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

Sequence variants occur every few hundred bases in the human genome. We evaluated the relationship between disease-causing mutations and neutral sequence 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. Each of these variants appeared frequently in both A-T and non-A-T chromosomes. However, there was remarkable linkage disequilibrium between the polymorphic loci, resulting in only 7 haplotypes in analyzed chromosomes. These 7 haplotypes fell into 3 major ancestral groups. No individual polymorphic variant or haplotype correlated reliably with the presence of an A-T mutation. Thus, comparing the frequency of neutral variants at the A-T locus in diseased 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 loci for many common diseases.