LIKELIHOOD METHODS FOR LOCATING DISEASE GENES IN NONEQUILIBRIUM POPULATIONS

Until recently, attempts to map disease genes on the basis of populati on associations with linked markers have been based on expected values of linkage disequilibrium. These methods suffer from the large varian ces imposed on disequilibrium measures by the evolutionary process, bu t a more serious problem for many diseases is that they assume an equi librium population. For diseases that arose only a few hundred generat ions ago, it is more appropriate to concentrate on the initial growth phase of the disease. We invoke a Poisson branching process for this e arly growth, and estimate the likelihood for the recombination fractio n between marker and disease loci, on the basis of simulated disease p opulations. The limits of the resulting support intervals for the reco mbination fraction vary inversely with the age of the disease in gener ations. We illustrate the procedure with data on cystic fibrosis and d iastrophic dysplasia, for which the method appears appropriate, and fo r Friedreich ataxia and Huntington disease, for which it does not. A v aluable aspect of the method is the ability in some cases to compare l ikelihoods of the three orders for a disease locus and two linked mark er loci.