Region-specific rates of molecular evolution: A fourfold reduction in the rate of accumulation of “Silent” mutations in transcribed versus nontranscribed regions of homologous DNA fragments derived from two closely related mouse species

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Abstract
We have sequenced homologous DNA fragments of 2.7 and 2.8 kbp derived from the closely related mouse speciesMus musculus domesticus (M. domesticus) andMus musculus musculus (M. musculus), respectively. These two species diverged approximately 1 million years ago. Each DNA fragment contains 1.35 kbp of the 3′ end of the constitutively expressed 2.2-kbpaprt (adenine phosphoribosyltransferase) gene and a similarly sized nontranscribed region downstream of theaprt gene. Theaprt gene region contains protein coding sequences (0.35 kbp), intronic sequences (0.75 kbp), and a 3′ nontranslated sequence (0.25 kbp). Both theM. domesticus andM. musculus downstream regions share three partial copies of the B1 repetitive element with theM. musculus downstream region containing an additional complete copy of this element. A comparison of the 2.7-and 2.8-kbp DNA fragments revealed a total of 63 molecular alterations (i.e., mutations) that were approximately fourfold more abundant in the nontranscribed downstream region than in the transcribedaprt gene. Of the 11 mutations observed in the transcribed region, 7 were found in introns, 3 in the 3′ untranslated sequence, and 1 was a synonymous change in an exon. A comparison of the human andM. domesticus aprt genes has previously revealed no homology in either the intronic or 3′ nontranslated regions with the exception of a 26-bp sequence in intron 3 and sequences at the exon/intron boundaries necessary for correct mRNA splicing (Broderick et al.,Proc. Natl. Acad. Sci. USA, 84:3349, 1987). Therefore, there does not appear to be selective pressure for sequences within these regions. We conclude that there is a lower rate of accumulation of “silent” mutations in the transcribed mouseaprt gene than in a contiguous nontranscribed downstream region. A possible molecular mechanism involving preferential DNA repair for the transcribed region is discussed.