Haplotype analysis of hemochromatosis: evaluation of different linkage-disequilibrium approaches and evolution of disease chromosomes. 1997

R S Ajioka, and L B Jorde, and J R Gruen, and P Yu, and D Dimitrova, and J Barrow, and E Radisky, and C Q Edwards, and L M Griffen, and J P Kushner
Division of Hematology/Oncology, Eccles Institute of Human Genetics, University of Utah Health Sciences Center, Salt Lake City 84132, USA. rich_ajioka@hlthsci.med.utah.edu

We applied several types of linkage-disequilibrium calculations to analyze the hereditary hemochromatosis (hh) locus. Twenty-four polymorphic markers in the major histocompatibility complex (MHC) class I region were used to haplotype hh and normal chromosomes. A total of 169 hh and 161 normal chromosomes were analyzed. Disequilibrium values were found to be high over an unusually large region beginning 150 kb centromeric of HLA-A and extending nearly 5 Mb telomeric of it. Recombination in this region was approximately 28% of the expected value. This low level of recombination contributes to the unusually broad region of linkage disequilibrium found with hh. The strongest disequilibrium was found at locus HLA-H (delta = .84) and at locus D6S2239 (delta = .85), a marker approximately 10 kb telomeric to HLA-H. All disequilibrium methods employed in this study found peak disequilibrium at HLA-H or D6S2239. The cys282tyr mutation in HLA-H, a candidate gene for hh, was found in 85% of disease chromosomes. A haplotype phylogeny for hh chromosomes was constructed and suggests that the mutation associated with the most common haplotype occurred relatively recently. The age of the hh mutation was estimated to be approximately 60-70 generations. Disequilibrium was maintained over a greater distance for hh-carrying chromosomes, consistent with a recent mutation for hh. Our data provide a reasonable explanation for previous difficulties in localizing the hh locus and provide an evolutionary history for disease chromosomes.

