Hybrid Gene Origination Creates Human-Virus Chimeric Proteins during Infection

Cell. 2020 Jun 25;181(7):1502-1517.e23. doi: 10.1016/j.cell.2020.05.035. Epub 2020 Jun 18.


RNA viruses are a major human health threat. The life cycles of many highly pathogenic RNA viruses like influenza A virus (IAV) and Lassa virus depends on host mRNA, because viral polymerases cleave 5'-m7G-capped host transcripts to prime viral mRNA synthesis ("cap-snatching"). We hypothesized that start codons within cap-snatched host transcripts could generate chimeric human-viral mRNAs with coding potential. We report the existence of this mechanism of gene origination, which we named "start-snatching." Depending on the reading frame, start-snatching allows the translation of host and viral "untranslated regions" (UTRs) to create N-terminally extended viral proteins or entirely novel polypeptides by genetic overprinting. We show that both types of chimeric proteins are made in IAV-infected cells, generate T cell responses, and contribute to virulence. Our results indicate that during infection with IAV, and likely a multitude of other human, animal and plant viruses, a host-dependent mechanism allows the genesis of hybrid genes.

Keywords: RNA hybrid; cap-snatching; chimeric proteins; gene origination; influenza; segmented negative-strand RNA viruses; uORFs; upstream AUG; viral RNA; viral evolution.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / genetics
  • Animals
  • Cattle
  • Cell Line
  • Cricetinae
  • Dogs
  • Humans
  • Influenza A virus / metabolism
  • Mice
  • Mutant Chimeric Proteins / genetics
  • Mutant Chimeric Proteins / metabolism
  • Open Reading Frames / genetics
  • RNA Caps / genetics*
  • RNA Caps / metabolism
  • RNA Virus Infections / genetics*
  • RNA Virus Infections / metabolism
  • RNA Viruses / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Viral / metabolism
  • RNA-Dependent RNA Polymerase / genetics
  • RNA-Dependent RNA Polymerase / metabolism
  • Recombinant Fusion Proteins / genetics*
  • Recombinant Fusion Proteins / metabolism
  • Transcription, Genetic / genetics
  • Viral Proteins / metabolism
  • Virus Replication / genetics


  • 5' Untranslated Regions
  • Mutant Chimeric Proteins
  • RNA Caps
  • RNA, Messenger
  • RNA, Viral
  • Recombinant Fusion Proteins
  • Viral Proteins
  • RNA-Dependent RNA Polymerase