Commentary
Slippery Slope of New Biology of Recombination in Influenza
Recombinomics Commentary 19:07
June 26, 2008
we found many sequences in the database that show very strong apparent evidence of homologous recombination. As a rough test for this, we divided the nucleotide sequence of each segment into two equal halves. For each pair of segments, we compared the number of nucleotide differences between them in the first half (i.e. 5’ in the positive strand) with the number of nucleotide differences in the second half. The idea is that if two segments are nearly identical in one part of their sequence, but very different in another part, this is strong evidence of homologous recombination, with the divergent parts explained by a recombination event.
The above comments are from the paper, “Anomalies in influenza genome database: New biology or lab errors?” Like an earlier paper, “Homologous recombination is very rare or absent in human influenza A virus”, the presence of sequences with clear cut recombination are acknowledged, but the papers try to link the examples to lab artifacts, suggesting re-sequencing of sequences with clear recombination, using the rationale that contaminated sequences will yield sequences with different cross-over points, which will reveal the contamination.
However, the sequence database includes similar sequences with matching crossover points, which provide a more rigorous proof of true homolgous recombination, because a lab artifact would require that all matching sequences are contaminated with the same sequences and the amplification process results in identical cross over points. Thus, these sequences alone would eliminate the issue of contamination.
In addition to multiple sequences that match, the database also has examples of re-sequenced samples, and the re-sequence result exactly matches the initial sequence. Thus, there are now many examples of homologous recombination which is not explained by sample contamination.
The cited sequences have dramatic examples of recombination between divergent sequences. However, template switching would be more common in sequences that are closely related and co-infections are more likely to involve closely related sequences. Thus, the presence of homologous recombination between distantly related sequences would support more frequent recombination between closely related sequences. These recombinations would appear as single nucleotide polymorphisms, which are linked to antigenic drift which is thought to be due to de novo mutations resulting from copy errors.
Examples of concurrent acquisition of the same polymorphism onto divergent genetic backgrounds, as well as aggregation of diverse polymorphisms into the same gene, provide examples of movement of single nucleotide polymorphisms via recombination, which serious challenges the basic tenet of influenza evolution.
Thus, the recent paper on recombination in avian and swine influenza, like the earlier paper on recombination in human influenza, signals the demise of the role of random mutations in rapid influenza evolution.
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