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Concurrent Acquisition of a Single Nucleotide Polymorphism in Diverse Influenza H5N1 Clade 2.2 Sub-clades
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- Recombinomics, Inc
- US Navy Medical Research Unit 3 (NAMRU-3)
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- Document Type:
- Manuscript
- Date:
- Received 14 July 2007 11:45 UTC; Posted 16 July 2007
- Subjects:
- Biotechnology, Evolutionary Biology and Ecology, Genetics, Microbiology, Bioinformatics
- Abstract:
Highly pathogenic Influenza A H5N1 was first identified in Guangdong Province in 1996, followed by human cases in Hong Kong in 1997 1,2. The number of confirmed human cases now exceeds 300, and the associated Case Fatality Rate exceeds 60% 3. The genetic diversity of the serotype continues to increase. Four distinct clades or sub-clades have been linked to human cases 4-7. The gradual genetic changes identified in the sub-clades have been attributed to copy errors by viral encoded polymerases that lack an editing function, thereby resulting in antigenic drift 8. We report here the concurrent acquisition of the same polymorphism by multiple, genetically distinct, clade 2.2 sub-clades in Egypt, Russia, and Ghana. These changes are not easily explained by the current theory of “random mutation” through copy error, and are more easily explained by recombination with a common source. This conclusion is supported by additional polymorphisms shared by clade 2.2 isolates in Egypt and Germany.
Discussion
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26 votes
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8 comments
Data on multiple polymorphisms in the same gene was presented at the Options VI meeting in Toronto. I will be posting a paper at Nature Precedings shortly, showing those relationships. The HA sequence from the human H5N1 case in Nigeria has one set of polymorphisms from Germany and another from Egypt, in addition to sets of western African polymorphisms. That sequence is probably the best example of multiple clade 2.2 polymorphisms cobbled together in one gene.
H5N1 is a major recycler of polymorphisms.
The swine paper, hdl:10101/npre.2007.385.1, has examples of acquisitions of long stretches of genetic information, but the more common exchanges are between closely related sequences, which have a greater likelihood of infecting the same host, and have longer stretches of identity, which facilitates switching of templates.
The recombination can also be seen in plaque purified clones from samples which give mixed signals, such as the HK49 sequences mentioned in the paper.
The recent submission, doi:10.1038/npre.2007.553.1 has several examples of doubles, triplets, and even quadruple acquisitions. The human HA sequence from Nigeria has two regional markers from Germany, as well as a sub-regional polymorphism.
It also has three sub-Sahara markers and a subset of isolates from Sudan has a fourth polymorphism.
In addition, the sequence has a regional marker from Egypt, as well as a number of sub-regional markers from Egypt.
Several of the newly acquired polymorphisms in the 2007 Egyptian isolates have polymorphisms that trace back to Germany. Although there are polymorphisms from all three German sub-clades, the sub-clade with NA G743A (2.2.2.3) contributes multiple polymorphisms to various sub-clades in Egypt, creating examples of multiple polymorphisms on HA as well as associated polymorphisms on NA.
The publication of the recent (collected September 5, 2007) NA sequence, A/chicken/Krasnodar/300/2007(H5N1), also reveals G743A.
This sequence appears to be similar to the sequence of H5N1 detected in wild birds in Germany this past summer (Tyva/Mongolia/Afghanistan genetic backbone). Thus, G743A appears on yet another clade 2.2 genetic background, providing additional evidence of the acquisition of G743A by a mechanism other than “random mutation”.
The recent clade 2.2 H5N1 infection in Suffolk, England provides additional evidence for the involvement of wild birds in the spread of H5N1 in Europe. The affected population is free-range turkeys which mingle with wild birds on a large ornamental lake on the farm. The recently released OIE report describes the death of 200 turkeys prior to the start of the ongoing cull, indicating the infections were recent since most of the birds died three days ago. The farm has not introduced birds in the past four weeks, further implicating the wild birds that intermingle with the domestic poultry.
However, the most compelling data comes from the sequences of isolates from the farm. Officials from the Department from Environment Food and Rural Affairs have indicated that the H5N1 is most closely related to clade 2.2 isolates from summer outbreaks in wild birds in the Czech Republic and Germany. The German sequences have been described by reports from the Friederich-Loefler Institute. These reports indicate the German isolates are most closely related to isolates from Tyva/Mongolia, which were collected from wild birds dying in a massive H5N1 outbreak in the spring of 2006. Although these isolates are part of a larger group that includes isolates from Afghanistan, which is part of a larger group that includes isolates from Russia, India, Italy, Iran, the Tyva/Mongolia isolates are cluster on a distinct branch of hemagglutinin or neuraminidase (NA) phylogenetic trees.
As noted earlier, a recent isolate from Krasnodar also maps to the Tyva/Mongolai branch, and that isolate also has NA G743A, although this polymorphism was not present in the 2006 isolates from Tyva/Mongolia, or any of the more distantly related isolates from 2006.
The presence of the Tyva/Mongolia clade 2.2 sub-clade in the turkeys in England therefore adds addition support implicating wild birds in the spread of H5N1 in Europe because the vast majority of isolates in this group were from wild birds in Russia, Mongolia, Germany, and the Czech Republic.
The paper, “Phylogenetic analyses of highly pathogenic avian influenza virus isolates from Germany in 2006 and 2007 suggest at least three separate introductions of H5N1 virus” by Starik, et al, doi:10.1016/j.vetmic.2007.10.012 includes detail on three isolates collected in Germany during the summer of 2007. A/Cygnus olor/Germany/R1349/07 is from the south, A/Cygnus olor/Germany/R1359/07 is from central Germany, as is A/Podiceps nigricollis/Germany/R1393/07. The paper includes a phylogenetic tree which shows all three sequences clustering together. However each sequence is distinct, supporting independent introductions by wild birds. The sequences are most closely related to A/grebe/Tyva/Tyv06-02/2006, which was isolated from the massive wild bird outbreak in and around Uva Lake in Mongolia in 2006.
The location on the tree is virtually identical to A/chicken/Krasnodar/300/2007 isolated September 5, 2007. Based on comments by DEFRA, all of these sequences will be closely related to H5N1 in the Czech Republic, France, and England. They will likely have NA G743A, which was appended onto at least seven genetic backgrounds in 2007, including the Krasnodar isolate.
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- This document is licensed to the public under the Creative Commons Attribution 2.5 License
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Niman, Henry and Boynton, Bruce. Concurrent Acquisition of a Single Nucleotide Polymorphism in Diverse Influenza H5N1 Clade 2.2 Sub-clades. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2007.459.1> (2007)
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NS Unis on 16 July 2007 10:42 UTC
A viable explanation.
I look forward to additional data confirming this mechanism and a broader analysis of polymorphisms occuring in pairs and triplets across gene segments.