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Review
, 78 (1), 1-39

Bacterial Genome Instability

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Review

Bacterial Genome Instability

Elise Darmon et al. Microbiol Mol Biol Rev.

Abstract

Bacterial genomes are remarkably stable from one generation to the next but are plastic on an evolutionary time scale, substantially shaped by horizontal gene transfer, genome rearrangement, and the activities of mobile DNA elements. This implies the existence of a delicate balance between the maintenance of genome stability and the tolerance of genome instability. In this review, we describe the specialized genetic elements and the endogenous processes that contribute to genome instability. We then discuss the consequences of genome instability at the physiological level, where cells have harnessed instability to mediate phase and antigenic variation, and at the evolutionary level, where horizontal gene transfer has played an important role. Indeed, this ability to share DNA sequences has played a major part in the evolution of life on Earth. The evolutionary plasticity of bacterial genomes, coupled with the vast numbers of bacteria on the planet, substantially limits our ability to control disease.

Figures

FIG 1
FIG 1
Schematic organization of different transposable elements inserted into a genome. (A) Organization of a typical IS (represented as a rectangle). It contains a single open reading frame (sometimes two), encoding the transposase, that extends within the right inverted repeat (IRR). The transposase promoter (P) is partially localized in the left inverted repeat (IRL). DR is the target fragment that has been duplicated to become a direct repeat following the insertion of the IS. (B) Organization of a typical MITE. (C) Organization of a typical transposon. Long terminal inverted repeated (IR) sequences surround function modules of genes. (D) Organization of a typical composite transposon. A chromosomal sequence is transposed together with two IS elements that surround it (here ISs are in a direct orientation, but they can be inverted). At least one of the transposases needs to be active. The internal DR of the IS elements can be absent. (E) Organization of a typical conjugative transposon (or ICE). The element contains inverted repeats surrounding various modules of genes for maintenance (recombination), regulation, and dissemination (conjugation) and some accessory proteins. A conjugal origin of transfer, oriT, is situated in the dissemination module. (F) Schematic organization of Mu, a typical transposable bacteriophage. Mu is delimited by inverted repeats. The element contains various modules of genes for regulation, transposition, lysis, and head and tail proteins. The G region is invertible, enabling the synthesis of different tail fiber proteins.
FIG 2
FIG 2
Schematic diagram describing the synthesis of msDNA. The retron element (represented as a rectangle) is transcribed, and the retron-specific reverse transcriptase (RT) is produced, whereas the part of the mRNA containing the transcription product of the msr and msd genes folds into a particular secondary structure. Thanks to this structure, the 2′-OH group of a specific branching guanosine residue (G) becomes the primer permitting the reverse transcription of the msd gene, while RNase H cleaves the mRNA template. Transcription stops at a fixed point, resulting in the msDNA molecule: an RNA and a cDNA molecule covalently linked. (Based on references .)
FIG 3
FIG 3
Schematic organization of a diversity-generating retroelement (DGR). A DGR (represented as a rectangle) is generally composed of two repeated sequences and one or two ORFs. VR is the variable repeat, which is at the 3′ end of a variable gene. TR is the template repeat, and its sequence is invariable. orf2 is not always present and differs in the function of the system. It is sometimes named atd (accessory tropism determinant) or hrdC (helicase and RNase D C terminal). The order of these elements is changeable. The template repeat is transcribed and integrated at the place of the variable repeat by a reverse transcription process that also exchanges some adenines for random nucleotides. RT is the reverse transcriptase.
FIG 4
FIG 4
