Positive selection on the H3 hemagglutinin gene of human influenza virus A

被引:257
作者
Bush, RM [1 ]
Fitch, WM
Bender, CA
Cox, NJ
机构
[1] Univ Calif Irvine, Dept Ecol & Evolutionary Biol, Irvine, CA 92697 USA
[2] Ctr Dis Control & Prevent, Influenza Branch, Atlanta, GA USA
关键词
influenza; virus; positive selection; hemagglutinin; evolution;
D O I
10.1093/oxfordjournals.molbev.a026057
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 sires. 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.
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页码:1457 / 1465
页数:9
相关论文
共 28 条
  • [1] THE ANTIGENIC STRUCTURE OF THE INFLUENZA-VIRUS A/PR/8/34 HEMAGGLUTININ (H-1 SUBTYPE)
    CATON, AJ
    BROWNLEE, GG
    YEWDELL, JW
    GERHARD, W
    [J]. CELL, 1982, 31 (02) : 417 - 427
  • [2] The molecular epidemiology of influenza viruses
    Cox, NJ
    Bender, CA
    [J]. SEMINARS IN VIROLOGY, 1995, 6 (06): : 359 - 370
  • [3] THE MIDAS DISPLAY SYSTEM
    FERRIN, TE
    HUANG, CC
    JARVIS, LE
    LANGRIDGE, R
    [J]. JOURNAL OF MOLECULAR GRAPHICS, 1988, 6 (01): : 13 - &
  • [4] POSITIVE DARWINIAN EVOLUTION IN HUMAN INFLUENZA-A VIRUSES
    FITCH, WM
    LEITER, JME
    LI, XQ
    PALESE, P
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (10) : 4270 - 4274
  • [5] Long term trends in the evolution of H(3) HA1 human influenza type A
    Fitch, WM
    Bush, RM
    Bender, CA
    Cox, NJ
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (15) : 7712 - 7718
  • [6] A MAXIMUM-LIKELIHOOD APPROACH TO THE DETECTION OF SELECTION FROM A PHYLOGENY
    GOLDING, B
    FELSENSTEIN, J
    [J]. JOURNAL OF MOLECULAR EVOLUTION, 1990, 31 (06) : 511 - 523
  • [7] SEQUENCE EVOLUTION WITHIN POPULATIONS UNDER MULTIPLE TYPES OF MUTATION
    GOLDING, GB
    AQUADRO, CF
    LANGLEY, CH
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1986, 83 (02) : 427 - 431
  • [9] CODOMINANT MIXTURES OF VIRUSES IN REFERENCE STRAINS OF INFLUENZA-VIRUS DUE TO HOST-CELL VARIATION
    GUBAREVA, LV
    WOOD, JM
    MEYER, WJ
    KATZ, JM
    ROBERTSON, JS
    MAJOR, D
    WEBSTER, RG
    [J]. VIROLOGY, 1994, 199 (01) : 89 - 97
  • [10] EGG FLUIDS AND CELLS OF THE CHORIOALLANTOIC MEMBRANE OF EMBRYONATED CHICKEN EGGS CAN SELECT DIFFERENT VARIANTS OF INFLUENZA-A (H3N2) VIRUSES
    HARDY, CT
    YOUNG, SA
    WEBSTER, RG
    NAEVE, CW
    OWENS, RJ
    [J]. VIROLOGY, 1995, 211 (01) : 302 - 306