Non-random reassortment in human influenza A viruses - PubMed (original) (raw)

Non-random reassortment in human influenza A viruses

Raul Rabadan et al. Influenza Other Respir Viruses. 2008 Jan.

Abstract

Background: The influenza A virus has two basic modes of evolution. Because of a high error rate in the process of replication by RNA polymerase, the viral genome drifts via accumulated mutations. The second mode of evolution is termed a shift, which results from the reassortment of the eight segments of this virus. When two different influenza viruses co-infect the same host cell, new virions can be released that contain segments from both parental strains. This type of shift has been the source of at least two of the influenza pandemics in the 20th century (H2N2 in 1957 and H3N2 in 1968).

Objectives: The methods to measure these genetic shifts have not yet provided a quantitative answer to questions such as: what is the rate of genetic reassortment during a local epidemic? Are all possible reassortments equally likely or are there preferred patterns?

Methods: To answer these questions and provide a quantitative way to measure genetic shifts, a new method for detecting reassortments from nucleotide sequence data was created that does not rely upon phylogenetic analysis. Two different sequence databases were used: human H3N2 viruses isolated in New York State between 1995 and 2006, and human H3N2 viruses isolated in New Zealand between 2000 and 2005.

Results: Using this new method, we were able to reproduce all the reassortments found in earlier works, as well as detect, with very high confidence, many reassortments that were not detected by previous authors. We obtain a lower bound on the reassortment rate of 2-3 events per year, and find a clear preference for reassortments involving only one segment, most often hemagglutinin or neuraminidase. At a lower frequency several segments appear to reassort in vivo in defined groups as has been suggested previously in vitro.

Conclusions: Our results strongly suggest that the patterns of reassortment in the viral population are not random. Deciphering these patterns can be a useful tool in attempting to understand and predict possible influenza pandemics.

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Figures

Figure 1

Figure 1

Hamming distance in third codon position between human H1N1 influenza strains (237 cases of human H1N1 from 1977 to 2006) in segment 1 versus segment 3. The red line is the best line fit to the data.

Figure 2

Figure 2

Hamming distance in third codon position between human H3N2 influenza strains in the New York state (208 sequences from 2000 to 2003) in segment 1 versus segment 2. In red are the pairs of sequences that contain A/New York/11/2003(H3N2).

Figure 3

Figure 3

Hamming distance in third codon position between human H3N2 influenza strains in the New York state (208 sequences from 2000 to 2003) in segment 1 versus segment 2. If we create new segments by randomly permuting the third codon positions of both segments together, we create a new distribution (in red is one example). If there are no reassortments the permuted distribution and the real one should be similar (around the diagonal).

Figure 4

Figure 4

The evolutionary rate in different segments is similar if we take into account the changes in third codon positions. In this figure is represented the Hamming distance in third codon position between every pair of viruses found in New York State between 1995 and 2006 (581 sequences). On the left is shown the distance in third codon position in segment 1 versus segment 4, and on the right segment 2 versus segment 4. It can be appreciated that most of the points are along the slope 1 line, indicating similar rates between the different segments.

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