C-X-C and C-X3-C motifs: CXCL5 (P = 8.1610 24 work. Care will be required to distinguish between true coevolution and correlations that can be explained by dependencies on expression levels or other covariates of evolutionary rate [79] . Our finding that PSGs are expressed at lower levels and in a more tissue-specific manner than non-PSGs is consistent with a well-known negative correlation v with expression level, and a positive correlation of v with tissue bias (t or c). Various explanations have been proposed for the observed decrease in v among genes expressed at high levels and/or expressed broadly across tissues, including selection for translational efficiency, selection against misfolding, or increased selection due to pleiotropy [62, 68, 65] . In any case, these genes do appear to experience a reduction in their evolutionary ''flexibility'' compared with genes expressed at low levels and/or nonuniformly across tissues. Our observation of decreased rates of positive selection among these genes-and increased rates among lowexpression/high-tissue-bias genes-is consistent with this characterization. Interestingly, however, we observe that correlations of v with expression level and t hold strongly within non-PSGs, but are much less pronounced within PSGs. Thus, expression levels and patterns are strongly correlated with both the strength of negative selection and the likelihood of positive selection, but they are only weakly correlated with the strength of positive selection. It appears that genes may be more likely to come under positive selection if they are in a state of evolutionary flexibility brought on by reduced or tissue-specific expression, but once positive selection has taken hold their subsequent evolutionary course is not strongly dependent on their expression patterns.