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The role of DNA replication and isochores in generating mutation and silent substitution rate variance in mammals

Published online by Cambridge University Press:  14 April 2009

Adam Eyre Walker
Adam Eyre Walker
Affiliation:
Institute of Cell Animal and Population Biology, University of Edinburgh, Edinburgh, EH9 3JT, Great Britain
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It has been suggested that isochores are maintained by mutation biases, and that this leads to variation in the rate of mutation across the genome. A model of DNA replication is presented in which the probabilities of misincorporation and proofreading are affected by the composition and concentration of the free nucleotide pools. The relationship between sequence G + C content and the mutation rate is investigated. It is found that there is very little variation in the mutation rate between sequences of different G + C contents if the total concentration of the free nucleotides remains constant. However, variation in the mutation rate can be arbitrarily large if some mismatches are proofread and the total concentration of free nucleotides varies. Hence the model suggests that the maintenance of isochores by the replication of DNA in free nucleotide pools of biased composition does not lead per se to mutation rate variance. However, it is possible that changes in composition could be accompanied by changes in concentration, thus generating mutation rate variance. Furthermore, there is the possibility that germ-line selection could lead to alterations in the overall free nucleotide concentration through the cell cycle. These findings are discussed with reference to the variance in mammalian silent substitution rates.

Type
Research Article
Information
Genetics Research , Volume 60 , Issue 1 , August 1992 , pp. 61 - 67
Copyright
Copyright © Cambridge University Press 1992

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