(The entire published article can be found at http://dx.doi.org/10.1371/journal.pbio.0030300 )
In the first large-scale effort to sequence the flu genome, Edward Holmes, David Lipman, and colleagues examined the genomes of 156 influenza A viruses (serotype H3N2) collected by New York State public
health officials between 1999 and 2004. “We found that there are
co-circulating minor variants that are not infecting many people,” says
Lipman. “One of these can cause the next major epidemic.”

These co-circulating viruses can exchange genes in a way that creates
novel, epidemiologically significant strains–a process that humans may
facilitate by simultaneously hosting more than one strain. The genetic
reshuffling demonstrated in this study is the first to examine in detail
a reassortment event leading to an epidemiologically significant
outcome–the emergence of the “Fujian” strain in the 2003-2004 flu season.

The Institute for Genomic Research, with funding from the National
Institute for Allergy and Infectious Diseases, sequenced the genomes of
the collected flu viruses. Examining these sequences, Holmes et al.
found that a relatively uncommon group of viruses acquired the
hemagglutinin gene (a highly variable viral protein that determines a
virus strain’s virulence) from a virus common during the previous year.
The reassorted virus, previously unnoticed because of its low virulence,
suddenly became capable of infecting thousands. Had scientists known
that co-circulating viruses can reassort, they may have seen “some kind
of warning sign,” says Lipman. “The key thing here is that the general
notion of epidemic flu is that there’s a series of successive mutations
from the flu we got the previous year.” But the new study shows that an
old, non-threatening virus–which might be accumulating mutations that
don’t affect virulence–can suddenly cause an epidemic with just one or
two more mutations.

These results suggest that “the potential diversity is greater than we
thought,” says Lipman. “We need to have more comprehensive information
on the entire genome [and] enough samples from around the world,” he
adds, to find the benign virus strain that will become next season’s
scourge. The more genomes scientists collect–and the more refined the
tools of genomics become–the greater the chances of developing more
effective vaccines.

Citation: Holmes EC, Ghedin E, Miller N, Taylor J, Bao Y, et al. (2005)
Whole-genome analysis of human influenza A virus reveals multiple
persistent lineages and reassortment among recent H3N2 viruses. PLoS
Biol 3(9): e300.