title: Genomic profiling of collaborative cross founder mice infected with respiratory viruses reveals novel transcripts and infection-related strain-specific gene and isoform expression.
abstract: 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.
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon.
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon.
authors.forename: Juliet
authors.initials: J
authors.lastname: Morrison
authors.affiliation: Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon Department of Genetics, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Martin T
authors.initials: MT
authors.lastname: Ferris
authors.affiliation: Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Gralinski
authors.affiliation: Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon Department of Genetics, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Whitmore
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon.
authors.forename: Richard
authors.initials: R
authors.lastname: Green
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Thomas
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tisoncik-Go
authors.affiliation: Illumina, Inc., San Diego, California.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Schroth
authors.affiliation: Department of Genetics, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Fernando
authors.initials: F
authors.lastname: Pardo-Manuel de Villena
authors.affiliation: Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Baric
authors.affiliation: Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon Department of Genetics, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Heise
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon.
authors.forename: Xinxia
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon honey@uw.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
mesh_terms: D000818:Animals; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016678:Genome; D009980:Influenza A virus; D008168:Lung / Q000378:metabolism / Q000821:virology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000235:genetics* / Q000821:virology; D010641:Phenotype; D012313:RNA / Q000235:genetics; D045473:Severe acute respiratory syndrome-related coronavirus; D017423:Sequence Analysis, RNA; D045169:Severe Acute Respiratory Syndrome / Q000235:genetics* / Q000821:virology; D013045:Species Specificity; D019562:Viral Load
chemical_list: D012313:RNA
keywords: RNA-seq; collaborative cross; isoform differential expression; mouse transcriptome annotation; viral infection