Increased Gene Dosage Plays a Predominant Role in the Initial Stages of Evolution of Duplicate Tem-1 Beta Lactamase Genes

Dhar, Riddhiman; Bergmiller, Tobias; Wagner, Andreas

doi:10.1111/evo.12373

Cited by 22 publications

(22 citation statements)

References 122 publications

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“…Previous studies have addressed the importance of MCPs in the evolution of new functions21,29,30, and the co-existence of mutant and ancestral allele variants encoded in the same plasmid has recently been demonstrated in laboratory evolution experiments21,31 and clinical settings32. However, the prevalence of plasmid-mediated heterozygosity in nature remains largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Multicopy plasmids allow bacteria to escape from fitness trade-offs during evolutionary innovation

et al. 2018

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Understanding the mechanisms governing innovation is a central element of evolutionary theory. Novel traits usually arise through mutations in existing genes, but trade-offs between new and ancestral protein functions are pervasive and constrain the evolution of innovation. Classical models posit that evolutionary innovation circumvents the constraints imposed by trade-offs through genetic amplifications, which provide functional redundancy. Bacterial multicopy plasmids provide a paradigmatic example of genetic amplification, yet their role in evolutionary innovation remains largely unexplored. Here, we reconstructed the evolution of a new trait encoded in a multicopy plasmid using TEM-1 β-lactamase as a model system. Through a combination of theory and experimentation, we show that multicopy plasmids promote the coexistence of ancestral and novel traits for dozens of generations, allowing bacteria to escape the evolutionary constraints imposed by trade-offs. Our results suggest that multicopy plasmids are excellent platforms for evolutionary innovation, contributing to explain their extreme abundance in bacteria.

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Section: Discussionmentioning

confidence: 99%

Multicopy plasmids allow bacteria to escape from fitness trade-offs during evolutionary innovation

et al. 2018

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“…The problem, however, is that they mainly consider the consequences rather than the process of duplicate gene evolution (Innan and Kondrashov, 2010). In addition, none of these models take into consideration the cross-regulation between duplicate genes, and paralogs were generally assumed to evolve more or less independently (Innan and Kondrashov, 2010;Baker et al, 2013;Dhar et al, 2014;Rogozin, 2014). In reality, many duplicate genes are parts of the same regulatory network, in which the expression and function of one copy are dependent on those of the other, or vice versa (Kafri et al, 2006;Sémon and Wolfe, 2007;Conant et al, 2014).…”

mentioning

confidence: 99%

Gain of An Auto-regulatory Site Led to Divergence of the Arabidopsis APETALA1 and CAULIFLOWER Duplicate Genes in the Time, Space and Level of Expression and Regulation of One Paralog by the Other

Wang

Zhang

et al. 2016

Plant Physiol.

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How genes change their expression patterns over time is still poorly understood. Here, by conducting expression, functional, bioinformatic, and evolutionary analyses, we demonstrate that the differences between the Arabidopsis (Arabidopsis thaliana) APETALA1 (AP1) and CAULIFLOWER (CAL) duplicate genes in the time, space, and level of expression were determined by the presence or absence of functionally important transcription factor-binding sites (TFBSs) in regulatory regions. In particular, a CArG box, which is the autoregulatory site of AP1 that can also be bound by the CAL protein, is a key determinant of the expression differences. Because of the CArG box, AP1 is both autoregulated and cross-regulated (by AP1 and CAL, respectively), and its relatively high-level expression is maintained till to the late stages of sepal and petal development. The observation that the CArG box was gained recently further suggests that the autoregulation and cross-regulation of AP1, as well as its function in sepal and petal development, are derived features. By comparing the evolutionary histories of this and other TFBSs, we further indicate that the divergence of AP1 and CAL in regulatory regions has been markedly asymmetric and can be divided into several stages. Specifically, shortly after duplication, when AP1 happened to be the paralog that maintained the function of the ancestral gene, CAL experienced certain degrees of degenerate evolution, in which several functionally important TFBSs were lost. Later, when functional divergence allowed the survival of both paralogs, CAL remained largely unchanged in expression, whereas the functions of AP1 were gradually reinforced by gains of the CArG box and other TFBSs.

