Key Points
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This article explores the mechanisms underlying major examples of microbial cell-to-cell heterogeneity that do not have a genotypic basis, that is, which do not arise from mutation or genome rearrangements. Consequently, bacterial phase variation is not addressed, but certain examples of epigenetically regulated antigenic variation are.
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Relevant examples of cell-surface antigenic variation include pili switching in Escherichia coli, variant surface glycoprotein expression in trypanosomes, var gene expression in the malaria parasite, and the expression of FLO-gene-encoded glycoproteins in yeast. The regulation in most of these cases is known to have a major epigenetic component.
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The yeast pathogen Candida undergoes spontaneous, high-frequency phenotypic switches in colony morphology, which might be linked to virulence. Evidence indicates that these switches have an epigenetic basis, but the master regulators have yet to be identified.
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A small minority of cells in genetically homogeneous microbial populations typically survive otherwise-inhibitory antibiotic treatments. The best-studied example in E. coli arises owing to occasional slow-growing cells in the population, which are thought to be reversibly limited for the function through which the drug normally acts.
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Individual cells in microbial cultures show variable resistances to stressors. This heterogeneity seems to have a deterministic origin in many cases, where dependencies on cell-cycle stage, cell age and metabolic oscillations have been demonstrated.
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Variable kinetics of flagellar rotation and reversal dictate individualized swimming behaviours and chemotaxis responses in bacterial cells. The chemotaxis response regulator CheY and the methyltransferase CheR are involved in regulating variability in the chemotaxis response.
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Competence or not for transformation with DNA, the decision to sporulate, and lysis or lysogeny in bacteriophage λ are major examples of phenotypes that produce binary (all or nothing) distributions in microbial populations. The binary nature typically involves an auto-regulatory feedback mechanism. A stochastic basis for the heterogeneity has been speculated, and some evidence supports this.
Abstract
Single cells in genetically homogeneous microbial cultures exhibit marked phenotypic individuality, a biological phenomenon that is considered to bolster the fitness of populations. Major phenotypes that are characterized by heterogeneity span the breadth of microbiology, in fields ranging from pathogenicity to ecology. The cell cycle, cell ageing and epigenetic regulation are proven drivers of heterogeneity in several of the best-known phenotypic examples. However, the full contribution of factors such as stochastic gene expression is yet to be realized.
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Acknowledgements
The author gratefully acknowledges the support of the National Institutes of Health and the Biotechnology and Biological Sciences Research Council for heterogeneity-related work. J. Behnke and E. Louis are thanked for helpful comments on sections of this article.
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Glossary
- Phenotypic heterogeneity
-
The presence of individual cells in a genetically homogeneous population that exhibit dissimilar phenotypes.
- Stochasticity
-
A fluctuation in transcription or translation, despite constant environmental conditions.
- Epigenetic regulation
-
A regulatory process producing a heritable effect on gene expression that does not involve a change in DNA sequence.
- Deterministic switch
-
A switch that is triggered by mechanisms other than random variation or noise.
- Translational bursting
-
Bursts of protein production from each mRNA transcript, typically occurring at low mRNA abundances.
- Telomere silencing
-
Epigenetic repression of the basal expression of genes located near to telomeres.
- Heterochromatin
-
Usually a tightly packed form of DNA that is mostly genetically inactive.
- Euchromatin
-
The lightly staining regions of the nucleus that generally contain decondensed, transcriptionally active regions of the genome.
- Persister cells
-
Cells that persist following antibiotic treatment in an otherwise-sensitive clonal population.
- Hetero-resistance
-
Heterogeneous resistance to an antimicrobial agent in a genetically homogeneous population of cells.
- Toxin?antitoxin module
-
Paired loci found in the chromosomes of almost all free-living bacteria, and many plasmids and phage genomes. They encode a toxin and its antidote that have been shown to contribute to plasmid stability by a mechanism called post-segregational killing. They are also proposed to function in bacterial programmed cell death or stress physiology.
- Two-population model
-
The existence of two subpopulations within a cell culture, with widely differing gene-expression states or phenotypes.
- Respiratory oscillation
-
Short-term metabolic cycles of oxidation and reduction in Saccharomyces cerevisiae, which become synchronized during continuous culture.
- Cu,Zn-superoxide dismutase
-
A major superoxide scavenging enzyme that functions as an antioxidant and binds zinc and copper.
- Epigenetically bistable
-
An epigenetic mechanism determining that two stable states of cells occur simultaneously in a population.
- Binary microbial phenotype
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A phenotype that is characterized by only two states (distinct from a graded phenotype).
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Avery, S. Microbial cell individuality and the underlying sources of heterogeneity. Nat Rev Microbiol 4, 577–587 (2006). https://doi.org/10.1038/nrmicro1460
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DOI: https://doi.org/10.1038/nrmicro1460
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