Simultaneous estimation of all the parameters of a stepwise mutation model

Abstract

Minisatellite and microsatellite are short tandemly repetitive sequences dispersed in eukaryotic genomes, many of which are highly polymorphic due to copy number variation of the repeats. Because mutation changes copy numbers of the repeat sequences in a generalized stepwise fashion, stepwise mutation models are widely used for studying the dynamics of these loci. We propose a minimum chi-square (MCS) method for simultaneous estimation of all the parameters in a stepwise mutation model and the ancestral allelic type of a sample. The MCS estimator requires knowing the mean number of alleles of a certain size in a sample, which can be estimated using Monte Carlo samples generated by a coalescent algorithm. The method is applied to samples of seven (CA)(n) repeat loci from eight human populations and one chimpanzee population. The estimated values of parameters suggest that there is a general tendency for microsatellite alleles to expand in size, because (1) each mutation has a slight tendency to cause size increase and (2) the mean size increase is larger than the mean size decrease for a mutation. Our estimates also suggest that most of these CA-repeat loci evolve according to multistep mutation models rather than single-step mutation models. We also introduced several quantities for measuring the quality of the estimation of ancestral allelic type, and it appears that the majority of the estimated ancestral allelic types are reasonably accurate. Implications of our analysis and potential extensions of the method are discussed.