Whole-genome sequencing of several isolates from single hosts has revealed previously unsuspected within-host diversity of many bacterial pathogens.
Within-host bacterial populations are subject to multifarious evolutionary forces including mutation, genetic drift, natural selection and fluctuating population size.
Within-host evolution limits the utility of sampling a single genome per host for reconstructing transmission relationships, conferring a benefit to sequencing several genomes per host.
Resistance to some antimicrobials frequently evolves independently in individual hosts, revealing the substantial potential of bacteria to adapt in the human body.
Within-host adaptation has a major role in the evolution of opportunistic infections in immunocompromised patients by otherwise free-living bacteria.
The study of within-host genomic evolution promises to shed light on whether pathogens tend to become more or less virulent within the host, and the selective pressures underlying this evolution.
Whole-genome sequencing has opened the way for investigating the dynamics and genomic evolution of bacterial pathogens during the colonization and infection of humans. The application of this technology to the longitudinal study of adaptation in an infected host — in particular, the evolution of drug resistance and host adaptation in patients who are chronically infected with opportunistic pathogens — has revealed remarkable patterns of convergent evolution, suggestive of an inherent repeatability of evolution. In this Review, we describe how these studies have advanced our understanding of the mechanisms and principles of within-host genome evolution, and we consider the consequences of findings such as a potent adaptive potential for pathogenicity. Finally, we discuss the possibility that genomics may be used in the future to predict the clinical progression of bacterial infections and to suggest the best option for treatment.
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X.D. is funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC; grant BB/L023458/1) and the UK National Institute for Health Research (NIHR) Health Protection Research Unit on Modelling Methodology (grant HPRU-2012-10080). T.E.P. and D.W.C. are NIHR senior investigators. D.J.W. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (grant 101237/Z/13/Z). This study was supported by the Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust (grant WT098615) and the UK Department of Health (grant HICF-T5-358), the NIHR Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance (grant HPRU-2012-10041) and the NIHR Oxford Biomedical Research Centre. The views expressed in this publication are those of the authors and not necessarily those of the funders.
The authors declare no competing financial interests.
- Evolutionary rates
The rates at which substitutions arise in a lineage (also known as molecular clock rates). Population genetics theory predicts a constant rate in a neutrally evolving population with a constant mutation rate, irrespective of changes in population size.
- Multi-locus sequence typing
(MLST). A molecular epidemiology approach in which strains are typed by their nucleotide sequences at several loci, typically 400–500 bp fragments of seven housekeeping genes.
- Genome assembly
A bioinformatics process in which overlapping sequencing reads are combined into longer, contiguous sequences known as 'contigs', ideally a single contig per chromosome but usually several.
- Variant calling
A bioinformatics process that determines the nucleotide at a given genomic site based on sequencing reads.
The quantifiable frequency or severity of disease.
- Pulsed-field gel electrophoresis
(PFGE). A molecular epidemiology marker that enables strains to be typed by the lengths of the DNA molecules obtained after cutting the genome using a restriction enzyme.
- Variable-number tandem repeats
(VNTR). A molecular epidemiology marker that enables strains to be typed by counting the number of copies of a specific repeat sequence, which may consist of one or more nucleotides and is known to occur at a given location in the genome.
- Multi-locus enzyme electrophoresis
(MLEE). A molecular epidemiology approach in which strains are typed by the electrophoretic properties of several proteins.
- Point mutations
Mutations that change a single nucleotide.
- Mismatch repair systems
A mechanism found in all bacteria that repairs the mistakes introduced into the genome during DNA replication to enable clonal reproduction.
- Phase variation
A mechanism that bacteria use to enable the rapid evolution of a specific trait in which frequently occurring, reversible mutations control gene expression.
- Horizontal gene transfer
The uptake of genetic material by a recipient cell using various mechanisms, such as transformation of naked DNA, bacteriophage-mediated transduction or plasmid-mediated conjugation.
- Homologous recombination
An evolutionary event in which a segment of the genome of a recipient cell is replaced with a homologous segment of the genome from a donor cell.
