Genome-wide transposon mutagenesis of paramyxoviruses reveals constraints on genomic plasticity: implications for vaccine and gene therapy

Ikegame, S.; Beaty, S. M.; Stevens, C.; Won, T. S.; Park, A.; Sachs, D.; Hong, P.; Thibault, P. A.; Lee, B.

doi:10.1101/2020.03.30.016493

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bioRxiv · 10.1101/2020.03.30.016493

Genome-wide transposon mutagenesis of paramyxoviruses reveals constraints on genomic plasticity: implications for vaccine and gene therapy

Ikegame, S.·Beaty, S. M.·Stevens, C.·Won, T. S.·Park, A.·Sachs, D.·Hong, P.·Thibault, P. A.·Lee, B.

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Abstract

The antigenic and genomic stability of paramyxoviruses remains a mystery. Here, we evaluate the genetic plasticity of Sendai virus (SeV) and mumps virus (MuV), sialic acid-using paramyxoviruses that infect mammals from two Paramyxoviridae subfamilies (Orthoparamyxovirinae and Rubulavirinae). We performed saturating whole-genome transposon insertional mutagenesis, and identified important commonalities: disordered regions in the N and P genes near the 3 genomic end were more tolerant to insertional disruptions; but the envelope glycoproteins were not, highlighting structural constraints that contribute to the restricted antigenic drift in paramyxoviruses. Nonetheless, when we applied our strategy to a fusion-defective Newcastle disease virus (Avulavirinae subfamily), we could select for F-revertants and other insertants in the 5 end of the genome. Our genome-wide interrogation of representative paramyxovirus genomes from all three Paramyxoviridae subfamilies provides a family-wide context in which to explore specific variations within and among paramyxovirus genera and species.

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Ikegame, S., Beaty, S. M., Stevens, C., Won, T. S., Park, A., Sachs, D., Hong, P., Thibault, P. A., Lee, B.. 2020-03-31. Genome-wide transposon mutagenesis of paramyxoviruses reveals constraints on genomic plasticity: implications for vaccine and gene therapy. https://doi.org/10.1101/2020.03.30.016493

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