### Estimating the rate of molecular evolution: incorporating non-contemporaneous sequences into maximum likelihood phylogenies

**Rambaut A**

(2000) *Bioinformatics* **16**, 395-399.

**Motivation:** TipDate is a program that will use sequences that have been isolated at different dates to estimate their rate of molecular evolution. The program provides a maximum likelihood estimate of the rate and also the associated dare of the most recent common ancestor of the sequences, under a model which assumes a constant rate of substitution (molecular clock) but which accommodates the elates of isolation. Confidence intervals for these parameters are also estimated.

**Results:** The approach was applied to a sample of 17 dengue virus serotype 4 sequences, isolated at dates ranging from 1956 to 1994. The rate of substitution for this serotype was estimated to be 7.91 x 10(-4) substitutions per site per year (95% confidence intervals of 6.07 x 10(-4) 9.86 x 10(-4)). This is compatible with a date of 1922 (95% confidence intervals of 1900-1936) for the most recent common ancestor of these sequences.