Schematic organization of an active integron. An integron (represented as a rectangle) is constituted of a stable platform and a variable part. The stable platform is integrated into the host genome or a plasmid. It is composed of a site-specific recombinase gene (intI) and its promoter (PintI) as well as a primary recombination site, attI, upstream of the intI gene and the Pc promoter, located in the intI gene or the attI site. The variable part is formed by cassettes, each containing a gene and an attC recombination site. (A) Integration of gene cassettes into the stable platform of the integron. IntI mediates recombination between the attC site of the incoming cassette and the attI site of the integron so that the gene cassette integrates behind the Pc promoter, allowing gene expression. Successive integrations permit the formation of an array of gene cassettes, with the newly integrated cassette being nearest Pc. (B) Excision and reinsertion of a gene cassette. A gene in a cassette that is too far from Pc is not expressed anymore. IntI can mediate the excision of any gene cassette in the integron by recombination between the two attC sites surrounding the gene and its reinsertion in attI behind the Pc promoter. Therefore, the integron contains a reservoir of genes that can be rearranged and used by the cell under selective environments.
FIG 5
FIG 5
Schematic organization and mechanism of action of a basic CRISPR-Cas system (represented as an open rectangle). A CRISPR-Cas system is usually composed of cas genes (maroon arrows) and a leader sequence (blue rectangle) containing a promoter on the 5′ end of a CRISPR array, formed by short identical direct repeats (DR) (blue triangles) alternating with unique sequences (spacers) (colored octagons). (A) Adaptation is the first step of CRISPR-Cas immunity. A plasmid or bacteriophage DNA invades the bacterium. In rare cases, Cas proteins recognize this DNA as a threat (often thanks to a PAM sequence) (dashed open squares) and introduce a new repeat and spacer sequence into the CRISPR array between the leader sequence and the first repeat. This spacer corresponds to the protospacer in the foreign DNA (colored diamonds), a sequence near the PAM motif, if present. (B) The promoter in the leader sequence allows the transcription of the CRISPR array into a pre-crRNA (pre-CRISPR RNA). Cas proteins cleave the pre-crRNA into crRNAs, each containing a part of a repeat and a spacer. (C) Cas proteins and a specific crRNA target and inactivate the foreign DNA previously encountered, if present again in the cell. Some cellular proteins might help the Cas proteins in any of all these different stages.
FIG 6
FIG 6
Two classes of illegitimate recombination events. (A) Strand slippage. Strand annealing at regions of DNA microhomology (indicated by black arrows) can occur during DNA synthesis, resulting in deletions, duplications, and other rearrangements. This figure depicts the formation of a deletion by strand slippage. (B) Annealing of DNA ends. Strand annealing can also occur at DNA ends following resection and the formation of single-stranded regions. Microhomologies (indicated by black arrows) facilitate annealing. Importantly, the deletion events depicted here are identical whether produced by strand slippage or by annealing of DNA ends.
FIG 7
FIG 7
Two possible mechanisms for the formation of a tandem duplication and its subsequent amplification or reduction. (A) A tandem duplication can be formed by a strand slippage mechanism where a DNA sequence is copied and microhomology is then used to reinvade and copy the same DNA sequence again. This process generates a novel junction sequence (NJ) between the two repeated copies of DNA sequence. The duplicated sequence can then be amplified or reduced by RecA-mediated homologous recombination. (B) A tandem duplication can occur by homologous recombination between repetitive sequences such as insertion sequences (ISs). This reaction does not generate novel junction sequences. Again, the duplicated sequence can then be amplified or reduced by RecA-mediated homologous recombination. (C) DIR/TID structures can be formed by strand slippage during DNA replication or DNA repair. These structures consist of two overlapping DNA palindromes and may not be stable enough to persist for long. Symmetric deletions that reduce the symmetry of the palindrome centers have been documented, which may occur via subsequent rounds of strand slippage.
FIG 8
FIG 8
Schematic organization of various examples of site-specific inversion systems. Inversion of the element results in the activation or inactivation of the transcription of the neighboring gene (A); the expression of either the a or the b gene (B); the expression of the a, b, or c gene selectively (C); the expression of a short or a longer protein (D); or the transcription of a gene encoding a protein with a different carboxyl-terminal domain (E).

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