eight class IIa haplotypes were associated with multiple traits in different age-sex classes, although many of these associations were removed after inclusion within animal models. The evidence of balancing selection and associations between class IIa haplotypes and phenotypes related to health offers a promising glimpse into the evolutionary mechanisms which may be operating to maintain diversity within this region.
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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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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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Chrisp, Jacqueline Anne. "Studies on the expression of the IL5 gene in T lymphocytes and the structure and expression of the novel MHC gene G1." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260728.
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Smith, Kathrine Jane. "Structural analysis of MHC Class I B allele single peptide complexes." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318816.
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Thorpe, Karen Louise. "Gene structure, phylogeny and mutation analysis of RING3 : a novel MHC-encoded gene." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325009.
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Adhikari, Raju. "The role of calnexin, calreticulin and heavy chain glycosylation in MHC class I assembly." Thesis, University of Oxford, 2002. http://ora.ox.ac.uk/objects/uuid:8d626bbd-4927-4a52-b892-461e968a1c96.
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Class I heavy chain (HC) must assemble with β-microglobulin (β2m) and acquire optimal peptide in order to be presented to cytotoxic T cells (CTLs). Calnexin is involved in the initial folding of class I HC and subsequent assembly with β2m. Incorporation of "empty" or suboptimally loaded class I molecules into the multimolecular loading complex is essential for them to acquire optimal peptides. The loading complex consists of several cofactors: TAP, tapasin, ERp57 and calreticulin. The precise role of calnexin and calreticulin in the regulated assembly and peptide loading and the significance of their physical interaction with other cofactors of the loading as well as preloading complex still remains unclear. Using mouse fibroblasts that lack calreticulin, I have studied the role of calreticulin in the assembly and loading of H2-Kb and H2-Db expressed in these cells. MHC class I molecules in calreticulin-deficient cells are able to assemble with β2m normally, but their subsequent loading with optimal, stabilising peptides is defective despite their ability to interact with the TAP complex. The "empty" or suboptimally loaded class I molecules exit the ER rapidly. Reflecting the loading defect, presentation of endogenously processed antigens by class I molecules in calreticulin-deficient cells is impaired. I have used a human calnexin-deficient cell line CEM.NKR to study assembly of class I in the absence of calnexin. The results demonstrate that contrary to current understanding, calnexin has an important role in class I HC assembly with 32- microglobulin. The role of heavy chain glycosylation in class I biogenesis is still controversial. My findings suggest asparagine (N)-linked glycosylation of human class I heavy chain at position 86 is optimal and any deviations from "normal" glycosylation results in poor loading with peptides and some defect in the assembly with β2m. Despite affecting the loading function, glycosylation did not have significant effect on presentation of a high affinity binding epitope to HLA-A*0201 specific CTLs. Finally, I show that co-operation from all domains of calreticulin is essential in order to generate a fully functional calreticulin. Interestingly, proline-rich (P) -domain of calreticulin downregulated expression of a number of cellular proteins including MHC class I HC, despite restoring the cytosolic calcium levels in calreticulindeficient cells. The effect of P-domain on class I expression was at the level of transcription.
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Vugmeyster, Yulia 1973. "The Major Histocompatibility Complex (MHC) and the proteasome-ubiquitin pathway in T cell development." Thesis, Massachusetts Institute of Technology, 2002. http://hdl.handle.net/1721.1/8322.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2002.Includes bibliographical references.
