A widely accepted tenet of evolutionary biology is that spontaneous mutations occur randomly with regard to their fitness effect. However, since the mutation rate varies along a genome and this variation can be subject to selection, organisms might evolve lower mutation rates at loci where mutations are most deleterious or increased rates where mutations are most needed. In fact, mechanisms of targeted hypermutation are known in organisms ranging from bacteria to humans. Here we review the main forces driving the evolution of local mutation rates and identify the main limiting factors. Both targeted hyper- and hypomutation can evolve, although the former is restricted to loci under very frequent positive selection and the latter is severely limited by genetic drift. Nevertheless, we show how an association of repair with transcription or chromatin-associated proteins could overcome the drift limit and lead to non-random hypomutation along the genome in most organisms.
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