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Human Molecular Genetics, 2003, Vol. 12, No. 6 647-656
© 2003 Oxford University Press

Haplotype-specific linkage disequilibrium patterns define the genetic topography of the human MHC

Tariq Ahmad1,*, Matt Neville2, Sara E. Marshall3, Alessandro Armuzzi1, Kim Mulcahy-Hawes1, Jonathan Crawshaw1, Hiroe Sato4, Khoon-Lin Ling1, Martin Barnardo5, Sue Goldthorpe1, Robert Walton2, Mike Bunce6, Derek P. Jewell1 and Ken I. Welsh4

1Gastroenterology Unit, University of Oxford, Gibson Laboratories, Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, UK, 2General Practice Research Group, Cancer Research UK, University of Oxford, Department of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, UK, 3Department of Immunology, Wright-Fleming Institute, Imperial College, London, UK, 4Clinical Genomics, National Heart and Lung Institute, Imperial College, London, UK, 5Department of Transplant Immunology, Oxford Transplant Centre, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK and 6Dynal Biotech Ltd, 11 Bassendale Road, Croft Business Park, Bromborough, CH62 3QL, UK

Received November 14, 2002; Accepted November 17, 2002

Detailed knowledge of linkage disequilibrium (LD) is regarded as a prerequisite for population-based disease gene mapping. Variable patterns across the human genome are now recognized, both between regions and populations. Here, we demonstrate that LD may also vary within a genomic region in a haplotype-specific manner. In 864 Caucasian unrelated individuals, we describe haplotype-specific LD patterns across the human MHC by the construction of gene-specific allelic haplotypes at 25 loci between HLA-A and Tapasin. Strong and extensive LD is found across both common and rare haplotypes, suggesting that haplotype structure is influenced by factors other than genetic drift, including both selection and differential haplotype recombination. Knowledge of haplotype-specific LD in the HLA may explain the apparent discrepant data from previous studies of global LD, help delineate key areas in mapping HLA-associated diseases and, together with recombination data, provide valuable information about a population's demographic history and the selective pressures operating on it.

* To whom correspondence should be addressed. Tel: +44 1865224938; Fax: +44 1865790792; E-mail: tariq.ahmad{at}ndm.ox.ac.uk


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