LINKAGE DISEQUILIBRIUM PREDICTS PHYSICAL DISTANCE IN THE ADENOMATOUS POLYPOSIS-COLI REGION

To test the reliability of linkage-disequilibrium analysis for gene ma pping, we compared physical distance and linkage disequilibrium among seven polymorphisms in the adenomatous polyposis coli (ADC) region on chromosome 5. Three of them lie within the APC gene, and two lie withi n the nearby MCC (mutated in colon cancer) gene. One polymorphism lies between the two genes, and one is likely to be 5' of MCC. Five of the se polymorphisms are newly reported. All polymorphisms were typed in t he CEPH kindreds, yielding 179-205 unrelated two-locus haplotypes. Lin kage disequilibrium between each pair of polymorphisms is highly corre lated with physical distance in this 550-kb region (correlation coeffi cient -.80, P <.006). This result is replicated in both the Utah and n on-Utah CEPH kindreds. There is a tendency for greater disequilibrium among pairs of polymorphisms located within the same gene than among o ther pairs of polymorphisms. Trigenic, quadrigenic, three-locus, and f our-locus disequilibrium measures were also estimated, but these measu res revealed much less disequilibrium than did the two-locus disequili brium measures. A review of 19 published disequilibrium studies, inclu ding this one, shows that linkage disequilibrium nearly always correla tes significantly with physical distance in genomic regions >50-60 kb but that it does not do so in smaller genomic regions. We show that th is agrees with theoretical predictions. This finding helps to resolve controversies regarding the use of disequilibrium for inferring gene o rder. Disequilibrium mapping is unlikely to predict gene order correct ly in regions (50-60 kb in size but can often be applied successfully in regions of 50-500 kb or so in size. It is convenient that this is t he range in which other mapping techniques, including chromosome walki ng and linkage mapping, become difficult.