The essential role of classical MHC molecules in T cell development as well as the proteasome role in antigen processing for MHC-mediated antigen presentation to T cells is well established. However, the contribution of nonclassical MHC molecules, the signals evoked by the MHC-TCR interactions, the signaling role of the proteasome-mediated proteolysis, and the regulation of the proteasome-ubiquitin proteolysis remain to be clarified. Here we address these more subtle but essential aspects of T cell development. We obtained mice deficient for MHC molecules encoded by the H-2K and H-2D genes. KbDb -/- mice have greatly reduced numbers of mature CD8+ T cells, indicating that selection of CD8+ T cells can not be compensated for by [beta]2m-associated molecules other than classical H-2K and D locus products. Spleen cells from KbDb -/- mice generate strong CD8+ MHC class I-specific responses after in vivo priming. Thus, a minor population of CD8+ T cells arises in the complete absence of classical MHC class I molecules. KbDb -/- animals also have self-tolerant natural killer (NK) cells that retain their cytotoxic potential. We utilize a fetal thymic organ culture (FTOC) system with a panel of proteasome inhibitors to implicate the proteasome in thymocyte apoptosis and negative selection. We find that proteasome inhibitors do not completely block but rather delay both dexamethasone- and antigen-triggered thymocyte apoptosis. We also show that proteasome activity is increased in apoptotic thymocytes,
(cont.) as visualized by active site labeling of proteasomal D subunits, indicating that proteasome functions as a positive regulator in thymocyte death cascade. We show that the deubiquitinating enzyme USP7 (HAUSP) is specifically and uniquely processed in apoptotic thymocytes. USP7 protein is highly expressed in thymus, spleen, and brain and is very similar in men and mice. Processing of USP7 does not occur in caspase 3-/- thymocytes but caspase 3 does not cleave USP7 directly. Our results suggest that thymocyte apoptosis leads to a modification of a deubiquitinating enzyme and may provide an additional link between the proteasome-ubiquitin pathway and the caspase cascade during programmed cell death.
by Yulia Vugmeyster.
Ph.D.
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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 studyTiivistelmä 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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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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McMillan, Heather Anne. "MHC, parasite burden and heterozygosity in the blue shark (Prionace glauca, L.1758)." Thesis, University of Aberdeen, 2013. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=205227.
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The blue shark (Prionace glauca) is a highly migratory pelagic elasmobranch that inhabits ocean basins globally. As a result, this shark is exposed to intensive ocean exploitation by commercial target fisheries, by-catch and for recreational pursuits globally. This top predator is therefore at high risk of becoming overfished. Advances to current knowledge of genetic population structure and diversity of this species would provide vital information required to initiate co-operative management approaches. In this study, the major histocompatibility complex (MHC) class IIa and IIβ genes were successfully isolated and characterised from blue sharks. Phylogenetic trees of the class II genes showed three major clades; one of teleost fish, one of tetrapods and one of sharks. The MHC class IIβ gene exon 2 primers successfully amplified partial sequences in blue sharks from several global locations. Analysis of sequences using denaturing gradient gel electrophoresis (DGGE) suggested the assay resolved different sequences up to one basepair, making the assay potentially very useful with further development. The class II genes presented in this study show conflicting evidence for the presence of more than one class II locus. To explore inheritance patterns of MHC exon 2 diversity, a single blue shark litter (mother + 19 pups) was cloned and sequenced, revealing evidence to suggest the possibility of more than one locus for class IIβ. Statistical analysis of parasite loads and diversities from blue shark spiral valves revealed no definitive population structure, supporting global and North Atlantic mtDNA and microsatellites genetic analyses presented here. The size (fork length) of sharks was found to be potentially influential when modelled with individual microsatellite heterozygosity and fork length. International co-operation will be required to prevent this species becoming extinct from global marine ecosystems. Reductions in numbers could lead to reduced genetic diversity, decreased immunity and ultimately an 'unhealthy' population.
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Baxter, Rebecca Jayne. "Role of the major histocompatibility complex in immune responsiveness in a Holstein Charolais cattle cross population." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5267.
