Using linked markers to infer the age of a mutation

Advances in sequencing and genotyping technologies over the last decade hav e enabled geneticists to easily characterize genetic variation at the nucle otide level. Hundreds of genes harboring mutations associated with genetic disease have now been identified by positional cloning. Using variation at closely linked genetic markers, it is possible to predict the times in the past at which particular mutations arose. Such studies suggest that many of the rare mutations underlying human genetic disorders are relatively young . Studies of variation at genetic markers linked to particular mutations ca n provide insights into human geographic history, and historical patterns o f natural selection and disease, that are not available from other sources. We review two approaches for estimating allele age using variation at link ed genetic markers. A phylogenetic approach aims to reconstruct the gene tr ee underlying a sample of chromosomes carrying a particular mutation, obtai ning a "direct" estimate of allele age from the age of the root of this tre e. A population genetic approach relies on models of demography, mutation, and/or recombination to estimate allele age without explicitly reconstructi ng the gene tree. Phylogenetic methods are best suited for studies of ancie nt mutations, while population genetic methods are better suited for studie s of recent mutations. Methods that rely on recombination to infer the ages of alleles can be fine,tuned by choosing linked markers at optimal map dis tances to maximize the information available about allele age. A limitation of methods that rely on recombination is the frequent lack of a fine scale linkage map. Maximum likelihood and Bayesian methods for estimating allele age that rely on intensive numerical computation are described, as well as "composite" likelihood and moment,based methods that lead to simple estima tors. The former provide more accurate estimates (particularly for large sa mples of chromosomes) and should be employed if computationally practical. Hum Mutat 18:87-100,2001. (C) 2001 Wiley-Liss, Inc.