High-Resolution Patterns of Meiotic Recombination across the Human Major Histocompatibility Complex

Cullen, Michael; Perfetto, Stephen P.; Klitz, William; Nelson, George W.; Carrington, Mary

doi:10.1086/342973

Cited by 198 publications

(232 citation statements)

References 67 publications

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“…This is in agreement with a similar lack of evidence for an enhanced recombination rate in the human MHC region. 39 The most important aim of our study was to assess the impact of Mhc class I-genotypes on disease progression in SIV-infected rhesus macaques. Therefore we studied the influence of Mhc class I haplotypes upon disease progression in SIV infection, rather than single gene alleles.…”

Section: Discussionmentioning

confidence: 99%

Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques

Sauermann

Siddiqui

et al. 2007

Genes Immun

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In both human immunodeficiency virus-infected humans and simian immunodeficiency virus (SIV)-infected macaques, genes encoded in the major histocompatibility complex (MHC) class I region are important determinants of disease progression. However, compared to the human human lymphocyte antigen complex, the macaque MHC region encodes many more class I genes. Macaques with the same immunodominant class I genes express additional Mhc genes with the potential to influence the disease course. We therefore assessed the association between of the Mhc class I haplotypes, rather than single gene variants, and survival time in SIV-infected rhesus macaques (Macaca mulatta). DNA sequence analysis and Mhc genotyping of 245 pedigreed monkeys identified 17 Mhc class I haplotypes that constitute 10 major genotypes. Among 81 vaccination-naive, SIV-infected macaques, 71 monkeys carried at least one Mhc class I haplotype encoding only MHC antigens that were incapable of inducing an effective anti-SIV cytotoxic T lymphocytes response. Study of these macaques enabled us to relate individual Mhc class I haplotypes to slow, medium and rapid disease progression. In a post hoc analysis, classification according to disease progression was found to explain at least 48% of the observed variation of survival time.

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Section: Discussionmentioning

confidence: 99%

Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques

Sauermann

Siddiqui

et al. 2007

Genes Immun

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“…The LMP/TAP gene cluster also features a well-characterized recombination hot spot within intron 2 of the TAP2 gene, 33,34 and additional recombination hot spots are located throughout the human MHC locus. 35 Until functional data are found to confirm associations with autoimmune disease suggested by genetic studies, definitive conclusions about genetic association in this region will remain controversial, as associations with autoimmune disease may be due to linkage disequilibrium with other genes in the MHC class II region. It has also been suggested that the action of several MHC genes, including the LMP/TAP genes, might contribute to autoimmune disease pathogenesis, and that statistical analyses might average the linkage of the various genes and identify only polymorphic genes located centrally in the MHC class II region.…”

Section: Discussionmentioning

confidence: 99%

Genes of the LMP/TAP cluster are associated with the human autoimmune disease vitiligo

She

McCormack

2003

Genes Immun

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Genes within the class II region of the major histocompatibility complex (MHC), including genes involved in antigen processing and presentation, have been reported to be associated with several autoimmune diseases. We report here that the LMP/TAP gene region is significantly associated with vitiligo, a disorder in which biochemical defects and/or autoimmune destruction cause melanocyte loss and resulting skin depigmentation. Case/control analyses revealed genetic association of vitiligo in Caucasian patients with an early age of onset with the transporter associated with antigen processing-1 (TAP1) gene. A familybased association method revealed biased transmission of specific alleles from heterozygous parents to affected offspring for the TAP1 gene, as well as for the closely linked LMP2 and LMP7 genes encoding subunits of the immunoproteasome. No association with vitiligo was found for the MECL1 gene, which encodes a third immunoproteasome subunit and is unlinked to the MHC class II region. These results suggest a possible role for the MHC class I antigen processing and/or presentation pathway in the antimelanocyte autoimmune response involved in vitiligo pathogenesis.

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“…LD is the nonrandom association of alleles at adjacent genetic loci and is the result of lack of recombination between loci at meiosis, generally indicating the loci are close together, thus having a low probability of recombination or in the case of LD between distant loci, that the population within which they are found is relatively young (eg Europeans). A further complicating factor is the uneven distribution of meiotic recombination, especially in the MHC, and recent evidence indicates that patterns of LD seen in the MHC are driven chiefly by recombination hotspots rather than population history [131][132][133] and can vary by haplotype. 134 One of the earliest studies of the TNF promoter polymorphisms 135 showed the extent of haplotypes across the MHC.…”

Section: Disease Associations-conclusionmentioning

confidence: 99%

Is there a future for TNF promoter polymorphisms?

2004

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The in vitro study of TNF promoter polymorphism (SNP) function was stimulated by the numerous case-control (association) studies of the polymorphisms in relation to human disease and the appearance of several studies claiming to show a functional role for these SNPs provided a further impetus to researchers interested in the role of TNF in their disease of interest. In this review we consider case-control studies, concentrating on the autoimmune and inflammatory diseases rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, and asthma, and on infectious diseases including malaria, hepatitis B and C infection, leprosy and sepsis/septic shock. We also review the available evidence on the functional role of the various TNF promoter polymorphisms. In general, case-control studies have produced mixed results, with little consensus in most cases on whether any TNF polymorphisms are actually associated with disease, although results have been more consistent in the case of infectious diseases, particularly malaria. Functional studies have also produced mixed results but recent work suggests that the much studied À308G/A polymorphism is not functional, while the function of other TNF polymorphisms remains controversial. Studies of the TNF region are increasingly using extended haplotypes that can better capture the variation of the MHC region.

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High-Resolution Patterns of Meiotic Recombination across the Human Major Histocompatibility Complex

Cited by 198 publications

References 67 publications

Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques

Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques

Genes of the LMP/TAP cluster are associated with the human autoimmune disease vitiligo

Is there a future for TNF promoter polymorphisms?

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