Diversity-generating retroelements

https://doi.org/10.1016/j.mib.2007.06.004Get rights and content

Parasite adaptation to dynamic host characteristics is a recurrent theme in biology. Diversity-generating retroelements (DGRs) are a newly discovered family of genetic elements that function to diversify DNA sequences and the proteins they encode. The prototype DGR was identified in a temperate bacteriophage, BPP-1, on the basis of its ability to generate variability in a gene that specifies tropism for receptor molecules on host Bordetella species. Tropism switching is a template-dependent, reverse transcriptase mediated process that introduces nucleotide substitutions at defined locations within a target gene. This cassette-based mechanism is theoretically capable of generating trillions of different amino acid sequences in a distal tail fiber protein, providing a vast repertoire of potential ligand–receptor interactions. Variable residues are displayed in the context of a specialized C-type lectin fold, which has evolved a unique solution for balancing protein diversity against structural stability. Homologous DGRs have been identified in the chromosomes of diverse bacterial species. These unique genetic elements have the potential to confer powerful selective advantages to their hosts, and their ability to generate novel binding specificities and dynamic antimicrobial agents suggests numerous applications.

Section snippets

Diversity, the spice of life

The ability to generate adaptive diversity through stochastic mechanisms is a conserved feature of host–parasite interactions [1]. DGRs are strikingly different from previously described genetic systems that mediate phase and antigenic variation. A particularly instructive paradigm for understanding the essence of DGR function is the mammalian immune system itself. The development of antibody and T cell receptor repertoires can be conceptually divided into three stages. The first employs a germ

Tropism switching by Bordetella bacteriophage

The infectious cycles of Bordetella species, which cause respiratory infections in mammals, are controlled by the BvgAS phosphorelay signal transduction system [9]. BvgAS mediates a transition between the Bvg+ phase, which is adapted to colonization of the respiratory tract, and the Bvg phase, which is adapted to ex vivo survival and growth in B. bronchiseptica, the broad host range evolutionary progenitor of Bordetella species that infect humans [10]. This phenotypic transition is associated

The diversity generator

Comparison of the 42.5 kb dsDNA genome of BPP-1 with BMP and BIP derivatives revealed a region of variability designated the variable repeat (VR, Figure 2). VR consists of a 134 bp sequence located at the 3′ end of the mtd (major tropism determinant) locus [7••]. Nucleotide substitutions are always present in tropic variants, and they occur at 23 discrete positions within VR. Variability hotspots are predominantly located in the first two bases of codons, maximizing the generation of amino acid

“Ordered disorder”  the C-type lectin scaffold

If sequence variation is to confer a selective advantage, a diversity generator must interface with a protein scaffold that can display amino acid variability while maintaining structural stability. Until the discovery of DGRs, the immunoglobulin (Ig) fold found in antibodies and T cell receptors provided the major paradigm for how this might occur [18]. Crystal structures of five Mtd variants representing different receptor specificities were determined at 1.56–2.52 Å resolution [19••]. Tropic

Diversity-generating retroelements are widespread in bacterial genomes

The ability to diversify protein domains involved in ligand–receptor interactions has the potential to confer a powerful selective advantage. Using the Bordetella phage DGR as a signature, homologous retroelements have been identified in nearly 30 genomes representing diverse bacterial species (S Zimmerly et al., personal communication, M Gingery et al., unpublished data) [17••]. The examples in Figure 4a include DGRs predicted in the genomes of a V. harveyi phage, a M. magneticum phage, and

Conclusions

It is remarkable to consider that over 40% of the human genome is comprised of retroelements and degraded derivatives of them [25]. Retrotransposons, retroviruses, non-LTR retroelements, group II introns, and related elements share two fundamental characteristics. First, they replicate through obligatory RNA intermediates using reverse transcriptase-dependent mechanisms [25, 26•, 27, 28]. Second, they do not appear to confer an obvious selective advantage to their hosts; they are neutral at

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to thank David Martin, MD and Partho Ghosh, PhD for their critical reading of the manuscript. BAM was supported by the UCLA Medical Scientist Training Program training grant GM 08042. This work was supported by NIH Grants AI 61598 and AI 71204, and UC Discovery Grant Bio04-10428 to JFM.

References (39)

  • J. Nikolich-Zugich et al.

    The many important facets of T-cell repertoire diversity

    Nat Rev Immunol

    (2004)
  • C.L. Williams et al.

    BvgA functions as both an activator and a repressor to control Bvg phase expression of bipA in Bordetella pertussis

    Mol Microbiol

    (2005)
  • D.A. Diavatopoulos et al.

    Bordetella pertussis, the causative agent of whooping cough, evolved from a distinct, human-associated lineage of B. bronchiseptica

    PLoS Pathog

    (2005)
  • C.A. Cummings et al.

    Species- and strain-specific control of a complex, flexible regulon by Bordetella BvgAS

    J Bacteriol

    (2006)
  • D.A. Diavatopoulos et al.

    Adaptive evolution of the Bordetella autotransporter pertactin

    J Evol Biol

    (2006)
  • J.T. Poolman et al.

    Acellular pertussis vaccines and the role of pertactin and fimbriae

    Expert Rev Vaccines

    (2007)
  • M. Hijnen et al.

    Epitope structure of the Bordetella pertussis protein P.69 pertactin, a major vaccine component and protective antigen

    Infect Immun

    (2004)
  • S. Mattoo et al.

    Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies

    Clin Microbiol Rev

    (2005)
  • M. Liu et al.

    Genomic and genetic analysis of Bordetella bacteriophages encoding reverse transcriptase-mediated tropism-switching cassettes

    J Bacteriol

    (2004)
  • Cited by (0)

    View full text