Abstract
Based on the biochemical kinetics of DNA replication and mutagenesis, including misincorporation and correction, a model has been developed for studying the relationships among the mutation rate (u), the G + C content of the sequence (f), and the G + C proportion in the nucleotide precursor pool (N). Also a measure for the next-nucleotide effect, called the maximum capacity of the next-nucleotide effect (MC), has been proposed. Under the normal physiological conditions of mammalian germ cells, our results indicate: (1) the equilibrium G + C content in a sequence is approximately equal to the G + C proportion in the nucleotide precursor pool, i.e., f ≈ N, which is independent of the next-nucleotide effect; (2) an inverted-V-shaped distribution of mutation rates with respect to G + C contents is predicted, when the next-nucleotide effect is week, i.e., MC ≈ 1; (3) the distribution becomes flatter (i.e., inverted-U-shaped) as MC increases, but the peak at 50% GC is still observed when MC < 2; and (4) the peak disappears when MC > 2.8, that is, when the next-nucleotide effect becomes strong. Our results suggest that changes in the relative concentrations of nucleotide precursors can cause variations among genes both in mutation rate and in G + C content and that compositional isochores (DNA segments with a homogeneous G + C content) can arise in a genome due to differences in replication times of DNA segments.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Bernardi G (1989) The isochore organization of the human genome. Annu Rev Genet 23:637–661
Bernardi G, Mouchiroud D, Gautier C (1988) Compositional patterns in vertebrate genomes: conservation and change in evolution. J Mol Evol 28:7–28
Bernardi G, Olofsson B, Filipski J, Zerial M, Salinas J, Cuny G, Meunier-rotival M, Rodier F (1985) The mosaic genome of warmblooded vertebrates. Science 228:953–958
Bulmer M, Wolfe KH, Sharp PM (1991) Synonymous nucleotide substitution rates in mammalian genes: implications for the molecular clock and the relationship of mammalian orders. Proc Natl Acad Sci USA 88:5974–5978
Dresler SL, Frattini MG, Robinson-Hill RM (1988) In situ enzymology of DNA replication and ultraviolet-induced DNA repair synthesis in permeable human cells. Biochemistry 27:7247–7254
Echols H, Goodman MF (1991) Fidelity mechanisms in DNA replication. Annu Rev Biochem 60:477–511
Eyre-Walker A (1992a) Evidence that both G + C rich and G + C poor isochores are replicated early and late in the cell cycle. Nucleic Acids Res 20:1497–1501.
Eyre-Walker A (1992b) The role of DNA replication and isochores in generating mutations and silent substitution rate variance in mammals. Genet Res 60:61–67
Fersht (1985) Enzyme structure and mechanism, 2nd ed. WH Freeman, New York, p 308, 363–367
Goldman MA (1988) The chromatin domain as a unit of gene regulation. Bioessays 9:50–55
Holmquist GP (1987) Role of replication time in the control of tissue of specific gene expression. Am J Hum Genet 40:151–173
Holmquist GP (1988) DNA sequences in G-bands and R-bands. In: Adolph KW (ed) Chromosomes and chromatin. CRC Press, Boca Raton, p 76
Holmquist GP (1992) Chromosome bands, their chromatin flavors, and their functional features. Am J Hum Genet 51:17–37
Ikemura T, Aota S (1988) Global variation in G + C content along vertebrate genome DNA: possible correlation with chromosome band structures. J Mol Biol 203:1–13
Kunkel TA (1988) Exonucleolytic proofreading. Cell 53:837–840
Kunkel TA (1992a) DNA replication fidelity. J Biol Chem 267: 18251–18254
Kunkel TA (1992b) Biological asymmetries and the fidelity of eukaryotic DNA replication. Bioessays 14:303–308
Kunz BA, Kohalmi SE (1991) Modulation of mutagenesis by deoxyribonucleotide levels. Annu Rev Genet 25:339–359
Leeds JM, Slabaugh MB, Mathews CK (1985) DNA precursor pools and ribonucleotide reductase activity: distribution between the nucleus and the cytoplasm of mammalian cells. Mol Cell Biol 5:3443–3450
Mathews CK, Ji J (1992) DNA precursor asymmetries, replication fidelity, and variable genome evolution. Bioessays 14:295–301
Mendelman LV, Petruska J, Goodman MF (1990) Base mispair extension kinetics. J Biol Chem 265:2338–2346
Modrich P (1991) Mechanisms and biological effects of mismatch repair. Annu Rev Genet 25:229–253
Ninio J (1987) Kinetics devices in protein synthesis, DNA replication, and mismatch repair. Cold Spring Harbor Symp Quant Biol 52: 639–646
Sueoka N (1988) Directional mutation pressure and neutral molecular evolution. Proc Natl Acad Sci USA 85:2653–2657
Sueoka N (1992) Directional mutation pressure, selective constraints, and genetic equilibria. J Mol Evol 34:95–114
Wolfe KH (1991) Mammalian DNA replication: mutation biases and the mutation rate. J Theor Biol 149:441–451
Wolfe KH, Sharp PM (1993) Mammalian gene evolution: nucleotide sequence divergence between mouse and rat. J Mol Evol 37:441–456
Wolfe KH, Sharp PM, Li WH (1989) Mutation rate differ among regions of the mammalian genome. Nature 337:283–285
Wong I, Patel SS, Johnson KA (1991) An induced-fit kinetic mechanism for DNA replication fidelity: direct measurement by single-turnover kinetics. Biochemistry 30:526–537
Author information
Authors and Affiliations
Additional information
Correspondence to: W.-H. Li
Rights and permissions
About this article
Cite this article
Gu, X., Li, W.H. A model for the correlation of mutation rate with GC content and the origin of GC-rich isochores. J Mol Evol 38, 468–475 (1994). https://doi.org/10.1007/BF00178846
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00178846