Transcript degradation and codon usage regulate gene expression in a lytic phage

Many viral genomes are small, containing only single- or double-digit numbers of genes and relatively few regulatory elements. Yet viruses successfully execute complex regulatory programs as they take over their host cells. Here, we propose that some viruses regulate gene expression via a carefully balanced interplay between transcription, translation, and transcript degradation. As our model system, we employ bacteriophage T7, whose genome of approximately sixty genes is well annotated and for which there is a long history of computational models of gene regulation. We expand upon prior modeling work by implementing a stochastic gene expression simulator that tracks individual transcripts, polymerases, ribosomes, and ribonucleases participating in the transcription, translation, and transcript-degradation processes occurring during a T7 infection. By combining this detailed mechanistic modeling of a phage infection with high-throughput gene expression measurements of several strains of bacteriophage T7, evolved and engineered, we can show that both the dynamic interplay between transcription and transcript degradation, and between these two processes and translation, appear to be critical components of T7 gene regulation. Our results point to targeted degradation as a generic gene regulation strategy that may have evolved in many other viruses. Further, our results suggest that detailed mechanistic modeling may uncover the biological mechanisms at work in both evolved and engineered virus variants.