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1918 RBD D225G in Lung Cases in Ukraine and Norway
Recombinomics Commentary 11:29
November 21, 2009

For the two 1918 HA variants, the South Carolina (SC) HA (with Asp190, Asp225) bound exclusively alpha2-6 receptors, while the New York (NY) variant, which differed only by one residue (Gly225), had mixed alpha2-6/alpha2-3 specificity, especially for sulfated oligosaccharides.

The above description is from a paper analyzing receptor binding domain differences in sequences from the 1918 pandemic.  The New York variant had D225G, the same change found in lung tissues from fatal swine H1N1 sequences in Brazil, Ukraine, and Norway.  The above result clearly demonstrated a change in receptor specificity for D225G, which was present in A/New York/1/1918 and A/London/1/1919, demonstrating the same change I 1918 that has been described in 2009.  Although WHO stated that this change was "not significant" in the Ukraine samples, it was associated with the fatal cases and is cause for concern.  The concern was increased by the announcement from Norway indicating the same change was found in fatal H1N1 lung infections there also.

Although there have been comments that this change was "spontaneous" and did not spread, the finding of the same change in all four deceased patients in Ukraine from two distinct locations, indicates it did spread, as did the finding of the same change in multiple cases in Brazil and Norway.  Although the concept of "random mutation" has been used to explain away the sudden appearance of the same polymorphism on multiple backgrounds, the appearance via recombination is a much stronger argument for the same change to appear at multiple locations at the same time.

The spontaneous mutation theory, which is the foundation of WHO policy and statements on significance of changes relies heavily on a "selection" component, arguing that the same change keeps appearing on different backgrounds because of string selection pressure.  However, this same phenomenon was described for a silent mutation on H5N1, which offers no clear selection pressure.  Similarly, a silent change was also found in seasonal H1N1 in sequences that had acquired the Tamiflu resistance marker, H274Y.  Thus, these silent (synonymous) changes string argue against a coincidental spontaneous mutation, and instead argue that this acquisition is concurrently acquired because of a widespread common donor.

The concept of acquisition via recombination has serious implications for the current pandemic.  It was used to predict the D225G change, in part because the change was "in play" and appearing in July/August sequences at increasing frequency, even though the H1N1 sequences represented different genetic backgrounds.  Similarly the clusters of Tamiflu resistance in Wales and North Carolina are also driven by recombination, as happened when the identical change was acquired in H1N1 seasonal flu in patients who were not taking Tamiflu (oseltamivir).

Thus, the concept of recombination predicts that the D225G receptor binding domain change, and the H274Y Tamiflu resistance change, which continue to spread via recombination

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