A model for the correlation of mutation rate with GC content and the origin of GC-rich isochores.
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 approximately 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 approximately 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.
Center for Demographic and Population Genetics, University of Texas, Houston 77225.
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D001482:Base Composition; D003596:Cytosine / Q000032:analysis*; D004247:DNA / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D004261:DNA Replication; D006147:Guanine / Q000032:analysis*; D006801:Humans; D008433:Mathematics; D008957:Models, Genetic; D009154:Mutation
D006147:Guanine; D003596:Cytosine; D004247:DNA