Human Molecular Genetics Advance Access originally published online on October 27, 2004
Human Molecular Genetics 2004 13(24):3089-3102; doi:10.1093/hmg/ddh337
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Human Molecular Genetics, Vol. 13, No. 24 © Oxford University Press 2004; all rights reserved
Recombination hotspots and block structure of linkage disequilibrium in the human genome exemplified by detailed analysis of PGM1 on 1p31
1Department of Molecular Genetics, Institute of Ophthalmology, University College London, 11–43 Bath Street, London EC1V 9EL, UK and 2MRC Human Biochemical Genetics Unit, Galton Laboratory, University College London, 4 Stephenson Way, London NW1 2HE, UK
Received July 20, 2004; Revised October 6, 2004; Accepted October 13, 2004
The distribution of linkage disequilibrium (LD) in the human genome has important consequences for the design of experiments that infer susceptibility genes for complex disease using association studies. Recent studies have shown a non-random distribution of human meiotic recombination associated with intervening tracts of LD. Little is known about the processes, patterns and frequency of reciprocal meiotic recombination in humans. However, this phenomenon can be better understood by the fine structure analysis of several genomic regions by mapping hotspots and characterizing regions with variable LD. Here, we report clustered hotspot activity with intervening blocks of LD within the human PGM1 gene (1p31) using data derived from meiotic and population studies. Earlier work has suggested a high recombination rate in two regions within the PGM1 gene, site A (exons 4–8) and site B (exons 1A–4). Sequencing of eight individuals across 6 kb of targeted regions in site B identified 18 informative SNPs. Individuals from three distinct populations, Caucasian (n=264), Chinese (n=222) and Vietnamese (n=187), were genotyped, and haplotypes were determined using estimate of haplotypes, ldmax and Arlequin. Allelic association and haplotype analysis in these samples revealed variable recombination rates across PGM1, demonstrating the presence of: (i) three hotspots and (ii) three haplotype blocks. The spatial arrangement of haplotype blocks was identical in all populations studied. The pattern of association within PGM1 represents a region decomposed into small blocks of LD, where increased recombination activity has disrupted the ancestral chromosome. Additionally, crossovers in phased data mapped preferentially to regions where LD collapses, which also overlap with sequence motifs.
* To whom correspondence should be addressed at: Department of Molecular Genetics, Institute of Ophthalmology, University College London, 11–43 Bath Street, London EC1V 9EL, UK. Tel: +44 2076086971; Fax: +44 2076086863; Email: naheed_rana{at}yahoo.co.uk
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