Yi and colleagues explore the versatility of the tandem DNA repeat:
β-lactamases [the enzyme that antibiotic resistant bacteria use to inactivate penicillins] can adapt to new antibiotics by mutations in their genes. The original and the extended substrate spectrums of β-lactamases define two phases of catalytic activity, and the conversion by point mutations is unidirectional from the initial to the new spectrum. We describe duplication mutations that enable reversible switching between the substrate spectrums, increasing the adaptability of the bacterium. We provide evidence supporting that two distinct groups of short sequences mediated the formation of DNA duplications in β-lactamases: direct repeats and novel elements that we named, SCSs (same-strand complementary sequences). Our study suggests that DNA duplication processes mediated by both direct repeats and SCSs are not just limited to the β-lactamase genes but comprise a fundamental mechanism in bacterial genome evolution.
Citation: Yi H, Song H, Hwang J, Kim K, Nierman WC, et al. (2014) The Tandem Repeats Enabling Reversible Switching between the Two Phases of β-Lactamase Substrate Spectrum. PLoS Genet 10(9): e1004640. doi:10.1371/journal.pgen.1004640
From the introduction:
As a ubiquitous feature of genomes, tandem repeats (TRs) are the sites at which recombination or replication slippage can occur [1]–[3]. Changes in the number of repeat units can confer phenotypic variability in eukaryotes, such as plasticity in skeletal morphology and tuning of the circadian rhythm, and are critical in repeat expansion diseases in humans, such as Huntington's disease [1]. In microorganisms, changes in TRs are the basis for one of the simplest and most prevalent reversible stochastic switching mechanisms, which is commonly known as “phase- or antigenic variation” [2]–[4]. Phase variation generally involves reversible switching that results in an “all-or-none” expressing phase of proteins, whereas antigenic variation alters the surface architecture of proteins that interact with the environment [3], [4].
Whereas biological consequences affected by alterations in preexisting TRs have been widely reported, processes underlying de novo TR formation and their biological implications have not been actively investigated. Along this line, it is intriguing that there have been reports of duplication mutations that occurred in the coding region of β-lactamase genes, expanding the substrate spectrum of the enzyme to include ceftazidime, a third-generation cephalosporin. A duplication of five amino acids was found in SHV-16 in a clinical isolate of Klebsiella pneumoniae [5] within the omega loop, which is a highly conserved structural domain constituting part of the active-site pocket [6]. In another report, a duplication of three residues was found in the omega loop of a class C β-lactamase in clinical strain Enterobacter cloacae GC1 [7]. The adaptation of β-lactamases in response to exposure to new antibiotics has been a major public health concern, and in almost all cases, point mutations resulting in an amino acid substitution in the enzymes have been responsible for this problem [8]–[10]. Although the biological legitimacy was unclear, the two cases of rare duplication mutations suggested that β-lactamases have potential as an excellent subject to investigate the nature of de novo TRs in connection with the evolution of the drug resistance.
In this study, we describe eleven de novo TRs that can occur in the coding region of a β-lactamase gene and allow genetic toggling when coupled with reversion, adjusting the substrate spectrum of the β-lactamase to a different β-lactam antibiotic challenge. At the DNA level, we describe pairs of direct repeats and a novel group of duo elements that we found instrumental in DNA duplication. We then note our findings of a high correlation that exists between direct repeats and TRs and also between the novel duo elements and TRs, supporting the notion that the DNA duplication we described here comprises a fundamental mechanism in bacterial genome evolution.
@ PLOS Genetics: The Tandem Repeats Enabling Reversible Switching between the Two Phases of β-Lactamase Substrate Spectrum:
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