Introduction: Molecular Basis of Genomic Stability and Change
In 1952, just before publication of the epochal work of Watson and Crick on the DNA double helix, H.J. Muller argued that mutation is the result of “some biochemical disorganization in which processes normally tending to hold mutation frequencies in check are to some extent interfered with” (8). This prescient statement crisply summarizes our contemporary picture (Fig. 1) of the molecular basis of genetic stability and change (5). There are great and persistent pressures on genomes to erode as a result of the physicochemical “decay” of DNA structure under normal physiological conditions, and to mutate as a result of replication errors and attack on DNA by endogenous and exogenous mutagens. Were it not for the existence of a complex array of biochemical and other mechanisms that counteract the natural tendency for DNA to mutate and disintegrate, cells could not survive, even under “normal” conditions, and genomes could not have evolved beyond a few hundred nucleotides in length (3, 9). As indicated in Fig. 1, the potential mutation rate per nucleotide (PMR) that would be associated with nonenzymatic, purely template-directed poljrmerization (3) of nucleic acids is very high (~10−2), whereas observed residual mutation rates (RMRs) are very low (~10−9). In this context, it is interesting to note that the most skillful human keypunch operators make about one mistake per 5,000 symbols copied.
KeywordsGenetic Stability Mutagen Burden Replicative Fidelity Persistent Pressure Mutagen Burden High
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