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Concurrent H5N1 Aquistions Confirmed and Extended

Recombinomics Commentary 06:18
May 9, 2008

The earlier report on the concurrent acquisition of the same polymorphism in three distinct locations, Egypt, Russia, and Ghana, has been confirmed and extended in the latest version, available at Nature Precedings.  The initial report described the acquisition of NA polymorphism G743A on a variety of clade 2.2 (Qinghai strain) genetic backgrounds.

In February, 2007 H5N1 outbreaks in Egypt was being closely monitored.  A few months earlier the Gharbiya cluster was reported.  Three family members died and the H5N1 sequences had two receptor binding domain changes (V223I and M230I) as well as Tamiflu (oseltamivir) resistance, N294S.  Consequently, H5N1 surveillance was enhanced.  Three sequences from chickens in Gharbiya were collected in mid-February and all three sequences had G743A.  This change was of interest because it had not been seen previously in any of the isolates from Egypt. 

One of the February sequences was closely related to the Gharbiya sequences, while the other two mid-February sequences were distinct and closely related to H5N1 collected in the summer of 2006.  Although these two sets of sequences were quite distinct, both had acquired the same polymorphism, G743A.

The sample that was closely related to Gharbiya was cloned (plaque purified) because the initially sequences had some mixed signals.  The cloning confirmed that the chicken was infected by two major H5N1 species.  The dominant strain was closely related to the Gharbiya cluster, while the minor species matched the other two mid-February sequences.  Thus, although there were two distinct sequences in the same host, both sequences had acquired G743A.  Two distinct sequences acquiring the same change at the same time was not easily explained by random mutations, the current explanation for the genetic drift prevalent in influenza evolution.

The random mutation explanation was further challenged by an outbreak in Moscow, which was also in mid February.  Sequences from that outbreak were released and those sequences were quite distinct from the clade 2.2.1 sequences in Egypt.  The Moscow sequences were clade 2.2.3 and were most closely related to 2006 sequences from Azerbaijan.  However, like the changes in Egypt, the 2007 sequences in Moscow had also acquired G743A.

Shortly after the outbreaks in Egypt and Russia, Ghana reported its first H5N1 outbreak.  The sequences from Ghana were closely related to sequences from an outbreak in the Ivory Coast at the end of 2006.  These sequences were quite distinct from the clade 2.2.1 in Egypt or the clade 2.2.3 in Russia, but the Ghana sequences had also acquired G743A. 

Moreover, in March there were additional outbreaks in Egypt that were distinct from the sequences in Gharbiya.  The sequences were from patients in southern Egypt and were closely related to earlier sequences from southern or central Egypt, yet those sequences had also acquired G743A.

Thus, the concurrent acquisition of G743A onto multiple genetic backgrounds in three distance location in Russia, Egypt, and Ghana was the basis for the original report in the summer of 2007.

However, in the past several months additional sequences from earlier outbreaks have been released.  In mid-February there was also an outbreak in Kuwait.  The sequences in Kuwait were clade 2.2.3, but were distinct from the sequences in Moscow.  The Kuwait sequences were closely related to sequences from Uvs Lake, which led to a massive die off of wild birds in the summer of 2007.  That strain was subsequently linked to the outbreak in South Korea at the end of 2006 as well as Japan at the beginning of 2007.  The sequences from Uvs Lake and South Korea did not have G743A, yet the mid-February outbreak in Kuwait did have G743A, showing that G743A had been appended onto yet another genetic background.

The outbreak in Kuwait was followed by outbreaks in Europe in the summer of 2007.  The sequences from domestic and wild birds in the Czech Republic have been released as have sequences from wild birds at multiple locations in Germany.  All NA sequences had G743A and all were the Uvs Lake strain.  Sequences from Krasnodar were also released from wild and domestic birds and those sequences were also the Uvs Lake strain and had G743A.

Similarly, in early 2007 there were outbreaks in Nigeria.  These sequences were distinct from those in Ghana, yet a subset of these sequences also had G743A.

Thus, these latest sequences confirm and extend the earlier observations.  In addition to Russia, Egypt, and Ghana, Kuwait and Nigeria also had H5N1 outbreaks that included the acquisition of G743A.

In each of the examples above, precursor sequences were reported that lacked G743A.  The 2007 sequences had acquired 2-6 changes, and in each case one of these small numbers of changes was G743A.  Explaining these acquisitions by random mutation is difficult, yet that is the current dogma used to explain H5N1 evolution.

The data is much more easily explained by recombination with a common source that had G743A.

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