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

Abstract

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 multi basic 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.

Putative host-derived insertions in the genomes of circulating SARS-CoV-2 variants

“…Interestingly, rRNAs have been established to be a source of insertions in influenza genomes, in some cases resulting in significantly more pathogenic viral variants (39,40). It has been speculated that these recombination events often occur with host rRNAs due to their abundance in the cells, the presence of recombination hotspots on rRNA molecules, and the utilization of host rRNAs during viral replication (39).…”

“…The putative 18S and 28S-derived insertions were identified in circulating variants of the SARS-CoV-2, and while these particular variants did not seem to spread widely, they do provide evidence that human genetic material can be a source of genomic insertions in SARS-CoV-2. Interestingly, rRNAs have been established to be a source of insertions in influenza genomes, in some cases resulting in significantly more pathogenic viral variants (39, 40). It has been speculated that these recombination events often occur with host rRNAs due to their abundance in the cells, the presence of recombination hotspots on rRNA molecules, and the utilization of host rRNAs during viral replication (39).…”

“…Interestingly, rRNAs have been established to be a source of insertions in influenza genomes, in some cases resulting in significantly more pathogenic viral variants (39, 40). It has been speculated that these recombination events often occur with host rRNAs due to their abundance in the cells, the presence of recombination hotspots on rRNA molecules, and the utilization of host rRNAs during viral replication (39). Similar factors may play a role in the formation of these rRNA-derived insertions in SARS-CoV-2, but the formation of double-membrane vesicles during SARS-CoV-2 would seemingly complicate this process.…”