Stress-induced modulators of repeat instability and genome evolution

Abstract

Evolution hinges on the ability of organisms to adapt to their environment. A key regulator of adaptability is mutation rate, which must be balanced to maintain genome fidelity while permitting sufficient plasticity to cope with environmental changes. Multiple mechanisms govern an organism's mutation rate. Constitutive mechanisms include mutator alleles that drive global, permanent increases in mutation rates, but these changes are confined to the subpopulation that carries the mutator allele. Other mechanisms focus mutagenesis in time and space to improve the chances that adaptive mutations can spread through the population. For example, environmental stress can induce mechanisms that transiently relax the fidelity of DNA repair to bring about a temporary increase in mutation rates during times when an organism experiences a reduced fitness for its surroundings, as has been demonstrated for double-strand break repair in Escherichia coli. Still, other mechanisms control the spatial distribution of mutations by directing changes to especially mutable sequences in the genome. In eukaryotic cells, for example, the stress-sensitive chaperone Hsp90 can regulate the length of trinucleotide repeats to fine-tune gene function and can regulate the mobility of transposable elements to enable larger functional changes. Here, we review the regulation of mutation rate, with special emphasis on the roles of tandem repeats and environmental stress in genome evolution.

Fig. 1

DNA mutagenesis can be regulated constitutively, temporally, and spatially. Constitutive mechanisms (a) include mutator alleles that drive global, permanent increases in mutation rates. Other mechanisms focus mutagenesis in time (b) and space (c) to improve the chances producing adaptive mutations, while minimizing deleterious mutations.

Fig. 2

Multiple DSBR pathways may contribute to the mutagenesis of tandem repeats. A: repair by HR with the insertion of repeat units; B: repair by HR with the deletion of repeat units; C: repair by NHEJ with a deletion of any number of bases that can disrupt the repeated unit pattern; D: repair by NHEJ with the insertion of nonrepeat bases; E: repair by SSA with the loss of a single or few repeat units; F: repair by synthesis-dependent strand annealing with the replication of additional repeat units. The orange lines indicate the repeat region, the blue lines indicate flanking nonrepetitive sequence, and the green lines indicate inserted nonrepeat sequence. The dashed orange lines indicate new synthesis of repeat region and the purple pac-man represents degradation of DNA during NHEJ.