Haplotype analysis of hemochromatosis: evaluation of different linkage-disequilibrium approaches and evolution of disease chromosomes.
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.
Ajioka
R S
RS
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
Jorde
L B
LB
Gruen
J R
JR
Yu
P
P
Dimitrova
D
D
Barrow
J
J
Radisky
E
E
Edwards
C Q
CQ
Griffen
L M
LM
Kushner
J P
JP
D019143:Evolution, Molecular; D005805:Genes, MHC Class I; D005819:Genetic Markers; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006432:Hemochromatosis / Q000235:genetics* / Q000276:immunology; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008565:Membrane Proteins; D017354:Point Mutation; D011110:Polymorphism, Genetic
D005819:Genetic Markers; C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins