Multi-SNP Analysis of MHC Region

Technology has become available to cost-effectively analyze thousands of single nucleotide polymorphisms (SNPs). We recently confirmed by genotyping a small series of class I alleles and microsatellite markers that the extended haplotype HLA-A1-B8-DR3 (8.1 AH) at the major histocompatibility complex (MHC) is a common and conserved haplotype. To further evaluate the region of conservation of the DR3 haplotypes, we genotyped 31 8.1 AHs and 29 other DR3 haplotypes with a panel of 656 SNPs spanning 4.8 Mb in the MHC region. This multi-SNP evaluation revealed a 2.9-Mb region that was essentially invariable for all 31 8.1 AHs. The 31 8.1 AHs were >99.9% identical for 384 consecutive SNPs of the 656 SNPs analyzed. Future association studies of MHC-linked susceptibility to type 1 diabetes will need to account for the extensive conservation of the 8.1 AH, since individuals who carry this haplotype provide no information about the differential effects of the alleles that are present on this haplotype.

[1]  J. Trowsdale.  HLA genomics in the third millennium. , 2005, Current opinion in immunology.

[2]  G Thomson,et al.  MHC microsatellite diversity and linkage disequilibrium among common HLA-A, HLA-B, DRB1 haplotypes: implications for unrelated donor hematopoietic transplantation and disease association studies. , 2005, Tissue antigens.

[3]  M. Rewers,et al.  "Extended" A1, B8, DR3 haplotype shows remarkable linkage disequilibrium but is similar to nonextended haplotypes in terms of diabetes risk. , 2005, Diabetes.

[4]  Stephan Beck,et al.  A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. , 2005, American journal of human genetics.

[5]  S. Keeney,et al.  Where the crossovers are: recombination distributions in mammals , 2004, Nature Reviews Genetics.

[6]  Pardis C Sabeti,et al.  Genetic signatures of strong recent positive selection at the lactase gene. , 2004, American journal of human genetics.

[7]  Sophie Palmer,et al.  Complete MHC haplotype sequencing for common disease gene mapping. , 2004, Genome research.

[8]  J. Bilbao,et al.  HLA‐DRB1 and MICA in Autoimmunity , 2003, Annals of the New York Academy of Sciences.

[9]  J. Hansen,et al.  Inheritable variable sizes of DNA stretches in the human MHC: conserved extended haplotypes and their fragments or blocks. , 2003, Tissue antigens.

[10]  Tariq Ahmad,et al.  Haplotype-specific linkage disequilibrium patterns define the genetic topography of the human MHC. , 2003, Human molecular genetics.

[11]  M. Carrington,et al.  High-resolution patterns of meiotic recombination across the human major histocompatibility complex. , 2002, American journal of human genetics.

[12]  Pardis C Sabeti,et al.  Detecting recent positive selection in the human genome from haplotype structure , 2002, Nature.

[13]  M. Rewers,et al.  Additional association of intra-MHC genes, MICA and D6S273, with Addison's disease. , 2002, Tissue antigens.

[14]  J. Královičová,et al.  Short tandem repeat (STR) haplotypes in HLA: an integrated 50-kb STR/linkage disequilibrium/gene map between the RING3 and HLA-B genes and identification of STR haplotype diversification in the class III region , 2001, European Journal of Human Genetics.

[15]  A. Jeffreys,et al.  High resolution analysis of haplotype diversity and meiotic crossover in the human TAP2 recombination hotspot. , 2000, Human molecular genetics.

[16]  P. Sham,et al.  The trimmed-haplotype test for linkage disequilibrium. , 2000, American journal of human genetics.

[17]  F. Christiansen,et al.  The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases , 1999, Immunological reviews.

[18]  M. Yoshino,et al.  Allele-dependent recombination frequency: homology requirement in meiotic recombination at the hot spot in the mouse major histocompatibility complex. , 1995, Genomics.

[19]  F. Christiansen,et al.  Ancestral haplotypes reveal the role of the central MHC in the immunogenetics of IDDM , 1992, Immunogenetics.

[20]  J. McCluskey,et al.  Disease Associations with Complotypes, Supratypes and Haplotypes , 1983, Immunological reviews.

[21]  E. Yunis,et al.  Extended major histocompatibility complex haplotypes in man: role of alleles analogous to murine t mutants. , 1982, Clinical immunology and immunopathology.

[22]  M. Abbal,et al.  HLA-A, B, C, DR antigens, Bf, C4 and glyoxalase I (GLO) polymorphisms in French Basques with insulin-dependent diabetes mellitus (IDDM). , 1982, Tissue antigens.

[23]  P. Concannon,et al.  Extended DR3-D6S273-HLA-B haplotypes are associated with increased susceptibility to type 1 diabetes in US Caucasians. , 2005, Tissue antigens.

[24]  H. Erlich,et al.  Rapid typing of HLA-DQB1 DNA polymorphism using nonradioactive oligonucleotide probes and amplified DNA , 2005, Immunogenetics.

[25]  E. Yunis,et al.  Conserved, extended MHC haplotypes. , 1992, Experimental and clinical immunogenetics.