Genomic Profiling of Collaborative Cross Founder Mice Infected with Respiratory Viruses Reveals Novel Transcripts and Infection-Related Strain-Specific Gene and Isoform Expression

Genetic variation between diverse mouse species is well-characterized, yet existing knowledge of the mouse transcriptome comes largely from one mouse strain (C57BL/6J). As such, it is unlikely to reflect the transcriptional complexity of the mouse species. Gene transcription is dynamic and condition-specific; therefore, to better understand the mouse transcriptional response to respiratory virus infection, we infected the eight founder strains of the Collaborative Cross with either influenza A virus or severe acute respiratory syndrome coronavirus and sequenced lung RNA samples at 2 and 4 days after infection. We found numerous instances of transcripts that were not present in the C57BL/6J reference annotation, indicating that a nontrivial proportion of the mouse genome is transcribed but poorly annotated. Of these novel transcripts, 2150 could be aligned to human or rat genomes, but not to existing mouse genomes, suggesting functionally conserved sequences not yet recorded in mouse genomes. We also found that respiratory virus infection induced differential expression of 4287 splicing junctions, resulting in strain-specific isoform expression. Of these, 59 were influenced by strain-specific mutations within 2 base pairs of key intron–exon boundaries, suggesting cis-regulated expression. Our results reveal the complexity of the transcriptional response to viral infection, previously undocumented genomic elements, and extensive diversity in the response across mouse strains. These findings identify hitherto unexplored transcriptional patterns and undocumented transcripts in genetically diverse mice. Host genetic variation drives the complexity and diversity of the host response by eliciting starkly different transcriptional profiles in response to a viral infection.