Neutral sequence variants and haplotypes at the 150 Kb ataxia-telangiectasia locus

Sequence variants occur every few hundred bases in the human genome. We eva luated the relationship between disease-causing mutations and neutral seque nce variants at the 150 Kb ataxia-telangiectasia (A-T) locus. Mutations at this locus cause a distinct autosomal recessive syndrome in homozygotes and predispose heterozygotes to cancer and coronary heart disease. Nine common neutral sequence variants were observed in the coding and splice junction regions of 132 chromosomes from Caucasian individuals of European origin. E ach of these variants appeared frequently in both A-T and non-A-T chromosom es. However, there was remarkable linkage disequilibrium between the polymo rphic loci, resulting in only 7 haplotypes in analyzed chromosomes. These 7 haplotypes fell into 3 major ancestral groups. No individual polymorphic v ariant or haplotype correlated reliably with the presence of an A-T mutatio n. Thus, comparing the frequency of neutral variants at the A-T locus in di seased and non-diseased populations is unlikely to uncover the relationship of mutations at this locus to common diseases. These data reflect general limitations on using single nucleotide polymorphisms (SNPs) to identify loc i for many common diseases. (C) 1999. Wiley-Liss, Inc.