Insertions of codons encoding basic amino acids in H7 hemagglutinins of influenza A viruses occur by recombination with RNA at hotspots near snoRNA binding sites

• Published in: RNA (Cambridge) Vol. 27; no. 2; pp. 123 - 132
• Main Authors: Gultyaev, Alexander P., Spronken, Monique I., Funk, Mathis, Fouchier, Ron A.M., Richard, Mathilde
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.02.2021
• Subjects: Amino Acids, Basic - genetics; Amino Acids, Basic - metabolism; Animals; Base Pairing; Base Sequence; Chickens - virology; Codon; Gene Expression Regulation; Hemagglutinin Glycoproteins, Influenza Virus - genetics; Hemagglutinin Glycoproteins, Influenza Virus - metabolism; Host-Pathogen Interactions - genetics; Humans; Hypothesis; Influenza A virus - genetics; Influenza A virus - metabolism; Influenza A virus - pathogenicity; Influenza in Birds - virology; Influenza, Human - virology; Mutagenesis, Insertional; Recombination, Genetic; RNA, Small Nucleolar - chemistry; RNA, Small Nucleolar - genetics; RNA, Small Nucleolar - metabolism; RNA, Viral - chemistry; RNA, Viral - genetics; RNA, Viral - metabolism; Sequence Alignment; Virulence; RNA recombination; influenza virus; avian influenza; snoRNA
• ISSN: 1355-8382; 1469-9001; 1469-9001
• DOI: 10.1261/rna.077495.120

The presence of multiple basic amino acids in the protease cleavage site of the hemagglutinin (HA) protein is the main molecular determinant of virulence of highly pathogenic avian influenza (HPAI) viruses. Recombination of HA RNA with other RNA molecules of host or virus origin is a dominant mechanism of multibasic cleavage site (MBCS) acquisition for H7 subtype HA. Using alignments of HA RNA sequences from documented cases of MBCS insertion due to recombination, we show that such recombination with host RNAs is most likely to occur at particular hotspots in ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), and viral RNAs. The locations of these hotspots in highly abundant RNAs indicate that RNA recombination is facilitated by the binding of small nucleolar RNA (snoRNA) near the recombination points.