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Non-random mutation: The evolution of targeted hypermutation and hypomutation

Authors

  • Iñigo Martincorena,

    Corresponding author
    1. Cancer Research UK London Research Institute, London, UK
    2. EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, UK
    • Cancer Research UK London Research Institute, London, UK.
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  • Nicholas M. Luscombe

    1. Cancer Research UK London Research Institute, London, UK
    2. UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London, UK
    3. Okinawa Institute of Science and Technology, Onna-son, Kunigami-gun, Okinawa, Japan
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Abstract

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.

Editor's suggested further reading in BioEssays Stress-induced mutation via DNA breaks in Escherichia coli: A molecular mechanism with implications for evolution and medicine Abstract

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