To determine whether gene expression patterns affect mutation rates and (or) selection intensity in mammalian genes, we studied the relationships between substitution rates and tissue distribution of gene expression. For this purpose, we analyzed 2400 human/rodent and 834 mouse/rat orthologous genes, and we measured (using EST sequence data) their expression patterns in 19 tissues from three development states. We show that substitution rates in non-synonymous sites (Ka) are strongly negatively correlated with tissue distribution breadth: almost three time lower in ubiquitous compared to tissue-specific genes. Ka values also vary considerably according to the tissues: the average rate is two times lower in brain-, muscle-, retina- and neuron- specific genes, than in lymphocyte-, lung - and liver-specific genes. Interestingly, 5' and 3' untranslated regions (UTRs) show exactly the same trend. These results demonstrate that the expression pattern is an essential factor in determining the selective pressure on functional sites, both in coding and non-coding regions. Conversely, silent substitution rates do not vary with the expression pattern, even in ubiquitously-expressed genes. This latter result thus suggests that synonymous codon usage is not constrained by selection in mammals. Besides, this result also shows that there is no reduction of mutation rates in genes expressed in the germline, contrarily to what had been hypothesized, based on the fact that transcribed DNA is more efficiently repaired than non-transcribed DNA.
Keywords: Mammals; Gene expression; Substitution rate; non-coding regions; Codon usage; DNA repair;