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Infectious disease is a major issue facing the livestock industry. Further understanding of the role of genetic factors in the observed phenotypic variability of the immune response to pathogens and vaccination could assist in designing improved preventative measures such as more efficacious vaccines and targeted breeding strategies to select for disease resistance. Major candidate genes for controlling immune responsiveness are located within the major histocompatibility complex (MHC). The highly polymorphic classical MHC genes are key determinants in the strength and type of immune response. However, it has proved difficult to establish genotyping approaches to define functionally relevant allelic variations for outbred species such as cattle, not least because the peptide binding clefts (PBC) of classical MHC molecules are highly polymorphic, and the genes within the MHC complex are closely linked. The overall aim of this project was to investigate the role of MHC genes in immune responsiveness in approximately 200 F2 and backcross Holstein-Charolais cattle. These animals were generated as part of the Roslin Bovine Genome (RoBoGen) herd, established through a quantitative trait loci (QTL) project, in which a number of phenotypic traits including immune traits were measured. The immune traits included responses to a Foot-and-mouth disease virus (FMDV) peptide, and vaccines against bovine respiratory syncytial virus (BRSV), para-influenza virus 3 (PIV-3) and bovine herpes virus-1 (BHV-1), as well as T cell response to Staphylococcus aureus. The immune phenotypes measured included IgG and interferon- (IFN- ) levels and T cell proliferation. The cattle MHC region, known as bovine leukocyte antigens (BoLA), resides on bovine chromosome 23. The BoLA region contains approximately 200 genes most of which are immune-related. Class II gene polymorphisms were considered to be the most likely to influence the immune traits measured, and the project primarily focused on the best defined gene, BoLA-DRB3. A sequence-based typing technique was successfully improved to facilitate genotyping of the PBC of BoLA-DRB3 in all generations of the RoBoGen herd (approximately 400 animals) and identified 24 distinct alleles. The sequence information obtained also enabled further analysis of the role of defined ‘pockets’ within the PBC, which directly determine peptide binding affinity. All datasets were statistically analysed using a residual maximum likelihood (REML) model and it was shown that several of the DRB3 alleles within the RoBoGen herd had highly significant (p<0.05) associations with the immune response to the FMDV peptide. In addition DRB3 alleles were identified which had significant associations with the response to the respiratory pathogen vaccinations and exposure to S. aureus. The pocket analysis also enabled the identification of several amino acid positions within the PBC which were significantly associated with the immune response traits. In order to explore whether DQ Class II gene polymorphisms also played a role in the variability of responses and whether BoLA Class I-Class II haplotypes could be discerned, microarrays which utilized allele specific oligonucleotides for BoLA Class I and Class II DQ genes were employed. In addition, to investigate whether the number of DQ gene pairs per chromosome influenced the responses, a quantitative polymerase chain reaction (qPCR) assay to determine DQA gene dosage was developed. However, due to the extremely complex nature of the BoLA region both, techniques would require improving to be used for large-scale studies. Nonetheless, information about haplotypes was determined from the microarray results and the qPCR technique lays the foundations for future development to investigate DQ gene dosage. The MHC region in cattle is very complex due the high level of polymorphisms and gene duplications. It is likely that many genes play a role in the immune response to both pathogens and vaccines. However, from the evidence presented here, polymorphisms in the PBC of BoLA-DRB3, particularly within the pockets, are significantly associated with variation in immune response to many different antigens and this information could be exploited in the design of vaccines or breeding cattle for improved disease resistance.
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Parasar, Parveen. "Determination of the Expression Patterns of Bovine Non-Classical Major Histocompatibility Complex (MHC) Class I Proteins." DigitalCommons@USU, 2013. http://digitalcommons.usu.edu/etd/1999.
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My dissertation hypothesis is that bovine trophoblast cells express cell-surface and secreted non-classical major histocompatibility complex class I (MHC-Ib) proteins which inhibit NK cells and other leukocytes by binding to inhibitory receptors (e.g., LILRB1, LILRB2, KIR2DL4, and/or CD94/NKG2A). Extremely polymorphic and ubiquitously expressed classical MHC class I (MHC-Ia) proteins, which present foreign antigenic peptides to CD8+ T lymphocytes, are involved in acceptance or rejection of tissue grafts. Non-classical MHC class I (MHC-Ib) glycoproteins, such as Human Leukocyte Antigen-G (HLA-G) and murine Qa-2, are important modulators of the maternal immune system during pregnancy. MHC-Ib proteins are: (a) oligomorphic or monomorphic, (b) expressed in specific tissues under specific condtions, and (c) produced as surface and/or soluble isoforms due to alternative splicing. Third trimester-bovine trophoblast cells express both MHC-Ia and MHC-Ib proteins. The MHC-Ib proteins expressed by trophoblast cells during the third trimester of pregnancy are encoded by four bovine leukocyte antigen (BoLA) loci: BoLA-NC1, BoLA-NC2, BoLA-NC3, and BoLA-NC4.
