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EVOLUTION OF THE MUTATION RATE Michael Lynch Dept. of Biology, Indiana University, Bloomington, Indiana USA Recent applications of whole-genome sequencing to mutation-accumulation lines have revealed that the mutation rate per nucleotide site per generation varies by about three orders of magnitude across the tree of cellular life, with some unicellular eukaryotes having the lowest rates, prokaryotes being somewhat intermediate, and multicellular species (especially mammals) having the highest rates. The observed patterns are explained by a remarkably simple set of rules. Species-specific mutation rates are inversely proportional to both the effective population size and the number of genomic sites under selective constraint, which together explain the majority of phylogenetic variation in replication fidelity. These observations are consistent with the drift-barrier hypothesis, which postulates that selection generally works to reduce the genome-wide deleterious mutation rate to the point at which the advantage of any further refinement is smaller than the power of random genetic drift. Other lines of evidence that appear to be consistent with this hypothesis include: patterns of variation in base-loading accuracy among different DNA polymerases; the direct demonstration of evolutionary changes in mutation rates in experimental populations with different effective sizes; and the extraordinary increase in the error rates of RNA polymerases, the effects of which are transient unlike inherited mutations. The case will be made that the implications of the drift-barrier hypothesis extend well beyond replication fidelity, providing a useful platform for understanding how a diversity of cellular features may have arisen over evolutionary time.