An isochore transition in the NF1 gene region coincides with a switch in the extent of linkage disequilibrium

Whole-genome association studies will be a powerful tool to identify genes responsible for common human diseases. A crucial task for association-mappi ng studies is the evaluation of the relationship between linkage disequilib rium (LD) and physical distance for the genomic region under study. Since i t is known that the extent of LD is nonuniformly distributed throughout the human genome, the required marker density has to be determined specificall y for the region under study. These regions may be related to isochores and chromosomal bands, as indicated by earlier cytogenetic findings concerning chiasma distribution in meiosis. Therefore we analyzed the neurofibromatos is type 1 (NF1) gene region on chromosome 17q11.2, which is characterized b y a nonuniform LD pattern and an L1-to-H2 isochore transition. Long-range L D within the NF1 gene was found to extend over 200 kb (D' = 0.937) in the L 1 isochore, whereas, in the neighboring H2 isochore, no LD is apparent betw een markers spaced by 26 kb (D' = 0.144). Recombination frequencies derived from the LD are at .00019 thigh LD) and .01659 (low LD) per megabase, the latter identical to the average value from segregation analysis. The bounda ry between these regions coincides precisely with a transition in the GC co ntent of the sequences, with low values (37.2%) in the region with long-ran ge LD and high values (51%) in the other. Our results suggest a correlation between the LD pattern and the isochores, at least in the NF1 region. If t his correlation can be generalized, the marker densities required for assoc iation studies have to be adjusted to the regional GC content and may be ch osen according to the isochores.