As wild organisms adapt to the laboratory environment, they become less relevant as biological models. It has been suggested that a commonly used S. cerevisiae strain has rapidly accumulated mutations in the lab. We report a low-to-intermediate rate of protein evolution in this strain relative to wild isolates. W HEN introduced into the lab, wild organisms often undergo selection for easier growth. This adaptation, and loss of selective pressures normally present in the wild, may have wide-ranging effects, such that the biology of a lab organism may no longer reflect that of wild populations. This concern has arisen in the recent literature for Saccharomyces cerevisiae (Liu et al. 1996;Bonhivers et al. 1998;Yvert et al. 2003;Deutschbauer and Davis 2005;Dunn et al. 2005;Gu et al. 2005;Qin and Lu 2006). The S288C yeast strain was bred in the 1950s from wild and commercial strains (Mortimer and Johnston 1986) and passed into use as a common lab strain. In a recent comparison of S288C with the clinical strain YJM789 (Gu et al. 2005), isolated in 1989(Tawfik et al. 1989, the phylogenetic lineage to the lab strain exhibited faster protein evolution. One interpretation of this result is that S288C accumulated more mutations during its longer tenure in the lab. Here we revisit this hypothesis in the context of a third strain, the vineyard isolate RM11-1a, which was introduced into the lab in 1996 (Torok et al. 1996;Brem et al. 2002).To parallel previous calculations (Gu et al. 2005), we first analyzed protein evolution in yeast strain pairs. We obtained ORF alignments of S288C, RM11-1a (hereafter RM), YJM789 (hereafter YJM), and S. paradoxus orthologs (Ronald et al. 2005) and eliminated frameshifts, for a total of 4162 genes. We reasoned that most assumptions of molecular evolution methods would be as valid here as when species are compared, and the approximation of constant generation time may be better in this case. As such, for each pair of S. cerevisiae strains plus S. paradoxus, we used PAML (Yang 1997) to infer maximum-likelihood branch lengths for the star tree describing each gene, assuming an independent evolutionary rate for each lineage. We then used nonsynonymous and synonymous changes in inferred trees to estimate genomewide evolutionary rates for each lineage as described (Chimpanzee Sequencing and Analysis Consortium 2005; Gu et al. 2005). The results are shown in Table 1. As expected, in a comparison of S288C and YJM, the lineage to the lab strain had a faster evolutionary rate. However, in other comparisons, the rate for the RM lineage was faster still (Table 1). Thus, the vineyard strain bears the strongest signature of rapid protein evolution.To confirm this, we sought to analyze the three S. cerevisiae strains and S. paradoxus simultaneously. As the genealogy of these genomes varies between loci (Ruderfer et al. 2006), we modeled each gene separately. For each gene, we inferred branch lengths, assuming independent evolutionary rates on all branches, fixing in turn each of the first three topo...