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Commentary
Spontaneous Mutation
Media Myth
Recombinomics
Commentary 07:39
November 24, 2009
The above comment from the WHO briefing on D225G (aka D222G) in Norway describes how the "mutations appear". However, this appearance is based on an outdated view of influenza evolution, which maintains that all newly acquired drift "mutations" are based on copy errors. For D225G, this would require the same copy error to occur again and again on multiple backgrounds, which simply is not reality based.
Although the "random mutation" explanation is one of the basic tenets of the WHO and CDC view of influenza evolution, this explanation is only viable in the absence of data. Extensive influenza sequence data moved this hypothesis into the indefensible category years ago, but it remains at the core of WHO explanations of drift variants, such as the comments above.
The "random mutation" and failure to spread would require each detection to be an independent event. Thus, in Norway, the same copy error would have been made in each of the three patients with D225G. Similarly, the same error would be required for each of the four fatal cases in Ukraine. Moreover, the same error would be made in the vaccine target, A/California/7/2009, because one of the 2:6 reassortants also had D225G. As the number of sequences with D225G increases, the likelihood that the same error happens again and again, among a very small number of differences (for HA in Ukraine, the only non-synonymous change was D225G), becomes untenable.,
The appearance of D225G on multiple genetic backgrounds of H1N1 parallels the sudden appearance of H274Y on multiple backgrounds of pandemic H1N1, which follows the same scenario of H274Y on multiple seasonal flu backgrounds in patients not taking Tamiflu. The acquisition of H274Y was readily explained by recombination, which led to the acquisition of key changes that were on clade 2C and then jumped to a clade 2B background. In addition to the H274Y jump to seasonal flu in patients not taking Tamiflu, silent changes were also observed, which also discounted heavy selection pressure favoring these changes.
For D225G, the change was present in one of the earliest isolates in the United States. It could jump from one background to another via recombination between sequences that are closely related. As a result, the new acquisitions lead to a new single nucleotide polymorphism, which looked like a point mutation, but was really recombination between closely related sequences.
Thus, both H274Y and D225G move from one genetic background to another via recombination. A new spontaneous mutation is not required for each isolate and the same sequence in a given area is just due to clonal expansion of an isolate with the new acquisition. This could be seen in the sequences from Ukraine. The Ternopil isolates had a marker found in all Ternopil isolates, including those from nasal washes that did not have D225G. The receptor binding domain change was appended onto this background. The same change was also on Lviv sequences from fatal cases which did not have the Ternopil marker. Thus, D225G moved from a Lviv to a Ternopil background via recombination (or vice verse). Moreover, the frequent jumping of the same polymorphism from one background to another allowed fro the prediction that D225G would be found on the Ukraine sequences. This type of concurrent acquisition has also been described for a silent mutation in H5N1, which again would be widespread in the absence of an obvious clear selection pressure.
Thus, the movement of the same polymorphism via recombination is common. It explains the sudden appearance of the same marker on multiple genetic backgrounds, and forms a basis for predicting changes.
However, the reliance on a "random mutation" produces "surprise after surprise" among influenza "experts" and creates "appearances" such as spontaneous mutations and lack of transmission which are not based on reality.
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