MBE Advance Access published online on March 10, 2004
Molecular Biology and Evolution, doi:10.1093/molbev/msh087
Molecular Biology and Evolution © Society for Molecular Biology and Evolution 2004; all rights reserved
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1 Department of Biology & Biochemistry, University of Bath, Bath, BA2 7AY, UK
* To whom correspondence should be addressed. E-mail: l.d.hurst{at}bath.ac.uk.
In mammals divergence at four-fold degenerate sites in codons (K4) and intronic sequence (Ki) are both used to estimate the mutation rate, under the supposition that both evolve neutrally. Does it matter which of these we use? Using either class of sequence can be defended because (1) K4 is the same as Ki (at least in rodents) and (2) there is no selectively-driven codon usage (hence no systematic selection on third sites). Here we re-examine these findings using 560 introns (for 136 genes) in the mouse-rat comparison, aligned by eye and using a new maximum likelihood protocol. We find that the rate of evolution at four-fold sites and at intronic sites is similar in magnitude, but only after eliminating putatively constrained sites from introns (first introns and sites flanking intron-exon junctions). Any approximate congruence between the two rates is not, however, owing to an underlying similarity in the mode of sequence evolution. Some dinucleotides are hypermutable and differently abundant in exons and introns (e.g. CpGs). More importantly, after controlling for relative abundance, all dinucleotides starting with A or T are more prevalent in mismatches in exons than in introns, while C-starting dinucleotides (except CG) are more common in introns. While C content at intronic sites is lower than at flanking four-fold sites, G content is similar, demonstrating that there exists a strong strand-specific preference for C nucleotides that is unique to exons. Transcription-coupled mutational processes and biased gene conversion cannot explain this, as they should affect introns and flanking exons equally. Therefore, by elimination, we propose this to be strong evidence for selectively-driven codon usage in mammals. Key Words:
codon usage bias, point substitution rate, purifying selection, introns, four-fold degenerate sites, dinucleotides
© 2004 Molecular Biology and Evolution © Society for Molecular Biology and Evolution 2004; all rights reserved.
Original Articles
Similar Rates but Different Modes of Sequence Evolution in Introns and at Exonic Silent Sites in Rodents: Evidence for Selectively-Driven Codon Usage
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