|
17th International HIV Drug Resistance Workshop10-14 June 2008, Sitges, Spain |
DIVERSITY-GENERATING RETROELEMENTS
Antivir Ther. 2008; 13(Suppl. 3):P3 (abstract no. P1)
JF Miller
Department of Microbiology, Immunology and Molecular Genetics, UCLA School of Medicine, Los Angeles, CA, USA
Host–parasite interactions are often driven by mechanisms that promote genetic variability. In the course of our studies on bacterial pathogenesis, we discovered a group of temperate bacteriophages that generate diversity in a gene that specifies tropism for receptor molecules on host Bordetella species, which cause respiratory infections in humans and other mammals. This microevolutionary adaptation is produced by a novel ‘diversity-generating retroelement’ (DGR) that combines the basic retroelement life-cycle of transcription, reverse transcription and integration with site-directed, adenine-specific mutagenesis. Central to this process is a reverse transcriptase-mediated exchange between two repeats, one serving as a donor template (TR) and the other as a recipient of variable sequence information (VR). Recent work has focused on the genetic basis of diversity-generation. The directionality of information transfer is determined by the initiation of mutagenic homing (IMH) sequence present at the 3′ end of VR. We have demonstrated that DGR function occurs through a TR-containing RNA intermediate by a unique target-primed reverse transcription mechanism that precisely regenerates target sequences. This non-proliferative, ‘copy and replace’ mechanism enables repeated rounds of protein diversification and optimization of ligand–receptor interactions. The potential utility of DGRs is illustrated by the identification of over 40 related elements in bacterial, phage and plasmid genomes. DGRs are present in human pathogens (Treponema, Legionella spp.), human commensals (Bacteroides, Bifidobacterium spp.), green sulfur bacteria (Chlorobium, Prosthecochloris spp.), cyanobacteria (Trichodesmium, Nostoc spp.), magnetotactic bacteria (Magnetospirillum spp.), and many other diverse species. DGRs comprise a new family of retroelements with the potential to confer powerful selective advantages to their host genomes.
2008-06-10
P1
Copyright © 2008 - International Medical Press Ltd.. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.