Ancestral haplotypes: conserved population MHC haplotypes

Degli-Esposti, Mariapia A.; Leaver, Anne; Christiansen, Frank; Witt, Campbell S.; Abraham, Lawrence J.; Dawkins, Roger L.

doi:10.1016/0198-8859(92)90023-g

Cited by 235 publications

(192 citation statements)

References 19 publications

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“…This is especially so in the region extending from HLA-B to HLA-DR, where haplotypes seem to have been conserved from remote ancestors and have been called conserved, extended, or ancestral haplotypes. It has been estimated that ϳ70% of the human haplotypes are conserved, extended haplotypes or recombinants of no more than two of them (17,32,33). It is generally accepted that a small number of these MHC conserved haplotypes are found in the majority of IgAD patients (5,7,8,10,11,13,19) and that these haplotypes share a susceptibility locus designated IGAD1.…”

Section: Discussionmentioning

confidence: 99%

MHC Susceptibility Genes to IgA Deficiency Are Located in Different Regions on Different HLA Haplotypes

Concha

Fernández‐Arquero

Gual

et al. 2002

The Journal of Immunology

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Familial predisposition to IgA deficiency (IgAD) suggests that genetic factors influence susceptibility. Most studies support a polygenic inheritance with a susceptibility locus (designated IGAD1) in the MHC, but its exact location is still controversial. This study aimed to map the predisposing IGAD1 locus (or loci) within the MHC by investigating the pattern of association of the disease with several markers in the region. DNA-based techniques were used to type individual alleles of four polymorphic HLA genes (HLA-DR, -DQA1, -DQB1, and HLA-B), six microsatellites (all located between HLA-DR and HLA-B), and three single nucleotide polymorphisms on the TNF gene. The frequencies of these alleles were compared among ethnically matched populations comprising 182 patients and 343 controls. Additionally, we investigated parents and siblings of 100 of these patients. All four parental haplotypes were established in each family (n = 400), and transmission disequilibrium tests were performed. Surprisingly, our results did not support the hypothesis of a unique susceptibility gene being shared by all MHC susceptibility haplotypes. On HLA-DR1 and -DR7-positive haplotypes IGAD1 mapped to the class II region, whereas on haplotypes carrying HLA-DR3 the susceptibility locus mapped to the telomeric end of the class III region, as reported previously. Our results show how, in complex diseases, individuals may be affected for different genetic reasons and a single linkage signal to a region of a chromosome may actually be the result of disease-predisposing alleles in different linked genes in different pedigrees.

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Section: Discussionmentioning

confidence: 99%

MHC Susceptibility Genes to IgA Deficiency Are Located in Different Regions on Different HLA Haplotypes

Concha

Fernández‐Arquero

Gual

et al. 2002

The Journal of Immunology

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“…The strong LD of SNPs in the CLIC1 gene, however, means that our association may be the result of a marker in a neighbouring or distant gene. Extended MHC haplotypes resulting from strong LD are thought to be important to the immune response required for species survival; 36,37 in utero such a haplotype could allow for the dampening of the immune response, while ex utero, the same haplotype would be less advantageous for immune dependent survival. In addition, it is also worthwhile considering hypotheses for TRD in the MHC that are not rooted in the immunology of pregnancy; candidate SNPs in the proinflammatory TNF/LTA region did not demonstrate TRD, and one of the most prominent examples of TRD involves distortion of sperm motility and survival in the HLA-homologous T-complex of mice.…”

Section: Discussionmentioning

confidence: 99%

An investigation of transmission ratio distortion in the central region of the human MHC

et al. 2005

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Transmission ratio distortion (TRD) describes a significant departure from expected Mendelian inheritance ratios that is fundamental to both the biology of reproduction and statistical genetics. The relatively high fetal wastage in humans, with consequent selection of alleles in utero, makes it likely that TRD is prevalent in the human genome. The central region of the human major histocompatibility complex (MHC) is a strong TRD candidate, as it houses a number of immune and regulatory genes that may be important in pregnancy outcome. We used a nonhaplotype-based method to select 13 tagging SNPs from three central MHC candidate regions, and analysed their transmission in 380 newborns and their parents (1138 individuals). A TRD of 54:46 was noted in favour of the common allele of a promoter SNP in the CLIC1 gene (P ¼ 0.025), with a similar distortion using haplotypes across the same gene region (P ¼ 0.016). We also found evidence that markers in the CLIC1 gene region may have been subject to recent selection (Po0.001). The study illustrates the potential benefits of screening for TRD and highlights the difficulties encountered therein.