Two MHC-Ia (N*01701 and N*01802) and three MHC-Ib (NC1*00501, NC3*00101 and NC4*00201) proteins showed cell-surface expression in transfection studies performed in murine P815 and human K562 cells. Two additional isoforms, NC1*00401 and NC2*00102, were not detected on the surface of these cells. Nevertheless, both class Ia proteins, N*01701 and N*01802, and five class Ib proteins, NC1*00401, NC1*00501, NC2*00102, NC3*00101, and NC4*00201, were detected in crude cell lysates on Western blots. Precipitation of proteins from culture supernatants showed that cell-surface MHC-Ia (N*01701 and N*01802) and MHC-Ib proteins (NC1*00501, NC3*00101, and NC4*00201) are shed from the surface of these cells into the media. The mechanism of shedding of these proteins is, however, not known. Monoclonal antibodies W6/32, IL-A88, H1A, H6A, H11A, H58A, and PT-85A recognized surface MHC-I isoforms with varying affinity. We were able to develop a sandwich enzyme-linked immunosorbent assay (ELISA) using either H1A or IL-A88 antibody as the capture antibody and the W6/32 antibody for detection. We produced monoclonal antibodies against cattle NC1*00501 and NC3*00101 proteins. One monoclonal antibody generated against BoLA-NC3*00101 was highly specific. Unfortunately, due to failure to clone the NC3*00101- hybridoma, we no longer have an infinite source of this monoclonal antibody for NC3*00101. We eluted peptides from NC3*00101-transfected MHC-null K562 cells and identified peptides using liquid chromatography-mass spectrum (LC-MS) analysis. Analysis of peptide binding data using the SAS Proc mixed statistical program, suggested that the peptide EVTNQLVVL is a potential peptide ligand, which can be used to make tetramers for enumeration of antigen-specific leukocytes.
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De, Juan Sanjuan Cristina. "Identification of major histocompatibility complex (MHC) class I chain-related (MIC) and HFE genes in cattle." Thesis, University of Bristol, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434741.
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Talken, Beth L. "Assembly of the Lw¹⁶ and Ld class I MHC molecules." free to MU campus, to others for purchase, 1996. http://wwwlib.umi.com/cr/mo/fullcit?p9720532.
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Simms, Michelle. "Characterization of the TNFa microsatellite's reliability, MHC associations and occurrence in two ethnically different SLE populations." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0004/MQ42446.pdf.
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Persson, Karina. "Structural studies of protein assemblies : MHC class I and lumazine synthase /." Uppsala : Swedish Univ. of Agricultural Sciences (Sveriges lantbruksuniv.), 1999. http://epsilon.slu.se/avh/1999/91-576-5499-9.pdf.
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Sivaganesh, Sivasuriya. "Recipient DCs presenting intact and processed MHC alloantigen mediate CD8⁸ T-cell responses." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609327.
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Meyer-Lucht, Yvonne. "Does variability matter? Major histocompatibility complex (MHC) variation and its associations to parasitism in natural small mammal populations." Phd thesis, Universität Potsdam, 2009. http://opus.kobv.de/ubp/volltexte/2009/3641/.
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The adaptive evolutionary potential of a species or population to cope with omnipresent environmental challenges is based on its genetic variation. Variability at immune genes, such as the major histocompatibility complex (MHC) genes, is assumed to be a very powerful and effective tool to keep pace with diverse and rapidly evolving pathogens. In my thesis, I studied natural levels of variation at the MHC genes, which have a key role in immune defence, and parasite burden in different small mammal species. I assessed the importance of MHC variation for parasite burden in small mammal populations in their natural environment. To understand the processes shaping different patterns of MHC variation I focused on evidence of selection through pathogens upon the host. Further, I addressed the issue of low MHC diversity in populations or species, which could potentially arise as a result from habitat fragmentation and isolation.
Despite their key role in the mammalian evolution the marsupial MHC has been rarely investigated. Studies on primarily captive or laboratory bred individuals indicated very little or even no polymorphism at the marsupial MHC class II genes. However, natural levels of marsupial MHC diversity and selection are unknown to date as studies on wild populations are virtually absent. I investigated MHC II variation in two Neotropical marsupial species endemic to the threatened Brazilian Atlantic Forest (Gracilinanus microtarsus, Marmosops incanus) to test whether the predicted low marsupial MHC class II polymorphism proves to be true under natural conditions. For the first time in marsupials I confirmed characteristics of MHC selection that were so far only known from eutherian mammals, birds, and fish: Positive selection on specific codon sites, recombination, and trans-species polymorphism. Beyond that, the two marsupial species revealed considerable differences in their MHC class II diversity. Diversity was rather low in M. incanus but tenfold higher in G. microtarsus, disproving the predicted general low marsupial MHC class II variation.
