FINE-SCALE GENETIC-MAPPING BASED ON LINKAGE DISEQUILIBRIUM - THEORY AND APPLICATIONS

Linkage-disequilibrium mapping (LDM) recently has been hailed as a pow erful statistical method for fine-scale mapping of disease genes. Afte r reviewing its historical background and methodological development, we present a general, mathematical, and conceptually coherent framewor k for LDM that incorporates multilocus and multiallelic markers and mu tational processes at the marker and disease loci. With this framework , we address several issues relevant to fine-scale mapping and propose some efficient computational methods for LDM. We implement various LD M methods that incorporate population growth, recurrent mutation, and marker mutations, on the basis of a general framework. We demonstrate these methods by applying them to published data on cystic fibrosis, H untington disease, Friedreich ataxia, and progressive myoclonus epilep sy. Since the genes responsible for these diseases all have been clone d, we can evaluate the performance of our methods and can compare ours with that of other methods. Using the proposed methods, we successful ly and accurately predicted the locations of genes responsible for the se diseases, on the basis of published data only.