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Genetic Reassortment Sparks Flu Virus Evolution

NEW YORK (GenomeWeb Daily News) – An influenza A virus associated with some of the most notorious flu epidemics in history apparently evolves not just by simple mutations but also through complex reassortments — gene swapping between similar viruses, new research suggests.
Researchers from Pennsylvania State University and elsewhere compared the genomes of 71 H1N1-type influenza viruses collected over nearly 90 years. The results, published online in the journal PLoS Pathogens today, suggest influenza A H1N1’s evolutionary history is filled with complex gene shuffling and swapping between different strains of the same subtype.
“These reassortment events appear to be able to generate new viruses that have vastly different genomes,” lead author Martha Nelson, a graduate student at Penn State's Center for Infectious Disease Dynamics, told GenomeWeb Daily News.
The H1N1 virus is associated with “classical” swine influenza as well as several notable human epidemics, including the 1918 epidemic that killed some 20 million to 50 million people. Another epidemic occurred in 1947, when H1N1’s antigenic profile changed, making it distinct from all the vaccines available at the time. Yet another followed in 1951, with smaller outbreaks popping up here and there in the intervening years.
Mysteriously, the H1N1 virus apparently vanished in 1957, only to reappear 20 years later. Since then H1N1 has competed with H3N2 influenza A for the dubious distinction of dominant flu agent.
In an effort to understand H1N1’s murky evolutionary history, Nelson and her colleagues assessed 71 different H1N1 strains, individually comparing each of the eight major regions of the virus’ genome. They obtained this sequence information, collected between 1918 and 2005, from the Influenza Genome Sequencing Project, a National Institutes of Allergy and Infectious Diseases project. The viruses were isolated from humans and swine from 17 countries on five continents.
When they began creating phylogenetic trees using manual sequence alignments and the PAUP software, Nelson and her colleagues discovered that H1N1 evolution does not march along in a series of linear mutations as previously suspected. Instead, the virus tends to go through intra-subtype reassortments. In other words, when two different H1N1 strains infect the same cell, they tend to trade genetic information, fueling viral evolution.
For example, the H1N1 strain associated with the 1947 epidemic had novel HA and PB2 genes, coding for the viral coat protein hemagglutinin and a polymerase, respectively. Because it is targeted by the human immune system, HA is commonly thought to evolve to avoid immune detection. As a result, it has been extensively studied.
Even so, while HA genetic reassortment did play a role in the 1947 epidemic, this study suggests it did not contribute to the 1951 outbreak. This underscores the need to look beyond one suspicious gene, Nelson noted. “It’s not just HA that causes the virus to be severe,” she said. “We really need to take a whole-genome approach.”
And while the study can’t explain where H1N1 went between 1957 and 1977 when it temporarily disappeared, it does confirm that the virus was out of circulation, both in human and animal populations. The team’s genetic analysis did not detect any evolution during that 20-year stretch. “What you can see from these [phylogenetic] trees is that the virus is exactly the same when it reappeared in 1977,” Nelson said. Her best guess is that the virus was dormant — perhaps frozen — somewhere until it was reintroduced in the late 70’s.
Ideally, such genomic analysis will eventually predict, not just explain, the direction of flu virus evolution. “That’s the holy grail of all of this work,” Nelson said. But, she added, because of the diversity of circulating flu viruses, health officials will likely need to use broad surveillance to understand influenza’s dizzying ability to evolve through reassortments and mutations.

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