Andrew E. Firth on virus gene expression

RNA viruses have compact multifunctional genomes. During the course of infection, the genome or its derivatives must direct translation of virus proteins, genome replication and genome packaging. To realize these multiple roles, RNA virus genomes commonly have many overlapping coding and non-coding functional elements.

Overlapping functional elements have often escaped detection because it can be difficult to disentangle the multiple roles of the constituent nucleotides via, for example, mutational analysis. On the other hand, RNA viruses evolve very rapidly and there are many sequenced isolates, thus providing potential for powerful comparative genomic analyses, even within single virus species. Firth haa been using comparative genomics to systematically identify “hidden” functional elements in RNA virus genomes. Computationally identified features can then be efficiently targeted for experimental analysis.

In parallel the research group is using RNA-Seq and Ribosome Profiling (Ribo-Seq) to study virus gene expression. Ribo-Seq is a high-throughput sequencing technique that maps the distribution of actively translating ribosomes on all mRNAs within a cell or tissue sample, thus giving a global snapshot of protein synthesis rates and translational regulation. They are particularly interested in characterizing non-canonical gene expression mechanisms – such as programmed ribosomal frameshifting, stop codon readthrough, ribosomal skipping, ribosomal reinitiation, IRES-mediated initiation, and programmed transcriptional slippage. Such mechanisms tend to be particularly prevalent in RNA viruses due to the unique constraints under which they evolve, but are also utilized in cellular gene expression and some have potential biotechnological applications.