UI MeSH Term Description Entries
D008565 Membrane Proteins Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. Cell Membrane Protein,Cell Membrane Proteins,Cell Surface Protein,Cell Surface Proteins,Integral Membrane Proteins,Membrane-Associated Protein,Surface Protein,Surface Proteins,Integral Membrane Protein,Membrane Protein,Membrane-Associated Proteins,Membrane Associated Protein,Membrane Associated Proteins,Membrane Protein, Cell,Membrane Protein, Integral,Membrane Proteins, Integral,Protein, Cell Membrane,Protein, Cell Surface,Protein, Integral Membrane,Protein, Membrane,Protein, Membrane-Associated,Protein, Surface,Proteins, Cell Membrane,Proteins, Cell Surface,Proteins, Integral Membrane,Proteins, Membrane,Proteins, Membrane-Associated,Proteins, Surface,Surface Protein, Cell
D011110 Polymorphism, Genetic The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level. Gene Polymorphism,Genetic Polymorphism,Polymorphism (Genetics),Genetic Polymorphisms,Gene Polymorphisms,Polymorphism, Gene,Polymorphisms (Genetics),Polymorphisms, Gene,Polymorphisms, Genetic
D005805 Genes, MHC Class I Genetic loci in the vertebrate major histocompatibility complex which encode polymorphic characteristics not related to immune responsiveness or complement activity, e.g., B loci (chicken), DLA (dog), GPLA (guinea pig), H-2 (mouse), RT-1 (rat), HLA-A, -B, and -C class I genes of man. Class I Genes,Genes, Class I,Genes, H-2 Class I,Genes, HLA Class I,MHC Class I Genes,H-2 Class I Genes,HLA Class I Genes,Class I Gene,Gene, Class I,Genes, H 2 Class I,H 2 Class I Genes
D005819 Genetic Markers A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. Chromosome Markers,DNA Markers,Markers, DNA,Markers, Genetic,Genetic Marker,Marker, Genetic,Chromosome Marker,DNA Marker,Marker, Chromosome,Marker, DNA,Markers, Chromosome
D006239 Haplotypes The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the MAJOR HISTOCOMPATIBILITY COMPLEX. Haplotype
D006432 Hemochromatosis A disorder of iron metabolism characterized by a triad of HEMOSIDEROSIS; LIVER CIRRHOSIS; and DIABETES MELLITUS. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. (Jablonski's Dictionary of Syndromes & Eponymic Diseases, 2d ed) Diabetes, Bronze,Bronze Diabetes,Bronzed Cirrhosis,Familial Hemochromatosis,Genetic Hemochromatosis,Haemochromatosis,Hemochromatoses,Iron Storage Disorder,Pigmentary Cirrhosis,Primary Hemochromatosis,Troisier-Hanot-Chauffard Syndrome,Von Recklenhausen-Applebaum Disease,Bronzed Cirrhoses,Cirrhoses, Bronzed,Cirrhoses, Pigmentary,Cirrhosis, Bronzed,Cirrhosis, Pigmentary,Disease, Von Recklenhausen-Applebaum,Diseases, Von Recklenhausen-Applebaum,Disorder, Iron Storage,Disorders, Iron Storage,Familial Hemochromatoses,Genetic Hemochromatoses,Haemochromatoses,Hemochromatose,Hemochromatoses, Familial,Hemochromatoses, Genetic,Hemochromatosis, Familial,Hemochromatosis, Genetic,Iron Storage Disorders,Pigmentary Cirrhoses,Recklenhausen-Applebaum Disease, Von,Recklenhausen-Applebaum Diseases, Von,Storage Disorder, Iron,Storage Disorders, Iron,Syndrome, Troisier-Hanot-Chauffard,Syndromes, Troisier-Hanot-Chauffard,Troisier Hanot Chauffard Syndrome,Troisier-Hanot-Chauffard Syndromes,Von Recklenhausen Applebaum Disease,Von Recklenhausen-Applebaum Diseases
D006680 HLA Antigens Antigens determined by leukocyte loci found on chromosome 6, the major histocompatibility loci in humans. They are polypeptides or glycoproteins found on most nucleated cells and platelets, determine tissue types for transplantation, and are associated with certain diseases. Human Leukocyte Antigen,Human Leukocyte Antigens,Leukocyte Antigens,HL-A Antigens,Antigen, Human Leukocyte,Antigens, HL-A,Antigens, HLA,Antigens, Human Leukocyte,Antigens, Leukocyte,HL A Antigens,Leukocyte Antigen, Human,Leukocyte Antigens, Human
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000071020 Hemochromatosis Protein A membrane protein and MHC class I antigen. It contains an IMMUNOGLOBULIN C1-SET DOMAIN and interacts with BETA 2-MICROGLOBULIN. It may also regulate the interaction of TRANSFERRIN with the TRANSFERRIN RECEPTOR. Mutations in the HFE gene are associated with cases of FAMILIAL HEMOCHROMATOSIS. HFE Protein,HLA-H Antigen,Antigen, HLA-H,HLA H Antigen
D015395 Histocompatibility Antigens Class I Membrane glycoproteins consisting of an alpha subunit and a BETA 2-MICROGLOBULIN beta subunit. In humans, highly polymorphic genes on CHROMOSOME 6 encode the alpha subunits of class I antigens and play an important role in determining the serological specificity of the surface antigen. Class I antigens are found on most nucleated cells and are generally detected by their reactivity with alloantisera. These antigens are recognized during GRAFT REJECTION and restrict cell-mediated lysis of virus-infected cells. Class I Antigen,Class I Antigens,Class I Histocompatibility Antigen,Class I MHC Protein,Class I Major Histocompatibility Antigen,MHC Class I Molecule,MHC-I Peptide,Class I Histocompatibility Antigens,Class I Human Antigens,Class I MHC Proteins,Class I Major Histocompatibility Antigens,Class I Major Histocompatibility Molecules,Human Class I Antigens,MHC Class I Molecules,MHC-I Molecules,MHC-I Peptides,Antigen, Class I,Antigens, Class I,I Antigen, Class,MHC I Molecules,MHC I Peptide,MHC I Peptides,Molecules, MHC-I,Peptide, MHC-I,Peptides, MHC-I

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