Newswise — In this week's journal Nature, senior author Steven Salzberg, professor and director of the Center for Bioinformatics and Computational Biology at the University of Maryland, and his co-authors report the first-ever large-scale sequencing of 209 complete genomes of influenza A, the ever-changing virus that makes humans sick with the "flu."
It is a technique the authors think can significantly reduce the guesswork scientists have had to rely on to predict which virus will emerge as the dominant player in approaching flu seasons.
"This is the first-ever large-scale project to sequence the influenza virus," said Salzberg. "It is already giving us remarkable new insights into the rapid evolution of the flu as it moves through the human population."
In these initial results for the Influenza Genome Sequencing Project, the authors also discovered the mutations that produced a surprise flu strain in 2003 that led to the mis-match of the season's flu vaccine with the season's dominant flu virus.
The Influenza Genome Sequencing Project is a joint project of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and several scientific partners, to help researchers understand how flu viruses evolve, spread and cause disease. The project is headquartered at The Institute for Genomic Research (TIGR), where it is led by Elodie Ghedin of TIGR.Until now, viruses have been analyzed by serotyping, an imprecise technique that can't keep track of influenza A's rapid genetic changes, a viral survival skill that makes it difficult for scientists to prepare an effective vaccine for coming flu seasons.
"Our sequencing project will help create a new, far more detailed surveillance system for the flu, to help decide which vaccine will be the right one from year to year," said Salzberg, who also holds an adjunct appointment at TIGR. "It promises to give us a more comprehensive picture of the pattern of transmission through human and animal populations." Shape Shifters
It is the ability of influenza A to change rapidly, or mutate its genetic code, that makes it so dangerous. The virus mutates from year to year, making it necessary to update flu vaccines annually. Less frequently, but with deadly outcomes, the virus goes through a major change called an antigenic shift, creating new strains to which humans have no immunity. This happens when two distinct flu strains exchange genes and is especially deadly when the exchange occurs between human and bird flu. The result can be a world wide pandemic, like the Spanish Flu of 1918, the 1957 Asian Flu, or the 1968 Hong Kong Flu.
Health experts are worried that another major pandemic caused by avian influenza may be looming on the horizon. "The H5N1 strain of the virus in birds has already sickened people in Asia," said Salzberg, "and the greatest concern is that it will mutate to become easily transmissible between humans."
Freeing Scientific Data
One unusual aspect of the project was that the authors released all of the sequence data immediately. A September 22 article in Nature criticized the U.S. Centers for Disease Control (CDC), for "hoarding" influenza data, not making it generally available to researchers.
"All of the sequences described in the NIAID project are rapidly being deposited in public sequence databases," Salzberg said. "We realize there is a chance that other scientists could 'scoop' us on our own data, but this data is too valuable for anyone to sit on.
"Our sequencing project will help create a new, far more detailed surveillance system for the flu, to help decide which vaccine will be the right one each year," said Salzberg. "It promises to give us a more comprehensive picture of the pattern of transmission through human and animal populations." Random Samples
Unlike previous analyses of influenza A, which have concentrated on samples pre-selected for virulence or unusual characteristics, Salzberg's team focused on random samples from New York state that spanned several years, a collection that showed what was actually thriving and changing in the general population.
What they found, says Salzberg, "was a surprising genetic diversity which showed that even in a geographically constrained population, there are a variety of influenza strains and there is potential for exchange between them that may be greater than previously suspected."
They also found clues to why the vaccine for the 2003-04 virus was not as effective as predicted. The sequencing revealed several distinct groups of viruses, or clades, circulating around the sample population. During the 2002-03 flu season, one of the minor clades contributed a gene to the dominant virus for that year. This new re-assortant strain rapidly took over, and became the dominant virus in the '03-04 season, and, because the flu itself had changed, the vaccine that season was ineffective.
"This finding shows that minor lineages can contribute genetic variation to the dominant lineage, creating an antigenically novel strain that the vaccine won't work against," said Salzberg. "In contrast to serologically-based sampling, yearly sequencing could reveal these co-circulating strains even before they mutate into a new strain.
"With large scale sequencing, we can get a good picture of what is evolving," said Salzberg. "The goal is to sequence thousands of influenza genomes, including avian influenza. By making the data public immediately, we can speed up the process of understanding how the virus is mutating all over the world."
Online version of the paper, "Large-scale Sequencing of Human Influenza Reveals the Dynamic Nature of Viral Genome Evolution" - http://www.nature.com/index.html
Links: More on the Influenza Genome Sequencing Project: http://www.tigr.org/msc/infl_a_virus/infl_a_virus.shtml
CBCB website: http://www.cbcb.umd.edu/
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