Bioinformatics studies of Influenza A hemagglutinin sequence data indicate recombination-like events leading to segment exchanges

Antara De, Tapati Sarkar, Ashesh Nandy

The influenza genome is highly variable due primarily to two mechanisms: antigenic drift and antigenic shift. A third mechanism for genetic change, known as copy choice or template switching, can arise during replication when, if two viral strains infect a cell, a part of a gene from the second viral strain can be copied into the growing progeny of a gene of the first viral strain as replacement leading to a new variety of the virus. This template switching between the same genes of the two strains is known as homologous recombination. While genetic drift and shift are well-understood, the presence or absence of intra-segment homologous recombination in influenza genomes is controversial. We are interested to study the possibility of subunit-wise homologous recombination. The idea is that where well-defined subunits are separated by consensus sequences, it might be possible for template switching to take place at such junctions. The influenza hemagglutinin gene has basically two subunits, HA1 and HA2, with HA1 being mostly surface exposed and containing the active site for binding to cells, while HA2 secures the hemagglutinin to the viral coat. We undertook a thorough search of the major human infecting influenza hemagglutinin gene sequences, viz., the H1N1, H5N1, H3N2 and H7N9 subtypes, over the period 2010-2014 in Asia to determine if certain sequences could be identified that had HA1 from a previous strain and HA2 from another. Our search yielded several instances where sequence identities between segments of various strains could be interpreted as indicating possibilities of segment exchange. In some cases, on closer examination they turn out to differ by a few mutations in each segment, due perhaps to the short time span of our database. The study reported here, and in combination with our earlier observations on the neuraminidase, shows that subunit-wise recombination-like events in the influenza genes may be occurring more often than have been accounted for and merits further detailed studies.