Deletions and duplications of chromosomal segments (copy-number variations or CNVs) constitute a major source of variation between individual humans, underlying human evolution and many diseases from mental illness and developmental disorders to cancer. CNVs form at rates far outstripping other kinds of mutagenesis, and appear to do so by similar mechanisms in bacteria, yeast, and human. We review models for the mechanisms of formation of CNVs. Whereas non-homologous end-joining mechanisms are well known, recent models focus on perturbation of DNA replication, and replication of non-contiguous DNA segments, including the proposal that repair of broken replication forks switches under stress from high-fidelity homologous recombinational to nonhomologous repair that promotes CNV. •Copy number variants (CNVs) arise by homologous recombination (HR) between repeated sequences (recurrent CNVs). Or by non-homologous mechanisms that occur throughout the genome (non-recurrent CNVs).• Non-recurrent CNVs frequently show microhomology at their end-points, and can have complex structure.• Locus-specific mutation frequency for CNV and other structural changes are 2 to 4 orders of magnitude greater than for point mutations.• HR mechanisms generally achieve accurate repair of DNA damage.• Double-strand breaks are repaired by HR or by end-joining mechanisms, which are generally non-homologous.• Broken replication forks with single double-strand ends are also repaired by HR.• There is evidence that repair of broken replication forks underlies some non-homologous recombination.• Repair of broken forks in stressed cells could cause non-homologous repair because of stress-induced down-regulation of HR proteins.• Models are presented for mechanisms by which stress might induce non-homologous events leading to CNV. NIH Public Access Author ManuscriptNat Rev Genet. Author manuscript; available in PMC 2010 May 4. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptHuman populations show extensive polymorphism in the number of copies of chromosomal segments, and of genes included in those segments, consisting of both additions and deletions1 -5 . This is known as copy number variation (CNV). A high proportion of the genome, currently estimated at up to 12%, is subject to CNV 1-4 , 6, which can arise both meiotically and somatically as shown by the finding that identical twins can differ in CNV7 and that different organs and tissues vary in copy number in the same individual 8 . CNV is at least as important in determining the differences between individual humans as single nucleotide polymorphisms (SNPs) 9 , and appears to be a major driving force in evolution, especially in the rapid evolution that has occurred, and continues to occur, within the human and great ape lineage10 -14. Changes in copy number might change the levels of expression of genes included in the regions of variable copy number, allowing transcription levels higher or lower than those that can be achieved by control of transcription of si...

Special mechanisms of mutation are induced in microbes under growth-limiting stress causing genetic instability, including occasional adaptive mutations that may speed evolution. Both the mutation mechanisms and their control by stress have remained elusive. We provide evidence that the molecular basis for stress-induced mutagenesis in an E. coli model is error-prone DNA double-strand break repair (DSBR). I-SceI-endonuclease-induced DSBs strongly activate stress-induced mutations near the DSB, but not globally. The same proteins are required as for cells without induced DSBs: DSBR proteins, DinB-error-prone polymerase, and the RpoS starvation-stress-response regulator. Mutation is promoted by homology between cut and uncut DNA molecules, supporting a homology-mediated DSBR mechanism. DSBs also promote gene amplification. Finally, DSBs activate mutation only during stationary phase/starvation but will during exponential growth if RpoS is expressed. Our findings reveal an RpoS-controlled switch from high-fidelity to mutagenic DSBR under stress. This limits genetic instability both in time and to localized genome regions, potentially important evolutionary strategies.

Our concept of a stable genome is evolving to one in which genomes are plastic and responsive to environmental changes. Growing evidence shows that a variety of environmental stresses induce genomic instability in bacteria, yeast, and human cancer cells, generating occasional fitter mutants and potentially accelerating adaptive evolution. The emerging molecular mechanisms of stressinduced mutagenesis vary but share telling common components that underscore two common themes. The first is the regulation of mutagenesis in time by cellular stress responses, which promote random mutations specifically when cells are poorly adapted to their environments, i.e., when they are stressed. A second theme is the possible restriction of random mutagenesis in genomic space, achieved via coupling of mutation-generating machinery to local events such as DNA-break repair or transcription. Such localization may minimize accumulation of deleterious mutations in the genomes of rare fitter mutants, and promote local concerted evolution. Although mutagenesis induced by stresses other than direct damage to DNA was previously controversial, evidence for the existence of various stress-induced mutagenesis programs is now overwhelming and widespread. Such mechanisms probably fuel evolution of microbial pathogenesis and antibiotic-resistance, and tumor progression and chemotherapy resistance, all of which occur under stress, driven by mutations. The emerging commonalities in stress-induced-mutation mechanisms provide hope for new therapeutic interventions for all of these processes.

Adaptive point mutation and amplification are induced responses to environmental stress, promoting genetic changes that can enhance survival. A specialized adaptive mutation mechanism has been documented in one Escherichia coli assay, but its enzymatic basis remained unclear. We report that the SOS-inducible, error-prone DNA polymerase (pol) IV, encoded by dinB, is required for adaptive point mutation in the E. coli lac operon. A nonpolar dinB mutation reduces adaptive mutation frequencies by 85% but does not affect adaptive amplification, growth-dependent mutation, or survival after oxidative or UV damage. We show that pol IV, together with the major replicase, pol III, can account for all adaptive point mutations at lac. The results identify a role for pol IV in inducible genetic change.