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“…49 The DQB1*02-DQA1* 05-DRB1*03-B*08 and DQB1*02-DQA1*05-DRB1*03-B*18 differentiate two distinct ancestral haplotypes termed AH8.1 and 18.2, respectively. 26 The DQB1*02-DQA1*05-DRB1*03-B*08 ancestral haplotype is also called an 'autoimmune' haplotype since it is associated with several autoimmune diseases, 57 like type 1 diabetes, myasthenia gravis, dermatitis herpetiformis and systemic lupus erythematosus. In total, 42 markers were used in the subsequent analyses, as all loci involved in selection of the HLA subgroups were omitted.…”

Section: Reconstruction Of Haplotypesmentioning

confidence: 99%

“…Most of the common MHC haplotypes are either ancestral haplotypes (about 25-30% in Caucasians) or recombinants (perhaps another 25-50%) of ancestral haplotypes. 26 The MHC is arranged into conserved extended haplotypes of variable size, at least up to 3.2 Mb, 27,28 which can be recognized by haplotype specific marker(s). 26 The ancestral MHC haplotypes are characterized by specific alleles at the HLA class II and I genes, as well as loci in the class III region.…”

Section: Introductionmentioning

confidence: 99%

“…26 The MHC is arranged into conserved extended haplotypes of variable size, at least up to 3.2 Mb, 27,28 which can be recognized by haplotype specific marker(s). 26 The ancestral MHC haplotypes are characterized by specific alleles at the HLA class II and I genes, as well as loci in the class III region. This scaffold of underlying MHC haplotypes of variable length, covering highly polymorphic loci and encompassing nearly the entire MHC region, could potentially hamper the conditions necessary to generate summarized LD maps of this complex region.…”

Section: Introductionmentioning

confidence: 99%

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Linkage disequilibrium and haplotype blocks in the MHC vary in an HLA haplotype specific manner assessed mainly by DRB103 and DRB104 haplotypes

et al. 2006

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First generation linkage disequilibrium (LD) and haplotype maps of the human major histocompatibility complex (MHC) have been generated in order to aid the unraveling of the numerous disease predisposing genes in this region by offering a first set of haplotype tagSNPs. Several parameters, like the population studied, the marker map used, the density of polymorphisms and the applied algorithm, are influencing the appearance of haplotype blocks and selection of tags. The MHC comprises a limited number of ancestral, conserved haplotypes. We address the impact of the underlying HLA haplotypes on the LD patterns, haplotype blocks and tag selection throughout the entire extended MHC (xMHC) by studying DR-DQ haplotypes, mainly those carrying DRB1*03 and DRB1*04 alleles. We observed significantly different degree and extent of LD calculated on different HLA backgrounds, as well as variation in the size and boundaries of the defined haplotype and tags selected. Our results demonstrate that the underlying ancestral HLA haplotypic architecture is yet another parameter to take into consideration when constructing LD maps of the xMHC. This may be essential for mapping of disease susceptibility genes since many diseases are associated with and map on particular HLA haplotypes.

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Ancestral haplotypes: conserved population MHC haplotypes

Cited by 235 publications

References 19 publications

MHC Susceptibility Genes to IgA Deficiency Are Located in Different Regions on Different HLA Haplotypes

MHC Susceptibility Genes to IgA Deficiency Are Located in Different Regions on Different HLA Haplotypes

An investigation of transmission ratio distortion in the central region of the human MHC

Linkage disequilibrium and haplotype blocks in the MHC vary in an HLA haplotype specific manner assessed mainly by DRB103 and DRB104 haplotypes

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Ancestral haplotypes: conserved population MHC haplotypes

Cited by 235 publications

References 19 publications

MHC Susceptibility Genes to IgA Deficiency Are Located in Different Regions on Different HLA Haplotypes

MHC Susceptibility Genes to IgA Deficiency Are Located in Different Regions on Different HLA Haplotypes

An investigation of transmission ratio distortion in the central region of the human MHC

Linkage disequilibrium and haplotype blocks in the MHC vary in an HLA haplotype specific manner assessed mainly by DRB1*03 and DRB1*04 haplotypes

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Linkage disequilibrium and haplotype blocks in the MHC vary in an HLA haplotype specific manner assessed mainly by DRB103 and DRB104 haplotypes