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Basic Tenet of H5N1 Evolution Challenged By G743A Acqusitions

Recombinomics Commentary
April 26, 2007

The simultaneous appearance of NA G743A has provided evidence to shake one of the basic tenets of influenza evolution, genetic drift via random mutations selected through adaptation.  The tracing of the polymorphism identifies the change on a variety of H5N1 genetic backgrounds, beginning with the outbreaks in South Korea and Japan in 2003/2004.  It then appeared in Clade 1 isolates in southeast Asia in 2004 followed by Clade 2.1 and 2.3 in Indonesia and China in 2005 (see list here).  This type of movement of polymorphisms is not uncommon and was present in a number of recent isolates in Egypt.

The recent isolates in Egypt created a large sequence data base with a significant temporal component.  The sequences in the 2006/2007 season were more genetically complex than 2006 and these new changes created new branches on the phylogenetic tree.

The detection of NA G743A in clade 2.2 Qinghai isolates was reported for a large number of isolates in Germany in February, 2006.  These sequences represented yet another jump of G743A, and these jumps became increasingly hard to explain by random mutation.  The short time between detection of G743A on one genetic background and its appearance on another background could be explained by an early precursor that evolved into several directions and its presence was simply detected simultaneously.

However, the recent series of sequences in Egypt create significant problems for the above explanation.  The sequences in Germany had additional HA and NA markers that produced distinct branches in the phylogenetic tree.  The isolates in Egypt did not have the regional markers found in Germany, which eliminated explanations involving modification of the full German Qinghai sequences to generate the Egyptian sequences.

Moreover, the earlier 2006/2007 sequences in Egypt formed separate branches prior to the G743A acquisitions,  The first isolate with G743A was collected February 15, 2007, when it was detected in 3 chicken isolates from Gharbiya. One of these isolates was closely related to the sequences from the Gharbiya cluster patients who died in December.  The other chicken isolates were similar to other bird isolates from the Nile Delta.  However, although these earlier isolates had a full compliment of Egyptian Qinghai markers, they did not have G743A.

The same was true in a series of more recent human isolates.  Isolates from siblings in Qena had polymorphisms that matched other isolates from central Egypt, including a 3 BP deletion on the HA sequences.  Thus, the earlier isolates form yet another readily distinguishable branch on the tree of Egyptian Qinghai isolates. The earlier isolates, collected from patients infected at the beginning of 2007 did not have G743A, yet the recent patients did.

Similarly, G743A was also reported on H5N1 isolates in Moscow in mid February, 2007.  The Moscow sequences were on a branch of the tree with 2006 isolates from Azerbaijan.  Once again the G743A polymorphism was appended onto isolates that formed distinct branches, which prior to February, 2007 did not have any isolates with G743A.

The simultaneous acquisition of G743A on multiple Qinghai genetic backgrounds is most easily explained via acquisition of the polymorphism from a common source, which would be migratory birds with the change.  Recombination between closely related sequences is conceptually easy to explain and the examples of discordance between Qinghai isolates are numerous.

This, although the evolution of H5N1 via acquisition of polymorphism through recombination is common, the simultaneous appearance of G743A creates significant problems for the random mutation explanation of influenza evolution, and questions the importance of such a mechanism in rapidly evolving genomes.

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