“Gene accordions” cause genotypic and phenotypic heterogeneity in clonal populations of Staphylococcus aureus

Belikova, Darya; Jochim, Angelika; Power, Jeffrey; Holden, Matthew T. G.; Heilbronner, Simon

doi:10.1038/s41467-020-17277-3

Cited by 23 publications

(31 citation statements)

References 71 publications

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“…These genes are not always conserved together (Liu et al, 2015), and their presence has been associated with bone infection (Sabat et al, 2006), resistance to host immunity (Sitkiewicz, Babiak & Hryniewicz, 2011;Askarian et al, 2017), biofilm formation (Barbu et al, 2014), and host-cell adhesion (Corrigan, Miajlovic & Foster, 2009;Cheng et al, 2009;Barbu et al, 2010;Askarian et al, 2016). Belikova et al (2020) showed that in USA300 sdr genes undergo frequent within-genome recombination during growth in lab conditions and during infection. The high number of synonymous mutations may be the result of repeats expanding or collapsing in evolved strains, causing base-calling artefacts when mapped onto the reference genomes.…”

Section: Patterns Of Acquisition Of Snps At Visa Endpoints Is Influenced By Genetic Backgroundmentioning

confidence: 99%

Effect of genetic background on the evolution of Vancomycin-Intermediate Staphylococcus aureus (VISA)

Davis

Peterson

et al. 2021

PeerJ

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Vancomycin-intermediate Staphylococcus aureus (VISA) typically arises through accumulation of chromosomal mutations that alter cell-wall thickness and global regulatory pathways. Genome-based prediction of VISA requires understanding whether strain background influences patterns of mutation that lead to resistance. We used an iterative method to experimentally evolve three important methicillin-resistant S. aureus (MRSA) strain backgrounds—(CC1, CC5 and CC8 (USA300)) to generate a library of 120 laboratory selected VISA isolates. At the endpoint, isolates had vancomycin MICs ranging from 4 to 10 μg/mL. We detected mutations in more than 150 genes, but only six genes (already known to be associated with VISA from prior studies) were mutated in all three background strains (walK, prs, rpoB, rpoC, vraS, yvqF). We found evidence of interactions between loci (e.g., vraS and yvqF mutants were significantly negatively correlated) and rpoB, rpoC, vraS and yvqF were more frequently mutated in one of the backgrounds. Increasing vancomycin resistance was correlated with lower maximal growth rates (a proxy for fitness) regardless of background. However, CC5 VISA isolates had higher MICs with fewer rounds of selection and had lower fitness costs than the CC8 VISA isolates. Using multivariable regression, we found that genes differed in their contribution to overall MIC depending on the background. Overall, these results demonstrated that VISA evolved through mutations in a similar set of loci in all backgrounds, but the effect of mutation in common genes differed with regard to fitness and contribution to resistance in different strains.

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Section: Patterns Of Acquisition Of Snps At Visa Endpoints Is Influenced By Genetic Backgroundmentioning

confidence: 99%

Effect of genetic background on the evolution of Vancomycin-Intermediate Staphylococcus aureus (VISA)

Davis

Peterson

et al. 2021

PeerJ

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“…In other cases, phenotypic heterogeneity arises without the involvement of environmental cues, and the underlying mechanisms are diverse. Genetic mechanisms include site-specific recombination (Scott and Simon, 1982;Reyes Ruiz et al, 2020), slipped-strand mispairing at tracts of repetitive DNA sequences (Moxon et al, 2006), and amplification of specific genome regions (Belikova et al, 2020;Tomanek et al, 2020). As described below, cell diversification into two or more phenotypic states can also be driven by nongenetic mechanisms, such as propagation of feedback loops (Ferrell, 2002) and formation of DNA methylation patterns .…”

Section: Introductionmentioning

confidence: 99%

Waddington’s Landscapes in the Bacterial World

Sánchez-Romero

Casadesús

2021

Front. Microbiol.

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Conrad Waddington’s epigenetic landscape, a visual metaphor for the development of multicellular organisms, is appropriate to depict the formation of phenotypic variants of bacterial cells. Examples of bacterial differentiation that result in morphological change have been known for decades. In addition, bacterial populations contain phenotypic cell variants that lack morphological change, and the advent of fluorescent protein technology and single-cell analysis has unveiled scores of examples. Cell-specific gene expression patterns can have a random origin or arise as a programmed event. When phenotypic cell-to-cell differences are heritable, bacterial lineages are formed. The mechanisms that transmit epigenetic states to daughter cells can have strikingly different levels of complexity, from the propagation of simple feedback loops to the formation of complex DNA methylation patterns. Game theory predicts that phenotypic heterogeneity can facilitate bacterial adaptation to hostile or unpredictable environments, serving either as a division of labor or as a bet hedging that anticipates future challenges. Experimental observation confirms the existence of both types of strategies in the bacterial world.

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“…Belikova et al. ( 79 ) observed that gene duplication and amplification occur frequently in the Staphylococcus aureus chromosome, concentrated in loci containing repetitive DNA elements that facilitate recombination; findings were consistent with an “accordion” model with high copy-number variants favored under selective conditions. An especially affected locus encoding “conserved staphylococcal antigens 1” ( csa1 ) displayed amplification up to 10 copies in clinical isolates, while introduction of an antibiotic resistance cassette within the locus resulted in amplifications up to 100- to 200-fold in the setting of antibiotic pressure ( 79 ).…”

Section: Discussionmentioning

confidence: 75%

Multiple genetic paths including massive gene amplification allow Mycobacterium tuberculosis to overcome loss of ESX-3 secretion system substrates

Lin

Asare

Shetty

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Mycobacterium tuberculosis (Mtb) possesses five type VII secretion systems (T7SS), virulence determinants that include the secretion apparatus and associated secretion substrates. Mtb strains deleted for the genes encoding substrates of the ESX-3 T7SS, esxG or esxH, require iron supplementation for in vitro growth and are highly attenuated in vivo. In a subset of infected mice, suppressor mutants of esxG or esxH deletions were isolated, which enabled growth to high titers or restored virulence. Suppression was conferred by mechanisms that cause overexpression of an ESX-3 paralogous region that lacks genes for the secretion apparatus but encodes EsxR and EsxS, apparent ESX-3 orphan substrates that functionally compensate for the lack of EsxG or EsxH. The mechanisms include the disruption of a transcriptional repressor and a massive 38- to 60-fold gene amplification. These data identify an iron acquisition regulon, provide insight into T7SS, and reveal a mechanism of Mtb chromosome evolution involving “accordion-type” amplification.

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“Gene accordions” cause genotypic and phenotypic heterogeneity in clonal populations of Staphylococcus aureus

Cited by 23 publications

References 71 publications

Effect of genetic background on the evolution of Vancomycin-Intermediate Staphylococcus aureus (VISA)

Effect of genetic background on the evolution of Vancomycin-Intermediate Staphylococcus aureus (VISA)

Waddington’s Landscapes in the Bacterial World

Multiple genetic paths including massive gene amplification allow Mycobacterium tuberculosis to overcome loss of ESX-3 secretion system substrates

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