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Recombination in the Gharbiya Cluster in Egypt
Recombinomics Commentary
January 23, 2007

The NA sequences from the Gharbiya cluster were released today at Genbank.  NAMRU-3 has released NA sequences from two family members from the Gharbiya cluster (A/Egypt/14724-NAMRU3/2006 and A/Egypt/14725-NAMRU3/2006), as well as from the first case this season (A/Egypt/12374-NAMRU3/2006), who died October 30, 2006.  This patient was also from Gharbiya, 12 miles north of the cluster.

The Gharbiya cluster was described in a WHO update, because H5N1 NA sequences from the two fatal cases had the Tamiflu resistance polymorphism, N294S.  This polymorphism has been identified in a patient in Vietnam who was initially treated with a maintenance dose of Tamiflu, 75 mg / day.  She improved and recovered when the dose was increased to 2 X 75 mg / day.  H5N1 from this patient had three readily detected versions of H5N1.  One sequence was wild type with regard to NA positions 274 and 294. Three clones had N294S, while six clones had H274Y.  H274Y has subsequently been isolated from several patients in Vietnam as well as one patient in Indonesia (from the Karo cluster).  Prior to the Gharbiya cluster, N294S had not been isolated from H5N1 patients in the absence of H274Y.  However, N294S has been identified in ducks in Zheijang and Hong Kong, raising the possibility that N294S is present in birds in Egypt, and was acquired via recombination that placed this polymorphism of an Egyptian Qinghai genetic background.

The NA sequences from the Gharbiya cluster provide additional evidence for acquisition of polymorphisms via recombination.  Recently the HA sequences from the cluster were released.  The HA sequences had the M230I polymorphism previous identified in the earlier sequence from Gharbiya.  However, both cluster sequences also had V223I, a receptor binding change that had previously been identifies in a Qinghai sequence from a bar-headed goose in Mongolia, as well as several geese sequences from Shantou.

The NA sequences have additional polymorphisms not found in the earlier sequence from Gharbiya.  In addition to N294S, the sequences have M29I in the NA sequences.  This polymorphism is also present in the same Shantou geese that have HA V223I.

The presence of two polymorphism in two genes that are shared by a common source provide additional evidence for the acquisition of polymorphisms via recombination.  The NA sequences are clearly Qinghai sequences, but have a number of additional polymorphisms that are closely linked to the Egyptian isolates from this season and last season, including C150A, C236A, A703G, G743A, T1088C, and G1281A.  Overlaid onto this genetic background are several newly acquired changes, including the non-synonymous changes that create N294S as well as M29I. 

The presence of NA M29I and HA V223I in both Gharbiya cluster members as well as the geese from Shantou indicates theses acquisitions are far from random.

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