Anonymous Marker Loci Within 400 Kb of HLA-A Generate Haplotypes in Linkage Disequilibrium with the Hemochromatosis Gene (HFE)

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 1994 Feb 1

PMID 8304342

Citations 22

Authors

J Yaouanq

M Perichon

M. Chorney

P Pontarotti

A LE TREUT

A El Kahloun

V Mauvieux

M Blayau

A M Jouanolle

B Chauvel

Affiliations

Soon will be listed here.

Abstract

The hemochromatosis gene (HFE) maps to 6p21.3 and is less than 1 cM from the HLA class I genes; however, the precise physical location of the gene has remained elusive and controversial. The unambiguous identification of a crossover event within hemochromatosis families is very difficult; it is particularly hampered by the variability of the phenotypic expression as well as by the sex- and age-related penetrance of the disease. For these practical considerations, traditional linkage analysis could prove of limited value in further refining the extrapolated physical position of HFE. We therefore embarked upon a linkage-disequilibrium analysis of HFE and normal chromosomes from the Brittany population. In the present report, 66 hemochromatosis families yielding 151 hemochromatosis chromosomes and 182 normal chromosomes were RFLP-typed with a battery of probes, including two newly derived polymorphic markers from the 6.7 and HLA-F loci located 150 and 250 kb telomeric to HLA-A, respectively. The results suggest a strong peak of existing linkage disequilibrium focused within the i82-to-6.7 interval (approximately 250 kb). The zone of linkage disequilibrium is flanked by the i97 locus, positioned 30 kb proximal to i82, and the HLA-F gene, found 250 kb distal to HLA-A, markers of which display no significant association with HFE. These data support the possibility that HFE resides within the 400-kb expanse of DNA between i97 and HLA-F. Alternatively, the very tight association of HLA-A3 and allele 1 of the 6.7 locus, both of which are comprised by the major ancestral or founder HFE haplotype in Brittany, supports the possibility that the disease gene may reside immediately telomeric to the 6.7 locus within the linkage-disequilibrium zone. Additionally, hemochromatosis haplotypes possessing HLA-A11 and the low-frequency HLA-F polymorphism (allele 2) are supportive of a separate founder chromosome containing a second, independently arising mutant allele. Overall, the establishment of a likely "hemochromatosis critical region" centromeric boundary and the identification of a linkage-disequilibrium zone both significantly contribute to a reduction in the amount of DNA required to be searched for novel coding sequences constituting the HFE defect.

Citing Articles

Allelic association under map error and recombinational heterogeneity: a tale of two sites.

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PMID: 9736742 PMC: 21648. DOI: 10.1073/pnas.95.19.11366.

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

Ajioka R, Jorde L, Gruen J, Yu P, Dimitrova D, Barrow J Am J Hum Genet. 1997; 60(6):1439-47.

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Genomic characterization of the region between HLA-B and TNF: implications for the evolution of multicopy gene families.

Gaudieri S, Leelayuwat C, Townend D, Kulski J, Dawkins R J Mol Evol. 1997; 44 Suppl 1:S147-54.

PMID: 9071023 DOI: 10.1007/pl00000064.

Haemochromatosis: a gene at last?.

Robson K, Shearman J, Merryweather-Clarke A, Pointon J, Rosenberg W, Walker A J Med Genet. 1997; 34(2):148-51.

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Recombinations defining centromeric and telomeric borders for the hereditary haemochromatosis locus.

Ajioka R, Yu P, Gruen J, Edwards C, Griffen L, Kushner J J Med Genet. 1997; 34(1):28-33.

PMID: 9032646 PMC: 1050843. DOI: 10.1136/jmg.34.1.28.

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