As pathogens are believed to be very powerful drivers of MHC diversity, I studied parasite burden in both host species to understand the reasons for the remarkable differences in MHC diversity. In both marsupial species specific MHC class II variants were associated to either high or low parasite load highlighting the importance of the marsupial MHC class II in pathogen defence. I developed two alternative scenarios with regard to MHC variation, parasite load, and parasite diversity. In the ‘evolutionary equilibrium’ scenario I assumed the species with low MHC diversity, M. incanus, to be under relaxed pathogenic selection and expected low parasite diversity. Alternatively, low MHC diversity could be the result of a recent loss of genetic variation by means of a genetic bottleneck event. Under this ‘unbalanced situation’ scenario, I assumed a high parasite burden in M. incanus due to a lack of resistance alleles. Parasitological results clearly reject the first scenario and point to the second scenario, as M. incanus is distinctly higher parasitised but parasite diversity is relatively equal compared to G. microtarsus. Hence, I suggest that the parasite load in M. incanus is rather the consequence than the cause for its low MHC diversity.
MHC variation and its associations to parasite burden have been typically studied within single populations but MHC variation between populations was rarely taken into account. To gain scientific insight on this issue, I chose a common European rodent species. In the yellow necked mouse (Apodemus flavicollis), I investigated the effects of genetic diversity on parasite load not on the individual but on the population level. I included populations, which possess different levels of variation at the MHC as well as at neutrally evolving genetic markers (microsatellites). I was able to show that mouse populations with a high MHC allele diversity are better armed against high parasite burdens highlighting the significance of adaptive genetic diversity in the field of conservation genetics. An individual itself will not directly benefit from its population’s large MHC allele pool in terms of parasite resistance. But confronted with the multitude of pathogens present in the wild a population with a large MHC allele reservoir is more likely to possess individuals with resistance alleles. These results deepen our understanding of the complex causes and processes of evolutionary adaptations between hosts and pathogens.In einer sich ständig verändernden Umwelt ist es unverzichtbar, sich fortwährend zu verändern und anzupassen. Dabei gründet sich das Anpassungsvermögen oder das evolutionäre Potential einer Art auf ihre genetische Variabilität. In der Krankheitsabwehr ist die Variabilität der Immungene ein besonders wichtiges und effektives Instrument, weil Pathogene sehr vielfältig sind und schnell evolvieren. Im Rahmen meiner Doktorarbeit habe ich mich mit der Variabilität des Immungen-Komplexes MHC (major histocompatibility complex) beschäftigt, der eine Schlüsselrolle in der Immunabwehr bei Vertebraten einnimmt. Anhand verschiedener Arten und Populationen von Kleinsäugern habe ich den Einfluss der MHC Vielfalt auf den Parasitenbefall unter natürlichen Bedingungen untersucht. Dabei interessierte mich insbesondere das Vorkommen geringer MHC Variabilität in Populationen, das möglicherweise eine Folge von Lebensraum-fragmentierung und Isolation ist. Obwohl Beuteltiere eine zentrale Rolle in der Evolution der Säugetiere spielen, ist über ihren MHC bislang nur sehr wenig bekannt. Einige Studien befassten sich mit Labor- oder Zootieren, und deuteten auf geringe oder sogar gar keine Variation im MHC Klasse II bei Beuteltieren hin. Allerdings gab es bislang nahezu keine Studien an frei lebenden Beuteltieren, deshalb war bislang ein natürliches Ausmaß der MHC Variabilität unbekannt. Anhand von zwei endemischen neotropischen Beuteltieren aus dem brasilianischen Küstenregenwald (Gracilinanus microtarsus, Marmosops incanus) habe ich überprüft, ob sich diese geringe MHC Vielfalt unter natürlichen Freilandbedingungen bestätigt. Erstmals konnte ich zeigen, dass der MHC II bei Beuteltieren charakteristische Merkmale positiver Selektion aufweist, die bisher nur von placentalen Säugern, Vögeln und Fischen bekannt waren: Positive Selektion auf spezifischen Aminosäurepositionen, Rekombination und Trans-Species-Polymorphismus. Darüber hinaus unterschieden sich die beiden Beuteltierarten beträchtlich in ihrer MHC II Variabilität. Während M. incanus sich als relativ wenig divers erwies, zeigte G. microtarsus eine zehnmal höhere Vielfalt und widerlegt damit die generelle Gültigkeit der ursprünglich angenommenen geringen MHC II Variabilität bei Beuteltieren. Um diese beachtlichen Diversitätsunterschiede zwischen den beiden Arten zu erklären, habe ich die Parasitenbelastung untersucht. Bei beiden Arten konnte ich nachweisen, dass bestimmte MHC Varianten mit entweder hoher oder niedriger Parasitenbelastung verknüpft waren. Solche Assoziationen spiegeln Pathogen-vermittelte Selektion wider, untermauern die Funktionalität des MHC Klasse II bei Beuteltieren und weisen auf dieselbe Bedeutsamkeit des MHC wie bei placentalen Säuger, Vögeln und Fischen hin. Ich entwickelte zwei alternative evolutionäre Szenarien, unter denen eine geringe MHC Variabilität denkbar ist. Im Szenario des ‘evolutionären Gleichgewichts’ ist geringe MHC Variabilität die Folge eines verminderten Selektionsdruckes durch wenige Parasiten, sodass eine geringe Parasitendiversität zu erwarten ist. Alternativ könnte eine geringe MHC Variabilität aber auch Folge eines kürzlich erlittenen Verlustes an genetischer Variabilität sein, beispielsweise durch ein Flaschenhalsereignis. Unter diesem Szenario des ‘Ungleichgewichts’ wäre bei M. incanus im Falle eines potentiellen Verlustes von Resistenzallelen eine starke Parasitenbelastung zu erwarten. Die parasitologischen Ergebnisse widersprechen dem ersten und deuten eher auf das zweite Szenario. M. incanus war deutlich stärker parasitiert als G. microtarsus, wohingegen die Parasitendiversität bei beiden Arten ungefähr gleich war. Die hohe Parasitenbelastung bei M. incanus ist offenbar weniger der Auslöser als vielmehr eine Folge seiner geringen MHC Vielfalt zu sein. Üblicherweise werden sowohl die Variabilität des MHC als auch seine Verknüpfung mit Parasitenbelastung innerhalb von einzelnen Populationen untersucht, nur selten wird die Variation zwischen Populationen in Betracht gezogen. Um Erkenntnisse auf dieser Ebene zu gewinnen, habe ich den Zusammenhang zwischen genetischer Vielfalt und Parasitenbelastung nicht auf der Ebene des Individuums, sondern auf der Populationsebene anhand der europäischen Gelbhalsmaus (Apodemus flavicollis) erforscht. Dabei wurden Populationen mit unterschiedlicher genetischer Variabilität am MHC und an neutralen genetischen Markern (Mikrosatelliten) betrachtet. Ich konnte nachweisen, dass Populationen, die über ein großes Spektrum verschiedener MHC Allele verfügen, besser gegen starke Parasitenbelastung gewappnet sind als Populationen mit einer geringen Anzahl MHC Allele. In einer MHC-diversen Population ist die Gegenwart von Individuen mit Resistenzallelen deutlich wahrscheinlicher, und damit die Überlebenswahrscheinlichkeit der Population. Diese Ergebnisse erweitern und vertiefen unsere Erkenntnisse zu die komplexen evolutionären Vorgängen und Mechanismen zwischen Wirt und Parasit in ihrem fortwährenden Wettstreit.
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Shoukry, Mohamed Naglaa. "Study of the cellular factors affecting presentation of retroviral superantigens by Major Histocompatibility Complex (MHC) class II molecules." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0030/NQ64669.pdf.
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Lyons, Amanda C. "Characterization of major histocompatibility complex class I loci of the lark sparrow (Chondestes grammacus) and insights into avian MHC evolution." Bowling Green State University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1383578046.
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Florence, William Clinton. "Increased stability of class II MHC-peptide complexes in macrophages infected with mycobacterium avium and the examination of a novel role for cathepsin L in the innate immune response to Francisella Novicida infection." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1173298339.
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Brimpari, Minodora. "Regulation of MHC class I and II expression in mouse Epiblast stem cells." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609719.
