ESTIMATING THE AGE OF MUTANT DISEASE ALLELES BASED ON LINKAGE DISEQUILIBRIUM

With more and more disease genes being mapped and/or cloned, there is a growing interest in dating the age of underlying mutations. The know ledge of the age of mutation is important to finely map disease genes by Linkage disequilibrium mapping. It would also help us understand th e origin, evolution, and dispersion of the mutant disease genes. Despi te increasing interests in dating disease mutations, the development o f appropriate statistical methods is largely fragmentary, and there is a lack of systematic treatment of the topic. We propose two classes o f methods for estimating the age of mutant allele at the disease locus based on linked marker data. Our methods can not handle only single-l ocus marker data, but also multi-locus marker data as well. Moreover, our methods can be used even when the location of the disease locus is unknown, and/or when there are mutations at the marker or disease loc us. We show that some previous results are special cases of our method s. We also derive a recursive equation previously obtained by Serre et al. [Hum Genet 1990;84:449-454] and provide an explicit solution to t he equation. To illustrate our methods, we applied them to two groups of data sets, one is cystic fibrosis data collected from several Europ ean populations, and the other is data on several genetic diseases (di astrophic dysplasia, progressive myoclonus epilepsy, congenital chlori de diarrhea, and Batten disease) all collected from the Finnish popula tion. The former data set allows us to trace the origin and dispersion of the most common mutation for cystic fibrosis. The latter provides an opportunity to examine whether all mutations for these diseases hav e the same age.