Here we present a phylogenetic analysis of positive selection in the six eutherian mammalian genomes for which high-coverage, high-quality sequence assemblies are now available: the human [21] , chimpanzee [6] , macaque [8] , mouse [22] , rat [23] , and dog [24] genomes. The phylogenetic depth of this data set helps considerably in addressing the problem of weak power. Indeed, these genomes have a near-optimal degree of divergence for PSG detection, being distant enough to produce a strong phylogenetic signal, yet close enough that gene structures are well conserved, alignment is fairly straightforward, and synonymous substitutions are not saturated (e.g., [25] ). In addition, our data set for the first time allows positive selection of mammalian genes to be examined genome-wide on a nontrivial phylogeny, so that insight can be gained into the particular ''selection histories'' of individual genes-that is, the branches of the phylogeny on which they experienced positive selection. In our analysis, we employ models of codon substitution that account for variation of selective pressure over branches on the tree and across sites in a sequence, which can capture signatures of molecular adaptation that affect small numbers of sites [26, 27] . Using a series of likelihood ratio tests (LRTs) based on these models, we identify more than four hundred genes that show strong signatures of positive selection during mammalian evolution. Our detailed analysis of the functional roles, selection histories, and expression patterns of these genes follows.