Single nucleotide polymorphism and linkage disequilibrium within the TCR alpha/delta locus

Much attention is being given to the identification of common disease genes through whole-genome linkage disequilibrium (LD) screens with single nucle otide polymorphisms (SNPs), Simulation studies have suggested that useful L D is unlikely to extend beyond 3 kb, and that, 500 000 SNPs may be needed f or comprehensive coverage of the genome, The TCR alpha/delta locus on chrom osome 14q contains many V, J and D segments that combine with constant doma ins to produce either an alpha or a delta chain of the T cell receptor. Mul tiple SNPs have been recognized within the V segments, and it has been sugg ested that variation within the locus may modify the course of autoimmune a nd allergic diseases. We have examined LD within an 850 kb section of the T CR alpha/delta locus on chromosome 14q by typing 24 V gene segment SNPs and two microsatellites. One hundred and fifty-nine nuclear and extended famil ies were genotyped in order to derive haplotypes, and the pair-wise LD betw een SNPs was investigated in 600 haplotypes from unrelated individuals (the parents), The mean extent of useful LD was much greater than suggested by simulations: significant LD was relatively common at 250 kb and was detecta ble beyond 500 kb, The mean extent of LD was twice as far between alleles o f low frequency than between common alleles, The distribution of LD was hig hly irregular and concentrated in three distinct islands, The results diffe r from those obtained by simulation, and if they are typical of other genom ic regions, suggest that the minimum number of markers necessary for compre hensive LD mapping may be reduced by at least an order of magnitude.