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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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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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Russell, Ratanasuda Roslin. "The Major Histocompatibility Complex (MHC) gene expression in health and disease : the application of different technologies for gene expression profiling." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615647.
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Sumners, Lindsay Hart. "Immunological Response to Clostridium perfringens in Two Genetically Divergent Lines of Chickens as Influenced by Major Histocompatibility Complex (MHC) Genotype." Thesis, Virginia Tech, 2011. http://hdl.handle.net/10919/43370.
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Chickens genetically selected for low (LA) or high (HA) antibody response to sheep red blood
cells (SRBC) displayed a correlated change in major histocompatibility complex (MHC), so that
LA chickens were 96% B13 and HA chickens were 96% B21. During a clinical outbreak of
necrotic enteritis, B21B21 genotypes experienced significantly less mortality (6% vs. 13 %)
compared to B13B13 genotypes. A study was carried out to assess immunological differences
between LA and HA lines during exposure to Clostridium perfringens. In Experiment 1,
chickens were orally gavaged with a low (10^7 CFU/mL) or high (10^9 CFU/mL) dose of C.
perfringens. In Experiment 2, chickens were orally gavaged with live coccidia oocysts on
experiment d 1, followed by 107 CFU/mL C. perfringens on d 5. Unfortunately, establishment of
necrotic enteritis infection was unsuccessful in both experiments as evidenced by lack of
significant intestinal lesions, as well as no negative effect on bird performance. In an ex vivo
study, peripheral blood mononuclear cells (PBMCs) were isolated from each genetic line,
cultured, stimulated with LPS (4 h), and exposed to varying concentrations of C. perfringens α-
toxin (1, 10, 100, 1000 U/L) for 2 and 4 h. Evaluation of cellular proliferation, percent
cytotoxicity and immunological gene expression was carried out in a variety of experiments.
Genetic lines were found to be highly divergent in all analyses.Master of Science
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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 AlpinesIntra-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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Gersch, Jeffrey Walter. "Microsatellite, mitochondrial, and major histocompatibility complex analyses of genetic structure in the nurse shark, Ginglymostoma cirratum, in the western Atlantic Ocean." OpenSIUC, 2012. https://opensiuc.lib.siu.edu/theses/936.
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The nurse shark, Ginglymostoma cirratum, is a sedentary shark species that inhabits coral reefs in the tropical and subtropical Atlantic Ocean and along the western coast of the Americas in the Pacific Ocean. Nurse shark tissue samples were collected from the Bahamas, Belize, Brazil, and Dry Tortugas National Park in Florida. 186 individuals were genotyped at 11 microsatellite loci, the control region of the mitochondrial genome was sequenced in 190 individuals, and 89 individuals from the Bahamas, Belize, and Dry Tortugas were genotyped at the major histocompatibility complex (MHC) class IIα locus. An analysis of molecular variance (AMOVA) for the microsatellite loci indicated significant subdivision only between the Bahamas and Dry Tortugas populations. An AMOVA for the mitochondrial control region sequences indicated significant subdivision between all population pairs. The AMOVA for MHC class IIα locus indicated significant subdivision between two population pairs: the Bahamas population and the Dry Tortugas population and the Belize population and the Dry Tortugas population. The nurse shark has the lowest mitochondrial DNA nucleotide diversity (π=0.0125%) and haplotype diversity (h=0.2402) of any shark species to date. There were 14 MHC alleles from 39 polymorphic sites; ten were the same as published alleles (Kasahara et al. 1993; Ohta et al. 2000). This study was the first study to use MHC class IIα genes as a marker for population genetics in sharks. Our results showed that MHC class IIα locus behaves as a diploid locus and is a powerful tool for determining population genetic structure between populations.
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Childers, Christopher P. "Sequence assembly and annotation of the bovine major histocompatibility complex (BoLA) class IIb region, and in silico detection of sequence polymorphisms in BoLA IIb." Texas A&M University, 2006. http://hdl.handle.net/1969.1/4821.
Full textAbstract:
Cattle are vitally important to American agriculture industry, generating over 24.6
billion pounds of beef (by carcass weight), and 79.5 billion dollars in 2005, and over 27
billion dollars in milk sales in 2004. As of July 2006, the U.S. beef and dairy industry is
comprised of 104.5 million head of cattle, 32.4 million of which were processed in 2005.
