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Novel H5N1 Bird Flu Cleavage Site in Sudan

Recombinomics Commentary

August 1, 2006

The HA sequences from isolates in Sudan (A/chicken/Sudan/1784/2006, A/chicken/Sudan/2115-9/2006, A/chicken/Sudan/2115-12/2006) were recently deposited at Genbank.  All three isolates are closely related to each other, but distinct from other Qinghai HA sequences, indicating they were independently introduced in Sudan.  Like other recent isolates, the sequences hold a number of informative polymorphisms. 

Eleven such changes are shared by the three sequences from Sudan.  Two changes, A196G and C1261T, are shared with about half of the Qinghai isolates.  Three other polymorphism, A433G, G643A, and A1708G, are shared with isolates from Kurgan, Nigeria, and the Ivory Coast.  One polymorphism, T1090G, is shared with all three isolates from the Crimea.  Two others, C613T and C694T, are found in grebe or duck isolates from Novosibirsk.  Three other polymorphisms, A1049G, G1648A, and A1684C are not found in other Qinghai isolates.

The A1049G change creates a novel HA cleavage site.  The most common HA cleavage site in H5N1 from Asia is RERRRKKR.  This cleavage site was first reported in a 1996 Guangdong goose and was also in the 1997 human H5N1 isolates in 1997.  this cleavage site is in most H5N1 isolates, including the Karo cluster in Indonesia.

The Qinghai isolates however, generally have a cleavage site of GERRRKKR.  This cleavage site was initially reported in Hong Kong geese, but more recently was in H5N1 from poultry in Hubei in 2004 or migratory birds from Jiangxi in 2005.  However, these isolates did not include the PB2 E627K change, which was first identified in Qinghai isolates at Qinghai Lake in 2005.  This strain infected long range migratory birds, which transmitted and transported the strain to India, Afghanistan, Europe, the Middle East and Africa.

Another related cleavage site REGRRKKR had also been detected in Hong Kong waterfowl in 2000, but more recently in tree sparrow sequences in Henan.  The Henan isolates had clear examples of recombination.

The Sudan isolates have a novel cleavage site of GEGRRKKR, which includes the characteristic "G" at the first position of the Qinghai strains, and a G at the third position, as reported for the tree sparrow sequences from 2004.  The novel cleavage sit has not been reported for any other sequence at Los Alamos or Genbank.

Changes in the HA cleavage site may affect tissue tropism.  Most of the human sequences from Indonesia have another novel HA cleavage site, RESRRKKR.  This sequence has been reported in human and cat sequences from Indonesia.  One isolate, Indonesia/5/05, was used in recent reassortment experiments.  These experiments by CDC scientists, used a ferret model.  The human sequence from Indonesia produced detectable H5N1 in the upper respiratory tract of the ferrets, indicating the human sequence had evolved to become more fit in mammals, although this evolution did not involve reassortment.  The human sequence also had a novel glycosylation site.

These changes do not involve mutations deemed "significant" by the WHO and consultants.  However, the changes within the H5N1 have produced an H5N1 that is more likely to be transmitted because H5N1 is in the upper respiratory tract.  These data indicate that more subtle genetic drift is driving H5N1 bird flu evolution.  Analysis of newly acquire polymorphisms, like the novel cleavage site in Sudan, have discordance with other recently acquire Qinghai polymorphisms, indicating H5N1 is evolving by recombination and not via random mutation.

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