Determinants of Substitution Rates in Mammalian Genes: Expression Pattern Affects Selection Intensity but Not Mutation Rate

Abstract

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 2,400 human/rodent and 834 mouse/rat orthologous genes, and we measured (using expressed sequence tag data) their expression patterns in 19 tissues from three development states. We show that substitution rates at nonsynonymous sites are strongly negatively correlated with tissue distribution breadth: almost threefold lower in ubiquitous than in tissue-specific genes. Nonsynonymous substitution rates also vary considerably according to the tissues: the average rate is twofold 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 in both coding and noncoding regions. Conversely, silent substitution rates do not vary with expression pattern, even in ubiquitously expressed genes. This latter result thus suggests that synonymous codon usage is not constrained by selection in mammals. Furthermore, this result also indicates that there is no reduction of mutation rates in genes expressed in the germ line, contrary to what had been hypothesized based on the fact that transcribed DNA is more efficiently repaired than nontranscribed DNA.

Evolutionary significance of gene expression divergence

“…Consistent with previously published results (Duret and Mouchiroud, 2000;Jordan et al, 2004), gene expression breadth showed a significant negative correlation with gene sequence divergence. More broadly expressed genes tend to be more conserved, on average, than genes with a narrow range of expression (data not shown; r= −0.90, P=0.002).…”

“…Selective constraints on the evolution of CDSs show a broad range of variation and have been related to a number of functional characteristics of genes and the proteins that they encode (Krylov et al, 2003). These characteristics include protein dispensability (Hirsh and Fraser, 2001;Jordan et al, 2002) and interactivity (Fraser et al, 2002(Fraser et al, ,2003Jordan et al, 2003) as well as gene expression level and breadth (Duret and Mouchiroud, 2000;Pal et al, 2001;Jordan et al, 2004;Zhang and Li, 2004). Of all of these factors, gene expression level is most strongly correlated with gene sequence divergence (Pal et al, 2003;Bloom and Adami, 2004;Rocha and Danchin, 2004), i.e., highly expressed genes tend to evolve slowly.…”

Codon Bias and Noncoding GC Content Correlate Negatively with Recombination Rate on the Drosophila X Chromosome

“…This is likely due to increased constraints on proteins expressed at high levels and/or in a broad range of tissues (Duret and Mouchiroud 2000;Krylov et al 2003;Pal et al 2001;Subramanian and Kumar 2004;Wright et al 2004). …”

Testing the neutral theory of molecular evolution using genomic data: a comparison of the human and bovine transcriptome

“…Recently, higher evolutionary rates have been reported in genes that are expressed in a narrow range of tissues than those that are widely expressed [8]. This finding could be explained by two different hypotheses.…”

“…A limitation of this approach is that for individual genes there may be too few known polymorphisms to estimate dN:dS or Dr:Dc ratios with sufficient accuracy. Therefore, the methods that identify functionally related groups of genes [7,8,23] will have more power to find evidence of adaptive evolution in patterns of divergence and polymorphism.…”