MHC Genomics and Disease: Looking Back to Go Forward

Ancestral haplotypes are conserved but extremely polymorphic kilobase sequences, which have been faithfully inherited over at least hundreds of generations in spite of migration and admixture. They carry susceptibility and resistance to diverse diseases, including deficiencies of CYP21 hydroxylase (47.1) and complement components (18.1), as well as numerous autoimmune diseases (8.1). The haplotypes are detected by segregation within ethnic groups rather than by SNPs and GWAS. Susceptibility to some other diseases is carried by specific alleles shared by multiple ancestral haplotypes, e.g., ankylosing spondylitis and narcolepsy. The difference between these two types of association may explain the disappointment with many GWAS. Here we propose a pathway for combining the two different approaches. SNP typing is most useful after the conserved ancestral haplotypes have been defined by other methods.

• Publication year

  2019

• Venue

  Cells

• Publication date

  2019-08-21

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3390/cells8090944PMID 31438577PMCID 6769595
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• A New Pedigree-Based SNP Haplotype Method for Genomic Polymorphism and Genetic Studies

  2019cited by this paper
• The MHC in the era of next-generation sequencing: Implications for bridging structure with function.

  2019cited by this paper
• HLAscan: genotyping of the HLA region using next-generation sequencing data

  2017cited by this paper
• What has GWAS done for HLA and disease associations?

  2017cited by this paper
• In celebration of Ruggero Ceppellini: HLA in transplantation

  2017cited by this paper
• Pedigree-Defined Haplotypes and Their Applications to Genetic Studies.

  2017cited by this paper
• Sequences of 95 human MHC haplotypes reveal extreme coding variation in genes other than highly polymorphic HLA class I and II

  2017cited by this paper
• Assembly and analysis of 100 full MHC haplotypes from the Danish population

  2017cited by this paper
• Analysis of haplotype sequences

  2016cited by this paper
• Genetics of ankylosing spondylitis—insights into pathogenesis

  2016cited by this paper
• Major Histocompatibility Complex: Disease Associations

  2015cited by this paper
• Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes

  2015cited by this paper
• Mutation versus polymorphism in evolution.

  2013cited by this paper
• Genomic evolution and polymorphism: segmental duplications and haplotypes at 108 regions on 21 chromosomes.

  2013cited by this paper
• Trans-species polymorphism, HLA-disease associations and the evolution of the MHC

  2009cited by this paper
• A HapMap harvest of insights into the genetics of common disease.

  2008cited by this paper
• Variation analysis and gene annotation of eight MHC haplotypes: The MHC Haplotype Project

  2008cited by this paper
• Identification of Two Independent Risk Factors for Lupus within the MHC in United Kingdom Families

  2007cited by this paper
• BMC Genetics BioMed Central

  2007cited by this paper
• Multi-SNP Analysis of MHC Region

  2006cited by this paper
• The haplotype structure of the human major histocompatibility complex.

  2006cited by this paper
• [International HapMap project].

  2005cited by this paper
• Susceptibility to IDDM Is marked by MHC supratypes rather than individual alleles

  2004cited by this paper
• Family studies of IgA deficiency

  2004cited by this paper
• The genetics of narcolepsy.

  2003cited by this paper
• A haplotype map of the human genome.

  2003cited by this paper
• Haplotype-specific linkage disequilibrium patterns define the genetic topography of the human MHC.

  2003cited by this paper
• The International HapMap Project

  2003cited by this paper
• A haplotype map of the human genome

  2003cited by this paper
• A pancreatic β-cell-specific homolog of glucose-6-phosphatase emerges as a major target of cell-mediated autoimmunity in diabetes

  2003cited by this paper
• In polymorphic genomic regions indels cluster with nucleotide polymorphism: Quantum Genomics.

  2003cited by this paper
• The Structure of Haplotype Blocks in the Human Genome

  2002cited by this paper
• Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.

  2002cited by this paper
• SNP profile within the human major histocompatibility complex reveals an extreme and interrupted level of nucleotide diversity.

  2000cited by this paper
• Potential for paralogous mapping to simplify the genetics of diseases and functions associated with MHC haplotypes

  2000cited by this paper
• Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease

  1999influential reference
• Recombination within the human MHC

  1999cited by this paper
• The chromosomal duplication model of the major histocompatibility complex

  1999cited by this paper
• HEREDITARY HAEMOCHROMATOSIS AS AN IMMUNOLOGICAL DISEASE

  1998cited by this paper
• The major histocompatability complex (MHC) contains conserved polymorphic genomic sequences that are shuffled by recombination to form ethnic-specific haplotypes

  1997cited by this paper
• Altered immune response to insulin in newly diagnosed compared to insulin-treated diabetic patients and healthy control subjects

  1997cited by this paper
• Beta-cell autoantibodies in infants and toddlers without IDDM relatives: diabetes autoimmunity study in the young (DAISY).

