Abstract
In the traditional view of molecular evolution, the rate of point mutation is uniform over the genome of an organism and variation in the rate of nucleotide substitution among DNA regions reflects differential selective constraints1,2. Here we provide evidence for significant variation in mutation rate among regions in the mammalian genome. We show first that substitutions at silent (degenerate) sites in protein-coding genes in mammals seem to be effectively neutral (or nearly so) as they do not occur significantly less frequently than substitutions in pseudogenes. We then show that the rate of silent substitution varies among genes and is correlated with the base composition of genes and their flanking DNA. This implies that the variation in both silent substitution rate and base composition3 can be attributed to systematic differences in the rate and pattern of mutation over regions of the genome. We propose that the differences arise because mutation patterns vary with the timing of replication of different chromosomal regions in the germline. This hypothesis can account for both the origin of isochores in mammalian genomes4 and the observation5 that silent nucleotide substitutions in different mammalian genes do not have the same molecular clock.
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References
Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge University Press, 1983).
Sharp, P. M. & Li, W.-H. Molec. biol. Evol. 4, 222–230 (1987).
Aota, S. & Ikemura, T. Nucleic Acids Res. 14, 6345–6355 (1986).
Bernardi, G. et al. Science 228, 953–958 (1985).
Li, W.-H., Tanimura, M. & Sharp, P. M. J. molec. Evol. 25, 330–342 (1987).
Li, W.-H., Gojobori, T. & Nei, M. Nature 292, 237–239 (1981).
Miyata, T. & Hayashida, H. Proc. natn. Acad. Sci. U.S.A. 78, 5739–5743 (1981).
Fukasawa, K. M. et al. Genetics 115, 177–184 (1987).
Miyata, T. et al. J. molec. Evol. 19, 28–35 (1982).
Filipski, J. J. theor. Biol. 134, 159–164 (1988).
Smithies, O., Engels, W. R., Devereux, J. R., Slightom, J. L. & Shen, S-h. Cell 26, 345–353 (1981).
Mouchiroud, D. & Gautier, C. Molec. biol. Evol. 5, 192–194 (1988).
Nadeau, J. H. & Taylor, B. A. Proc. natn. Acad. Sci. U.S.A. 81, 814–818 (1984).
Friedberg, E. C. DNA Repair (Freeman, New York, 1985).
Topal, M. D. & Fresco, J. R. Nature 263, 285–289 (1976).
Holmquist, G. P. Am. J. hum. Genet. 40, 151–173 (1987).
Leeds, J. M., Slabaugh, M. B. & Mathews, C. K. Molec. cell Biol. 5, 3443–3450 (1985).
Kelly, T. & Stillman, B. (eds) Cancer Cells 6: Eukaryotic DNA Replication (Cold Spring Harbor Laboratory, New York, 1988).
Fersht, A. R. & Knill-Jones, J. W. Proc. natn. Acad. Sci. U.S.A. 78, 4251–4255 (1981).
Holmquist, G., Gray, M., Porter, T. & Jordan, J. Cell 31, 121–129 (1982).
Brown, E. H. et al. Molec cell. Biol. 7, 450–457 (1987).
Filipski, J. FEBS Lett. 217, 184–186 (1987).
Bohr, V. A., Phillips, D. H. & Hanawalt, P. C. Cancer Res. 47, 6426–6436 (1987).
Prelich, G. & Stillman, B. Cell 53, 117–126 (1988).
Bernardi, G. & Bernardi, G. J. molec. Evol. 24, 1–11 (1986).
Gillespie, J. H. Genetics 113, 1077–1091 (1986).
Ikemura, T. Molec. biol Evol. 2, 13–34 (1985).
Hanai, R. & Wada, A. J. molec Evol. 27, 321–325 (1988).
Nei, M. & Graur, D. Evol. Biol. 17, 73–118 (1984).
Tajima, F. & Nei, M. Molec. biol. Evol. 1, 269–285 (1984).
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Wolfe, K., Sharp, P. & Li, WH. Mutation rates differ among regions of the mammalian genome. Nature 337, 283–285 (1989). https://doi.org/10.1038/337283a0
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DOI: https://doi.org/10.1038/337283a0
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