Burkholderia pseudomallei sequencing identifies genomic clades with distinct recombination, accessory and epigenetic profiles
- Tannistha Nandi1,
- Matthew Holden2,
- Xavier Didelot3,
- Kurosh Mehershahi4,
- Justin A Boddey5,
- Ifor Beacham5,
- Ian Peak5,
- John Harting6,
- Primo Baybayan6,
- Yan Guo6,
- Susana Wang6,
- Chee How Lee6,
- Bernice Sim1,
- Angela Essex-Lopresti7,
- Mitali Sarkar-Tyson7,
- Michelle Nelson7,
- Sophie Smither7,
- Catherine Ong8,
- Lay Tin Aw8,
- Hui Hoon Chua1,
- Stephen Michell9,
- David J Studholme9,
- Richard W Titball10,
- Swaine L Chen1,
- Julian Parkhill2 and
- Patrick Tan1,11
- 1 Genome Institute of Singapore;
- 2 The Wellcome Trust Sanger Institute;
- 3 University of Oxford;
- 4 National University of Singapore;
- 5 Griffith University (Gold Coast Campus);
- 6 Pacific Biosciences;
- 7 Defence Science and Technology Laboratory, UK;
- 8 Defense Medical and Environmental Research Institute, Singapore;
- 9 University of Exeter;
- 10 London School of Hygiene & Tropical Medicine
- ↵* Corresponding author; email: tanbop{at}gis.a-star.edu.sg
Abstract
Burkholderia pseudomallei (Bp) is the causative agent of melioidosis, a serious infectious disease of human and animals. To investigate population diversity, recombination, and horizontal gene transfer in closely-related Bp isolates, we performed whole-genome sequencing (WGS) on 106 clinical, animal, and environmental strains from a restricted Asian locale. Whole-genome phylogeny resolved multiple genomic clades of Bp largely congruent with multi-locus sequence typing (MLST). We discovered widespread recombination in the Bp core genome, involving hundreds of regions associated with multiple haplotypes. Highly recombinant regions exhibited functional enrichments which may contribute to virulence. We observed striking clade-specific patterns of recombination and accessory gene exchange, and provide evidence that this is likely due to ongoing recombination between clade members. Reciprocally, inter-clade exchanges were rarely observed, suggesting mechanisms restricting gene flow between clades. Interrogation of accessory elements revealed that each clade harbored a distinct complement of restriction-modification (RM) systems, predicted to cause clade-specific patterns of DNA methylation. Using whole-genome methylome sequencing, we confirmed that representative strains from separate clades indeed exhibit distinct methylation profiles. Finally, using an E. coli experimental system, we demonstrate that Bp RM systems can inhibit uptake of non-self DNA. Our data suggests that RM systems on mobile elements, besides preventing invasion of foreign DNA, may also contribute to limit the exchange of genes and gene variants between individuals of the same species. Genomic clades may thus represent functional units of genetic isolation in Bp, modulating intra-species genetic diversity.
- Received April 22, 2014.
- Accepted September 15, 2014.
- Published by Cold Spring Harbor Laboratory Press
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