HAPLOTYPE ANALYSIS TO DETERMINE THE POSITION OF A MUTATION AMONG CLOSELY LINKED DNA MARKERS

Positional cloning involves first finding linkage between an inherited phenotype (such as a disease) and a DNA marker, followed by the use o f a variety of physical and genetic mapping techniques to move from li nkage to mutation. If there is a founder effect within a population, c rossovers are often rare between the mutation causing the phenotype an d closely situated markers and increasing disequilibrium may be observ ed as the site of the mutation is approached. Standard coefficients of disequilibrium may, however, be insensitive to the relative position of close markers and the mutation, because they depend upon allele fre quencies in the normal population compared to those of the founder chr omosome. Using cystic fibrosis in European populations as a model syst em, alternative methods for determining the position of a mutation are discussed. These include haplotype parsimony and three-way interval l ikelihood analysis. Both methods predict the location of the major CF mutation accurately from a real set of more than 600 European CF chrom osomes.