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Convergent evolution and adaptation of Pseudomonas aeruginosa within patients with cystic fibrosis

Nature Genetics volume 47, pages 57–64 (2015)Cite this article

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Abstract

Little is known about how within-host evolution compares between genotypically different strains of the same pathogenic species. We sequenced the whole genomes of 474 longitudinally collected clinical isolates of Pseudomonas aeruginosa sampled from 34 children and young individuals with cystic fibrosis. Our analysis of 36 P. aeruginosa lineages identified convergent molecular evolution in 52 genes. This list of genes suggests a role in host adaptation for remodeling of regulatory networks and central metabolism, acquisition of antibiotic resistance and loss of extracellular virulence factors. Furthermore, we find an ordered succession of mutations in key regulatory networks. Accordingly, mutations in downstream transcriptional regulators were contingent upon mutations in upstream regulators, suggesting that remodeling of regulatory networks might be important in adaptation. The characterization of genes involved in host adaptation may help in predicting bacterial evolution in patients with cystic fibrosis and in the design of future intervention strategies.

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Figure 1: Overview of the present investigations.
Figure 2: Overview of the 474 genome-sequenced P. aeruginosa isolates.
Figure 3: Clone types found in more than one patient.
Figure 4: Pathoadaptive genes (n = 52).
Figure 5: The most frequently mutated functional classes and genes.
Figure 6: The order of mutations in mutants with two nonsynonymous mutations in the same regulatory pathway.

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NCBI Reference Sequence

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Acknowledgements

We thank U.R. Johansen, P. Poss, H. Nordbjerg, N. Kirkby, K. Bloksted and B.H. Erichsen for excellent technical assistance and T. Pressler and M. Skov for information about the patients' visits to the hospital. This work was supported by the Lundbeck Foundation, and H.K.J. was supported by a clinical research stipend from the Novo Nordisk Foundation.

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Authors and Affiliations

  1. Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark

    Rasmus Lykke Marvig & Helle Krogh Johansen

  2. Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark

    Rasmus Lykke Marvig, Lea Mette Sommer & Søren Molin

  3. Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark

    Lea Mette Sommer, Søren Molin & Helle Krogh Johansen

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  1. Rasmus Lykke Marvig
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  2. Lea Mette Sommer
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Contributions

S.M. and H.K.J. jointly supervised the study. R.L.M., S.M. and H.K.J. conceived and designed the experiments. H.K.J. collected clinical samples and provided clinical information. L.M.S. prepared the genomic libraries for whole-genome sequencing. R.L.M. designed the bioinformatics workflows for the analysis. R.L.M. and L.M.S. conducted whole-genome sequence analysis. R.L.M., L.M.S., S.M. and H.K.J. analyzed and interpreted the data. R.L.M. wrote the manuscript. L.M.S., S.M. and H.K.J. helped write the manuscript and provided revisions.

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Correspondence to Rasmus Lykke Marvig.

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Integrated supplementary information

Supplementary Figure 1 Patient origin and clone type of the 474 genome-sequenced isolates of P. aeruginosa.

Numbers in white squares denote the number of isolates of the respective clone type that have been isolated from the patient. Red numbers indicate the most prevalent clone type in the patient, and underlined numbers indicate that the clone type is the most recent clone type to be found in the respective patient. Names of clone types framed by blue boxes indicate that the clone type has been found in more than one patient. Patient IDs framed by blue boxes indicate that more than one clone type has been sampled from the patient.

Supplementary Figure 2 Overview of the time between the earliest and latest isolates of P. aeruginosa from each patient.

The bars indicate the time in years between the first and last genome-sequenced isolates from the respective patient.

Supplementary Figure 3 Number of SNPs accumulated since the MRCA of clonal isolates from the same patient.

We evaluated the within-patient diversity of clonal isolates by counting the number of SNPs that isolates have accumulated since the MRCA of clonal isolates from the same patient. The distribution of genetic distances was visualized using a box plot. Points that were beyond the quartiles by 1.5 times the interquartile range were considered to be outliers.

Supplementary Figure 4 Maximum-parsimonious phylogeny of 23 P. aeruginosa isolates of the DK12 clone type.

The phylogeny has a consistency of 0.95 and is based on 576 SNPs identified from whole-genome comparison of the isolates. Branch lengths are drawn to scale, and the scale bar indicates the number of SNPs that have accumulated over the branch. Alleles of P. aeruginosa reference strain PAO1 were used to determine the MRCA. The overall transition-to-transversion ratio was 3.6 (452 transitions, 125 transversions), but a mutational skew towards transition substitutions (88 transitions, 3 transversions) was observed in the branch leading to hypermutable isolate 104, which carries a 24-bp deletion in the DNA mismatch repair gene mutL.

Supplementary Figure 5 Maximum-parsimonious phylogeny of three P. aeruginosa isolates of the DK40 clone type.

The phylogeny has a perfect consistency of 1 and is based on 400 SNPs identified from whole-genome comparison of the isolates. The transition-to-transversion ratio of the SNPs was 2.1 (269 transitions, 131 transversions). Branch lengths are drawn to scale, and the scale bar indicates the number of SNPs that have accumulated over the branch. Alleles of P. aeruginosa reference strain PAO1 were used to determine the MRCA.

Supplementary Figure 6 Order of mutations in genotypes with multiple nonsynonymous mutations in the retS-gacA/S-rsmA/Z signaling pathway.

All mutations were acquired since the MRCA of each of the genotypes. The order of mutations was unambiguously inferred from maximum-parsimonious phylogenetic reconstructions (Online Methods).

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Tables 1, 4–6, 8 and 9. (PDF 1667 kb)

List of SNPs found to have accumulated in the recent evolutionary history of 36 clone types of P. aeruginosa.

The SNPs are described according to their position in the genome of P. aeruginosa reference strain PAO1. The SNPs are sorted according to the clone type in which they are found, and the rightmost columns indicate whether the mutation is present in the isolates of the given clone type. (XLSX 1370 kb)

List of indels found to have accumulated in the recent evolutionary history of 36 clone types of P. aeruginosa.

The indels are described according to their position in the genome of P. aeruginosa reference strain PAO1. The indels are sorted according to the clone type in which they are found, and the rightmost columns indicate whether the mutation is present in the isolates of the given clone type. (XLSX 511 kb)

Information about whole genome–sequenced clinical isolates.

(XLSX 75 kb)

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Marvig, R., Sommer, L., Molin, S. et al. Convergent evolution and adaptation of Pseudomonas aeruginosa within patients with cystic fibrosis . Nat Genet 47, 57–64 (2015). https://doi.org/10.1038/ng.3148

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