- Random genetic drift
Variations in allele frequency in a population caused by the random genetic sampling that occurs during the birth and death of individuals.
- Purifying selection
The tendency for an allele that incurs a survival or reproductive disadvantage to decrease in frequency and become lost. Deleterious alleles may nevertheless become fixed owing to random genetic drift.
- Diversifying selection
A form of recurrent positive selection that favours the emergence of new alleles in a population; for example, the selective pressure of the host immune system on antigen evolution in pathogens.
- dN/dS ratio
The ratio of the number of non-synonymous substitutions, which alter the protein sequence, to the number of synonymous substitutions, which do not alter the protein sequence, normalized by the ratio expected under neutrality. A dN/dS ratio below one indicates purifying selection and above one indicates positive selection.
The point at which an allele replaces all alternative alleles of the same locus in a population. This coincides with loss of the other alleles.
- Incomplete lineage sorting
A phenomenon whereby a gene tree is discordant with the population or species tree. This occurs when lineages that are ancestral to several different populations split before, and in a different order to, the splitting of the respective populations. For within-host populations, this causes discordance between phylogenies and transmission trees.
- Selective sweep
The rapid increase in frequency and fixation of an advantageous allele. Selective sweeps are caused by positive selection.
- Clonal interference
An evolutionary dynamic in which selectively advantageous alleles at a given locus in one lineage outcompete advantageous alleles at other loci in other lineages, causing them to become extinct. In organisms with the capacity for genome recombination, this can be avoided by combining all advantageous mutations in the same genome.
The effect whereby an allele can increase in frequency even though it is not favoured by selection, only because it is found in the same genomes as other alleles of other loci that have a selective advantage.
The unexpected influence of one locus on multiple, apparently unrelated, phenotypes.
A phenomenon whereby a previously existing trait confers an advantage in an environment to which it was not previously exposed (also known as exaptation).
- Fitness trade-offs
The existence of some constraint, possibly mechanistic or genetic, that causes adaptations to one selection pressure to be disadvantageous with respect to another.
- Convergent evolution
The occurrence of mutations resulting in the same phenotype in two or more independently evolving lineages; these often arise in the same gene and may even occur at the same site.
- Compensatory mutations
Mutations that redress, possibly only partially, the fitness cost of mutations conferring adaptation to specific selection pressures, such as antibiotic resistance. Without compensatory mutations, adaptations that incur a fitness cost may be lost when the selection pressure is removed.
The ability to rapidly adapt to a change in selective pressure, such as antibiotic use.
Varying levels of antibiotic resistance within an extremely closely related population, such as an individual colony.
- Stringent response
A stress response that diverts cellular resources towards survival during nutrient limitation by instigating widespread regulatory changes, including the upregulation of amino acid synthesis and protease production.
An adaptation that confers pathogenicity.
An individual or lineage with increased mutation rate, usually as a result of a loss of functionality in DNA repair systems.
- Positive selection
The tendency for an allele that confers a survival or reproductive advantage to increase in frequency and become fixed at a higher rate. Advantageous alleles may nevertheless become lost, owing to random genetic drift despite positive selection.
A bacterial phenotype describing the production of glycoproteins resembling mucus.
- Quorum sensing
Mechanism by which a cell responds to changes in population size or density, classically by the secretion and detection of small peptides (also known as pheromones).
An infectious disease caused by Burkholderia pseudomallei, endemic in South East Asia and Australia, which can lead to sepsis and pneumonia.
- Adaptive trade-off hypothesis
The hypothesis that the long-term evolutionary success of a pathogen requires a balance between the duration of infection and virulence, based on the assumption that an increase in virulence decreases the average duration of infection.
- Effective population size
The size of an idealized (neutrally evolving, homogeneous) population that is otherwise equivalent to an observed population. The effective population size is typically smaller than the number of individuals in the population, owing to population structure and variation in survival or reproductive viability. Effective population size is also known as Ne.
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Didelot, X., Walker, A., Peto, T. et al. Within-host evolution of bacterial pathogens. Nat Rev Microbiol 14, 150–162 (2016). https://doi.org/10.1038/nrmicro.2015.13
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