Molecular Biology and Evolution, Vol 16, 1457-1465, Copyright © 1999 by Society for Molecular Biology and Evolution
RM Bush, WM Fitch, CA Bender and NJ Cox
The hemagglutinin (HA) gene of influenza viruses encodes the major surface
antigen against which neutralizing antibodies are produced during infection
or vaccination. We examined temporal variation in the HA1 domain of HA
genes of human influenza A (H3N2) viruses in order to identify positively
selected codons. Positive selection is defined for our purposes as a
significant excess of nonsilent over silent nucleotide substitutions. If
past mutations at positively selected codons conferred a selective
advantage on the virus, then additional changes at these positions may
predict which emerging strains will predominate and cause epidemics. We
previously reported that a 38% excess of mutations occurred on the tip or
terminal branches of the phylogenetic tree of 254 HA genes of influenza A
(H3N2) viruses. Possible explanations for this excess include processes
other than viral evolution during replication in human hosts. Of particular
concern are mutations that occur during adaptation of viruses for growth in
embryonated chicken eggs in the laboratory. Because the present study
includes 357 HA sequences (a 40% increase), we were able to separately
analyze those mutations assigned to internal branches. This allowed us to
determine whether mutations on terminal and internal branches exhibit
different patterns of selection at the level of individual codons.
Additional improvements over our previous analysis include correction for a
skew in the distribution of amino acid replacements across codons and
analysis of a population of phylogenetic trees rather than a single tree.
The latter improvement allowed us to ascertain whether minor variation in
tree structure had a significant effect on our estimate of the codons under
positive selection. This method also estimates that 75.6% of the nonsilent
mutations are deleterious and have been removed by selection prior to
sampling. Using the larger data set and the modified methods, we confirmed
a large (40%) excess of changes on the terminal branches. We also found an
excess of changes on branches leading to egg-grown isolates. Furthermore, 9
of the 18 amino acid codons, identified as being under positive selection
to change when we used only mutations assigned to internal branches, were
not under positive selection on the terminal branches. Thus, although there
is overlap between the selected codons on terminal and internal branches,
the codons under positive selection on the terminal branches differ from
those on the internal branches. We also observed that there is an excess of
positively selected codons associated with the receptor-binding site and
with the antibody- combining sites. This association may explain why the
positively selected codons are restricted in their distribution along the
sequence. Our results suggest that future studies of positive selection
should focus on changes assigned to the internal branches, as certain of
these changes may have predictive value for identifying future successful
epidemic variants.
ORIGINAL ARTICLE
Positive selection on the H3 hemagglutinin gene of human influenza virus A
Department of Ecology and Evolutionary Biology, University of California at Irvine 92697, USA. rmbush@uci.edu
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