The inference of stepwise changes in substitution rates using serial sequence samples

It is frequently true that molecular sequences do not evolve in a strictly clocklike manner. Instead, substitution rate may vary for a number of reaso ns, including changes in selection pressure and effective population size, as well as changes in mean generation time. Here we present two new methods for estimating stepwise changes in substitution rates when serially sample d molecular sequences are available. These methods are based on multiple ra tes with dated tips (MRDT) models and allow different rates to be estimated for different intervals of time. These intervals may correspond to the sam pling intervals or to a priori-defined intervals that are not coincident wi th the times the serial samples are obtained. Two methods for obtaining est imates of multiple rates are described. The first is an extension of the ph ylogeny-based maximum-likelihood estimation procedure introduced by Rambaut . The second is a new parameterization of the pairwise distance least-squar es procedure used by Drummond and Rodrigo. The utility of these methods is demonstrated on a genealogy of HIV sequences obtained at five different sam pling times from a single patient over a period of 34 months.