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“…6, β = 0.20, F 1,13 = 8.46, and P < 0.05), and that copy number and repY mutations were highly correlated (τ = 0.74 and P < 0.0001). Mutations in plasmid copy number control mechanisms are a canonical mechanism to increase plasmid copy number and therefore gene dosing of plasmid cargo—in this case, increased dosing of β-lactamase production (25, 31, 32).…”

Section: Resultsmentioning

confidence: 99%

Modified Antibiotic Adjuvant Ratios Can Slow and Steer the Evolution of Resistance: Co-amoxiclav as a Case Study

Allen

Brown

2019

mBio

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As antibiotic resistance spreads, developing sustainable methods to restore the efficacy of existing antibiotics is increasingly important. One widespread method is to combine antibiotics with synergistically acting adjuvants that inhibit resistance mechanisms, allowing drug killing. Here we use co-amoxiclav (a clinically important combination of the β-lactam antibiotic amoxicillin and the β-lactamase inhibitor clavulanate) to ask whether treatment efficacy and resistance evolution can be decoupled via component dosing modifications. A simple mathematical model predicts that different ratios of these two drug components can produce distinct evolutionary responses irrespective of the initial efficacy. We test this hypothesis by selecting Escherichia coli with a plasmid-encoded β-lactamase (CTX-M-14), against different concentrations of amoxicillin and clavulanate. Consistent with our theory, we found that while resistance evolved under all conditions, the component ratio influenced both the rate and mechanism of resistance evolution. Specifically, we found that the current clinical practice of high amoxicillin-to-clavulanate ratios resulted in the most rapid adaptation to antibiotics via gene dosing responses. Increased plasmid copy number allowed E. coli to increase β-lactamase dosing and effectively titrate out low quantities of clavulanate, restoring amoxicillin resistance. In contrast, high clavulanate ratios were more robust—plasmid copy number did not increase, although porin or efflux resistance mechanisms were found, as for all drug ratios. Our results indicate that by changing the ratio of adjuvant to antibiotic we can slow and steer the path of resistance evolution. We therefore suggest using increased adjuvant dosing regimens to slow the rate of resistance evolution. IMPORTANCE As antibiotic resistance spreads, a promising approach is to restore the effectiveness of existing drugs via coadministration with adjuvants that inhibit resistance. However, as for monotherapy, antibiotic-adjuvant therapies can select for a variety of resistance mechanisms, so it is imperative that adjuvants be used in a sustainable manner. We test whether the rate of resistance evolution can be decoupled from treatment efficacy using co-amoxiclav, a clinically important combination of the β-lactam amoxicillin and β-lactamase inhibitor clavulanate. Using experimental evolution and a simple theoretical model, we show that the current co-amoxiclav formulation with a high proportion of amoxicillin rapidly selects for resistance via increased β-lactamase production. On the other hand, formulations with more clavulanate and less amoxicillin have similar efficacies yet prevent the selective benefit of increased β-lactamase. We suggest that by blocking common paths to resistance, treatment combinations with the adjuvant in excess can slow the evolution of resistance.

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Increased Gene Dosage Plays a Predominant Role in the Initial Stages of Evolution of Duplicate Tem-1 Beta Lactamase Genes

Cited by 22 publications

References 122 publications

Multicopy plasmids allow bacteria to escape from fitness trade-offs during evolutionary innovation

Multicopy plasmids allow bacteria to escape from fitness trade-offs during evolutionary innovation

Gain of An Auto-regulatory Site Led to Divergence of the Arabidopsis APETALA1 and CAULIFLOWER Duplicate Genes in the Time, Space and Level of Expression and Regulation of One Paralog by the Other

Modified Antibiotic Adjuvant Ratios Can Slow and Steer the Evolution of Resistance: Co-amoxiclav as a Case Study

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