Diversity-generating retroelements
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.
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