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Concurrent H5N1 Aquistions Challenge Basic Genetic Tenet

Recombinomics Commentary 14:23
May 9, 2008

The recent update on the current acquisition of the same genetic change (single nucleotide polymorphism – SNP) on multiple H5N1 clade 2.2 genetic backgrounds seriously challenges the basic tenet of influenza genetic which maintains that antigenic drift is due to selection of copy errors made during influenza A replication.  The initial paper cited the acquisition of G743A unto several genetic backgrounds in Russia, Egypt, and Ghana at the same time (early 2007). 

The update demonstrates that the same change appeared in Kuwait and Nigeria in the same time frame and onto additional genetic backgrounds.  Moreover, the update included additional precursor sequences which did not have the change.  The sequences related to the Kuwait acquisition were subsequently reported throughout Europe andthe Middle East in the following months, and public NA sequences confirmed G743A was present in wild bird and poultry isolates in the Czech Republic, multiple distinct sites in Germany, Krasnodar in southern Russia, and Saudi Arabia.

The likelihood that the same change appeared on these multiple genetic backgrounds via de novo copy errors is remote.  The sequences with G743A difference from precursor sequences at 2-6 positions, and the likelihood that the small number changes included G743A by independent copy errors would require an extremely strong selection pressure, but a tracing of the polymorphisms through the sequence database of H5N1 isolates fails to identify the strong selection pressure.

G743A is a synonymous change, so the pressure is not due to a change in the NA protein sequence.  Moreover, G743A has been reported on each of the major H5N1 clades, but is only on a small subset.  These isolates are displayed in the phylogenetic tree in figure 5 of the revised manuscript.  It was initially reported in sequences emerging from China in late 2003, early 2004.  In the north, it was present in sequences from South Korea and Japan, which were precursors to the clade 2.2 sequences subsequently found at Qinghai Lake in the spring of 2005.  However, G743A was also in clade 1, which caused the first reported human cases in Vietnam and Thailand in 2005.  It was subsequently found in clade 2.1 isolates in Indonesia and clade 2.3 isolates in China. However, the isolates with G743A represent a small subset of isolates in each sub-clade.

The small subset also applied to clade 2.2 in 2006.  G743A was almost exclusively in closely related sequences from isolates in southern Germany, Switzerland, and France.  These isolates were in a relatively small geographic area and limited to closely related sequences, even though distinct sequences were co-circulating in the area.  Germany had another sub-clade that was also reported in Denmark, Sweden, and Scotland.  Germany had a third sub-clade found over a wider region in Europe, however none of these published sequences had G743A.  In 2006 there was only one isolate in Nigeria that also had G743A.

However, the distribution of G743A in clade 2.2 isolates dramatically changed in early 2007.  As noted above, it was detected for the first time in Egypt in the Nile Delta in mid-2007 on distinct genetic backgrounds.  At the same time it appeared in Kuwait, Russia, Ghana, and Nigeria and was followed by appending to additional genetic backgrounds in Egypt.  These acquisitions in early 2007 was followed by a dramatic expansion of sequences related to those in Kuwait, which included virtually all sequences in central and western Europe, as well as Saudi Arabia in the Middle East.

Thus, the absence of G743A from most clade 2.2 isolates in 2006, followed by the appearance on most clade 2.2 sequences in 2007 is not easily explained by de novo mutations.  Similarly, the genetic differences between the clade 2.2 isolate acquiring this change precludes expansion of pre-existing sequences which had the change.

Consequently, the “random mutation” basic tenet of influenza genetics has been seriously challenged by the updated data, which point toward the acquisition of single nucleotide changes by recombination. The role of recombination is further supported by the aggregation of single nucleotide polymorphisms, as well as changes in swine and human influenza sequences.

Recombination provides a unifying hypothesis for the observations, which continue to increase as new sequences are released.

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