The health of the animals has always been an important concern for breeders, as healthy
animals grow faster and are more likely to reach market weight. Animals that exhibit
natural resistance to disease do not require chemicals to stimulate normal weight gain,
and are less prone to disease related wasting.
The major histocompatibility complex (MHC) is a collection of genes, many of
which function in antigen processing and presentation. The bovine MHC (BoLA) differs
from typical mammalian MHCs in that the class II region was disrupted by a
chromosomal inversion into two subregions, designated BoLA IIa and BoLA IIb. BoLA
IIb was transposed to a position near the centromere on bovine chromosome 23,while
BoLA IIa retains its position in BoLA. Comparative sequence analysis of BoLA IIb with
the human MHC revealed the location of the region containing the proximal inversion breakpoint. Gene content, order and orientation of BoLA IIb are consistent with the single
inversion hypothesis when compared to the corresponding region of the human class II
MHC (HLA class II). BoLA IIb spans approximately 450 kb.
The genomic sequence of BoLA IIb was used to detect sequence variation
through comparison to other bovine sequences, including data from the bovine genome
project, and two regions in the BAC scaffold used to develop the BoLA IIb sequence.
Analysis of the bovine genome project sequence revealed a total of 10,408 mismatching
bases, 30 out of 231 polymorphic microsatellites, and 15 sequences corresponding to the
validated SNP panel generated by the bovine genome sequencing project. The two
overlapping regions in the BoLA IIb BAC scaffold were found to have 888
polymorphisms, including a total of 6 out of 42 polymorphic microsatellites indicating
that each BAC derived from a different chromosome.
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Rodino, Kyle G. "Orientia tsutsugamushi Modulates Endoplasmic Reticulum Stress to Benefit its Intracellular Growth and Targets NLRC5 to Inhibit Major Histocompatibility Complex I Expression." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5264.
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Scrub typhus, caused by the obligate intracellular bacterium Orientia tsutsugamushi, afflicts one million people annually. Despite being a global health threat, little is known about O. tsutsugamushi pathogenesis. Here, we demonstrate that O. tsutsugamushi modulates the ER and ER-associated processes as mechanisms of nutritional virulence and immune evasion. To obtain amino acids to fuel replication, O. tsutsugamushi simultaneously induces ER stress and the unfolded protein response (UPR) while inhibiting ER-associated degradation (ERAD) during early infection time points. During exponential growth, the bacterium releases the ER bottleneck, resulting in generation of ERAD-derived amino acids that it parasitized for replication. The O. tsutsugamushi effector, Ank4, is linked to this process, as it impedes ERAD when ectopically expressed. O. tsutsugamushi expression of ank4 peaks during the ERAD inhibition window, but is absent when the pathway is restored. These data reveal a novel mechanism of nutritional virulence, whereby an obligate intracellular pathogen coordinates the modulation of multiple ER-associated processes. Like other intracellular pathogens, O. tsutsugamushi inhibits expression of MHC-I, but it does so in a novel manner by degrading the master regulator of MHC-I, NLRC5. This impedes production of the MHC-I components, human leukocyte antigen A and Beta-2 microglobulin. The NLRC5-reduction mechanism recapitulates across diverse cell types, but the degree and duration of inhibition is cell type-specific. NLRC5 modulation and MHC-I inhibition are linked to another O. tsutsugamushi Ank, Ank5. NLRC5 is a putative interacting partner of Ank5. Moreover, NLRC5 and MHC-I levels are reduced in cells ectopically expressing Ank5. To our knowledge, these are the first examples of a pathogen modulating NLRC5 to negatively regulate MHC-I expression and of a bacterial effector interacting with NLRC5. As we learn more about the bacterium’s ability to regulate its host cell, a unifying theme has emerged: modulation of the ER and ER-associated pathways. These projects reveal two novel mechanisms of O. tsutsugamushi pathogenesis, strategies to acquire the amino acids needed for replication and to decrease MHC-I antigen presentation by the host cell. These insights help in understanding how O. tsutsugamushi and potentially other related pathogens co-opt host cell processes to cause disease.
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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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Allen, Abigail E. "The Effects of a Set of Novel Compounds on Interferon-gamma Induced Major Histocompatibility Complex (MHC) Class II Molecules in Cultured Thyroid Cells." Ohio University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1534199427178941.
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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