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Swine Recombinants Destroy Influenza Genetics Basic Tenets
March 23, 2006
The recent Canadian swine H1N1 and H1N2 sequences have many examples of recombination as indicated earlier. However, a more detailed analysis of these sequences identifies a series of recombinations that effectively destroys the two basic tenets of influenza genetics which define genetic drift and shift. Genetic drift is said to be due to random mutations introduced by a “sloppy” polymerase which poorly replicates the eight gene segments of influenza. Genetic shift is said to be due to whole genes being swapped when a host is infected with two distinct flu strains. Although transcription errors do become fixed in circulation viruses and the viral genes do reassort during dual infections, the gene changes that are seen on an annual basis are largely due to recombination. The recombination can produce small changes such as single nucleotide changes (creating drift) or can swap large portions of individual genes (creating shift).
The recombination was readily seen in the recent swine isolates because full gene sequences of all eight segments were made public, and the recently released sequences not only had portions of genes that exactly matched prior isolates, but they also have portions of genes that exactly matched other recent isolates. These relationships were particularly striking and obvious in the PB2. Some of the acquisitions of portions of previously described isolates was delineated earlier. However, most of the portions of genes that did not match earlier isolates did match the current isolates.
One example was the parings in the PB2 gene of 11112 and 23866. The two genes matched each other in the first and last third of the sequence. However, most of the middle third of 23866 matched the 1977 sequence from the swine isolate from Tennessee, while the middle third of 11112 match the 1998 swine isolate from North Carolina.
Another example was the parings of the PB2 gene of 56626 and 53518. The genes matched each other for the first 550 BP, but the remainder of the 53518 sequence matched the 2002 sequence from Taiwan. In 56626 the middle 1000 BP matched the same region in 57561 and the region that was an exact match between the two recent isolates also contained the core region that matched the 1977 Tennessee sequence.
The third example was the pairings between 48235 and 55383. The first 1850 BP in the two sequences were exact matches, but this region also included over 1600 BP that also were an exact match of the 1977 Tennessee sequence.
Thus, these pairing clearly showed that the PB2 genes were generated by a series of recombinations involving large portions of the genes which constituted genetic shifts. Moreover, the identity of large positions of genes between isolates from 2003 or 2004 and 1977 indicated that the polymerase could copy the sequences with a high degree of fidelity, producing an exact match between isolates that were at least 26 years apart.
As noted earlier, the same 1977 isolate from Tennessee contributes large portions of the PA genes found in six of the seven isolates. The remaining avian genes have additional examples of easily identifiable recombination.
The swine sequences evolved slowly, preserving the identity of sequences acquired earlier via recombination. These large acquisitions can also be found in more rapidly evolving avian sequences, although the multiple sets of recombination reduces the size of the acquisitions. Moreover, in many instances the region that was expected to contain newly acquired sequences was missing from the sequence database. Full sequences of these isolates including H5N1 bird flu, would produce additional examples of recombination.
There also appear to be more instances of acquisitions of smaller regions which frequently have a high degree of identity, so the acquired new sequence may be limited to a single nucleotide change. The recombinant nature of these smaller differences can be traced to the same parent contributing new genetic information to multiple locations with a gene segment or acquisitions of new genetic information in multiple segments.
These two types of recombination account for the vast majority of the year to year changes in related influenza genes.