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Genetic Diversity of Influenza Underscores Presence, Transmission of Minor Variants

NEW YORK (GenomeWeb) – When influenza is passed from person to person, different co-circulating strains may be transmitted, as can different lineages of the same strain, according to researchers from New York University and elsewhere.

NYU's Elodie Ghedin and her team sequenced and analyzed flu strains collected from 84 people, including 67 index patients and 17 other household members, to examine both within-host viral diversity and how that diversity is transmitted to new hosts. As they reported in Nature Genetics today, the researchers found that minor variants are often transmitted between donors and recipients.

"A flu virus infection is not a homogeneous mix of viruses, but rather a mix of strains that gets transmitted as a swarm in the population," Ghedin, the paper's senior author and a professor at NYU, said in a statement. "Current vaccines target the dominant strains, because they are the ones that seem to infect the largest number of individuals. But our findings reveal an ability of minor strains to elude these vaccines and spread the virus in ways not previously known."

She and her colleagues collected nasal swabs from 67 index patients and 17 other members of their household during the first wave of the 2009 H1N1 pandemic when the seasonal H3N2 flu was co-circulating. After performing whole-genome deep sequencing on those samples, the researchers estimated within-host genetic diversity by mapping polymorphic sites onto the consensus genome assembly and generating a list of SNVs. From this, they noted that within-host genetic diversity was higher for H3N2 than it was for H1N1/2009.

Three antigenic sub-lineages of H3N2 were circulating within the sample, as were three clades of H1N1/2009, they said, noting that one patient had a mixed infection of both seasonal and pandemic flu. They added that finding such a case within their small sample suggests that co-infections of different flu strains may not be that rare.

Mixed infections of different lineages of the same strain were more common. By comparing SNVs shared both within and between households, the researchers found that about two-thirds of the H3N2-infected patients and 40 percent of the H1N1/2009-infected patients likely harbored mixed lineage infections. Patients, they noted, often carried a dominant haplotype belonging to one viral lineage, but also a minor haplotype that reflected a separate lineage.

This, Ghedin and her colleagues added, suggests that a number of the SNVs they observed aren't de novo mutations, but are mutations shared across the community.

These mutations also seem to be shared across seasons, they added. By comparing antigenic hemagglutinin consensus sequence data from GenBank and the human 2008 H3 sequences, they found an increase in the frequency of specific nucleotides at some variant positions in subsequent seasonal H3N2 epidemics.

These minor variants can also help infer transmission between hosts. For instance, the researchers found that minor variants present in one sample were dominant in a sample obtained at a later date. This increase in frequency, they added, likely reflected a selective advantage within the patient.

The researchers' sample includes 21 pairs from the same household in which the flu was passed from one person to the other. Within these pairs, Ghedin and her colleagues found that most variants present in the donor were also present in the recipient — and often at similar relative frequencies, suggesting a lack of a genetic bottleneck at transmission.

For example, for H1N1/2009, a donor variant present at a frequency of 10 percent has a 64 percent chance of being transmitted to the recipient, the researchers reported, while for H3N2, a donor variant present at a frequency of 10 percent has an 86 percent chance of being passed on.

Based on this, the researchers further calculated that an effective population size of a mean 192 viral particles for H1N1/2009 and a mean of 248 viral particles for H3N2, by one estimation, is passed between host and recipient.

"The combination of unique data, sequencing approaches, and mathematical methods create a nuanced picture of the transmission of diversity during a pandemic," co-author Benjamin Greenbaum, from the Icahn School of Medicine at Mount Sinai, added.