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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.