Major factors influencing linkage disequilibrium by analysis of different chromosome regions in distinct populations: demography, chromosome recombination frequency and selection.

Linkage disequilibrium (LD) mapping of disease genes is complicated by population- and chromosome-region-specific factors. We have analysed demographic factors by contrasting intermarker LD results obtained in a large cosmopolitan population (UK), a large genetic isolate (Sardinia) and a subisolate (village of Gavoi) for two regions of the X chromosome. A dramatic increase of LD was found in the subisolate. Demographic history of populations therefore influences LD. Chromosome-region-specific effects, namely the pattern and frequency of homologous recombination, were next delineated by the analysis of chromosome 6p21, including the HLA region. Patterns of global LD in this region were very similar in the UK and Sardinian populations despite their entirely distinct demographies, and correlate well with the pattern of recombinations. Nevertheless, haplotypes extend across recombination hot spots indicative of selection of certain haplotypes. Subisolate aside, chromosome-region-specific differences in LD patterns appear to be more important than the differences in intermarker LD between distinct populations.

[1]  J. Todd,et al.  The inter-regional distribution of HLA class II haplotypes indicates the suitability of the Sardinian population for case-control association studies in complex diseases. , 2000, Human molecular genetics.

[2]  John A. Todd,et al.  The genetically isolated populations of Finland and Sardinia may not be a panacea for linkage disequilibrium mapping of common disease genes , 2000, Nature Genetics.

[3]  Pui-Yan Kwok,et al.  Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28 , 2000, Nature Genetics.

[4]  Jonathan Scott Friedlaender,et al.  Haplotypes and linkage disequilibrium at the phenylalanine hydroxylase locus, PAH, in a global representation of populations. , 2000, American journal of human genetics.

[5]  A. Jeffreys,et al.  High resolution analysis of haplotype diversity and meiotic crossover in the human TAP2 recombination hotspot. , 2000, Human molecular genetics.

[6]  J. Stephens,et al.  Significant admixture linkage disequilibrium across 30 cM around the FY locus in African Americans. , 2000, American journal of human genetics.

[7]  J. Ott,et al.  Predicting the range of linkage disequilibrium. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[8]  L. Excoffier,et al.  A linkage disequilibrium map of the MHC region based on the analysis of 14 loci haplotypes in 50 French families , 2000, European Journal of Human Genetics.

[9]  N E Morton,et al.  Genetic epidemiology of single-nucleotide polymorphisms. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Mario Pirastu,et al.  Population choice in mapping genes for complex diseases , 1999, Nature Genetics.

[11]  M. Carrington,et al.  A scan for linkage disequilibrium across the human genome. , 1999, Genetics.

[12]  L. Kruglyak.  Prospects for whole-genome linkage disequilibrium mapping of common disease genes , 1999, Nature Genetics.

[13]  N. Morton,et al.  Allelic association between marker loci. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[14]  L Kruglyak,et al.  Genetic isolates: separate but equal? , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Carrington,et al.  Recombination within the human MHC , 1999, Immunological reviews.

[16]  J. Bodmer,et al.  Molecular typing for HLA class I using ARMS-PCR: further developments following the 12th International Histocompatibility Workshop. , 1999, Tissue antigens.

[17]  K. Weiss,et al.  Linkage disequilibrium mapping of complex disease: fantasy or reality? , 1998, Current opinion in biotechnology.

[18]  A. Cambon-Thomsen,et al.  Microsatellites in the HLA region: 1998 update. , 1998, Tissue antigens.

[19]  D. Schlessinger,et al.  YAC/STS map of 15Mb of Xp21.3-p11.3, at 100kb resolution, with refined comparisons of genetic distances and DMD structure. , 1998, Gene.

[20]  Amanda J. Wilson,et al.  A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients , 1998, Nature Genetics.

[21]  S. Pääbo,et al.  Demographic history and linkage disequilibrium in human populations , 1997, Nature Genetics.

[22]  R. Mazzarella,et al.  X chromosome map at 75-kb STS resolution, revealing extremes of recombination and GC content. , 1997, Genome research.

[23]  S Beck,et al.  Characterization of recombination in the HLA class II region. , 1997, American journal of human genetics.

[24]  R. Campbell,et al.  Mapping of 10 novel microsatellites in the MHC class III region: application to the study of autoimmune disease. , 1997, The Journal of rheumatology.

[25]  C. Boitard,et al.  Absence of primary association between DM gene polymorphism and insulin-dependent diabetes mellitus or celiac disease. , 1996, Human immunology.

[26]  G. Thomson.  Mapping disease genes: family-based association studies. , 1995, American journal of human genetics.

[27]  M. Carrington,et al.  Recombination rates across the HLA complex: use of microsatellites as a rapid screen for recombinant chromosomes. , 1995, Human molecular genetics.

[28]  N. Maclaren,et al.  Association of LMP2 and LMP7 genes within the major histocompatibility complex with insulin-dependent diabetes mellitus: population and family studies. , 1995, American journal of human genetics.

[29]  Rengert Elburg,et al.  The human colonization of Sardinia: a Late-Pleistocene human fossil from Corbeddu cave , 1995 .

[30]  Cécile Fizames,et al.  The 1993–94 Généthon human genetic linkage map , 1994, Nature Genetics.

[31]  D. Chaplin,et al.  Highly informative typing of the human TNF locus using six adjacent polymorphic markers. , 1993, Genomics.

[32]  E. Thompson,et al.  Performing the exact test of Hardy-Weinberg proportion for multiple alleles. , 1992, Biometrics.

[33]  R. Lewontin,et al.  On measures of gametic disequilibrium. , 1988, Genetics.

[34]  H. Erlich,et al.  Allelic sequence variation of the HLA-DQ loci: relationship to serology and to insulin-dependent diabetes susceptibility. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[35]  P. Hedrick,et al.  Gametic disequilibrium measures: proceed with caution. , 1987, Genetics.