  1996cited by this paper
• A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis

  1996cited by this paper
• Matching for MHC haplotypes results in improved survival following unrelated bone marrow transplantation.

  1995cited by this paper
• HLA-DQB1*0602 Is Associated With Dominant Protection From Diabetes Even Among Islet Cell Antibody–Positive First-Degree Relatives of Patients with IDDM

  1995cited by this paper
• HLA and narcolepsy

  1993cited by this paper
• Polymorphic MHC ancestral haplotypes affect the activity of tumour necrosis factor‐alpha

  1993cited by this paper
• Ancestral haplotypes: conserved population MHC haplotypes.

  1992cited by this paper
• An approach to the localization of the susceptibility genes for generalized myasthenia gravis by mapping recombinant ancestral haplotypes

  1992cited by this paper
• Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping

  1989cited by this paper
• Some disease-associated ancestral haplotypes carry a polymorphism of TNF.

  1989cited by this paper
• HLA-linked congenital adrenal hyperplasia results from a defective gene encoding a cytochrome P-450 specific for steroid 21-hydroxylation.

  1984cited by this paper
• Myasthenia gravis and HLA antigens in American blacks and other races.

  1984cited by this paper
• Extended major histocompatibility complex haplotypes in type I diabetes mellitus.

  1984cited by this paper
• HLA-LINKED CONGENITAL ADRENAL HYPERPLASIA RESULTS FROM A DEFECTIVE GENE ENCODING A CYTOCHROME P-450

  1984cited by this paper
• Complement allotyping in SLE: association with C4A null.

  1983cited by this paper
• MHC "supratype" predicting heterozygous 21-hydroxylase deficiency.

  1983cited by this paper
• Disease Associations with Complotypes, Supratypes and Haplotypes

  1983cited by this paper
• Extended major histocompatibility complex haplotypes in man: role of alleles analogous to murine t mutants.

  1982cited by this paper
• The prevalence of ankylosing spondylitis among B27 positive normal individuals--a reassessment.

  1979influential reference
• HLA in systemic lupus erythematosus: influence on severity.

  1978cited by this paper
• Ankylosing spondylitis and HL-A 27.

  1973cited by this paper
• High association of an HL-A antigen, W27, with ankylosing spondylitis.

  1973cited by this paper

• High rates of MHC mismatches in HLA matched unrelated donor/recipient pairs and potential impact on hematopoietic cell transplant outcome.

  2024cites this paper
• Race, ethnicity, ancestry, and aspects that impact HLA data and matching for transplant

  2024cites this paper
• HLA‐OLI: A new MHC class I pseudogene and HLA‐Y are located on a 60 kb indel in the human MHC between HLA‐W and HLA‐J

  2023cites this paper
• Autoimmune Haplotype AH8.1 Normalizes the Level of Tumor Necrosis Factor in the Blood Sera of Breast-Cancer Patients

  2023cites this paper
• Characterizing the diversity of MHC conserved extended haplotypes using families from the United Arab Emirates

  2022cites this paper
• Transcriptome-wide association study of HIV-1 acquisition identifies HERC1 as a susceptibility gene

  2022cites this paper
• Human leukocyte antigen super-locus: nexus of genomic supergenes, SNPs, indels, transcripts, and haplotypes

  2022cites this paper
• Rapid single-tube splice variants typing of the BF gene based on dual-primer RT-PCR amplification that influence resistance/susceptibility to Mareks disease in chicken

  2022cites this paper
• Major histocompatibility complex (MHC) associations with diseases in ethnic groups of the Arabian Peninsula

  2021cites this paper
• Association of HLA-B Gene Polymorphisms with Type 2 Diabetes in Pashtun Ethnic Population of Khyber Pakhtunkhwa, Pakistan

  2021cites this paper
• Mitochondrial pathway polygenic risk scores are associated with Alzheimer’s Disease

  2020cites this paper
• The Immune System and Its Contribution to Variability in Regenerative Medicine

  2020cites this paper
• The MHC in the era of next-generation sequencing: Implications for bridging structure with function.

  2019cites this paper
• Allele Specific Expression in Human – Genomic Makeup and Phenotypic Implications

  2019cites this paper
• Genomic Diversity of the Major Histocompatibility Complex in Health and Disease

  2019cites this paper
• Neurobiology of Aging

  year unknowncites this paper