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Variability and conservation in hepatitis B virus core protein.

Chain BM, Myers R - BMC Microbiol. (2005)

Bottom Line: Polymorphisms were found at 44 out of 185 amino acid positions analysed and were clustered predominantly in those parts of HBVc forming the outer surface and spike on intact capsid.The structural requirements of capsid assembly are likely to play a major role in limiting diversity.The phylogenetic analysis further suggests that immunological selection does not play a major role in driving HBVc diversity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology and Molecular Pathology, University College London, W1T 4JF UK. b.chain@ucl.ac.uk

ABSTRACT

Background: Hepatitis B core protein (HBVc) has been extensively studied from both a structural and immunological point of view, but the evolutionary forces driving sequence variation within core are incompletely understood.

Results: In this study, the observed variation in HBVc protein sequence has been examined in a collection of a large number of HBVc protein sequences from public sequence repositories. An alignment of several hundred sequences was carried out, and used to analyse the distribution of polymorphisms along the HBVc. Polymorphisms were found at 44 out of 185 amino acid positions analysed and were clustered predominantly in those parts of HBVc forming the outer surface and spike on intact capsid. The relationship between HBVc diversity and HBV genotype was examined. The position of variable amino acids along the sequence was examined in terms of the structural constraints of capsid and envelope assembly, and also in terms of immunological recognition by T and B cells.

Conclusion: Over three quarters of amino acids within the HBVc sequence are non-polymorphic, and variation is focused to a few amino acids. Phylogenetic analysis suggests that core protein specific forces constrain its diversity within the context of overall HBV genome evolution. As a consequence, core protein is not a reliable predictor of virus genotype. The structural requirements of capsid assembly are likely to play a major role in limiting diversity. The phylogenetic analysis further suggests that immunological selection does not play a major role in driving HBVc diversity.

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Synonymous/nonsynonymous mutation rates and selection in HBVc. Panel a shows the distribution of synonymous (dS) and non-synonymous (dN) substitutions (the number of such substations per site), and the ratio dN/dS along the sequence of HBVc. Gaps indicate dS = 0. Panel b shows the posterior probability p+ that dN/dS>1 for each position of HBVc, as calculated by PAML. The probability that dN/dS<1 (purifying selection) is not plotted for clarity but is given by (1- p+).
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Figure 5: Synonymous/nonsynonymous mutation rates and selection in HBVc. Panel a shows the distribution of synonymous (dS) and non-synonymous (dN) substitutions (the number of such substations per site), and the ratio dN/dS along the sequence of HBVc. Gaps indicate dS = 0. Panel b shows the posterior probability p+ that dN/dS>1 for each position of HBVc, as calculated by PAML. The probability that dN/dS<1 (purifying selection) is not plotted for clarity but is given by (1- p+).

Mentions: The evolutionary pressures on sequence diversity were analysed in more detail by analysing synonymous (S) /nonsynonymous (N) nucleotide variation within the 40 viral sequences shown in Table 1. The overall distribution pattern of synonymous /nonsynonymous mutation rates is shown in fig 5a. The protein shows evidence of strong purifying selection throughout the sequence, with dN/dS ratios (using a sliding window of 36 base pairs) mostly below 0.1, The apparent dS rate was not homogenous along the length of the gene. The sharp decrease in substitution rate from around position 110 most likely reflects the start of the overlapping open reading frame of the polymerase, and this area was therefore excluded from further analysis. The identification of site-specific positive or neutral selection operating within an area of overall purifying selection has received considerable attention [18-21], and a number of methodologies have been adopted. We applied maximum-likelyhood analysis as implemented using Bayes Empirical Bayes method in the software package PAML [22] and compared a number of models of site-specific selection distribution [18]. The best likelihood value was obtained using model 8 (see Methods) which includes a positive selection subset. The posterior probabilities for the positive (ω = 1.38) classes are plotted in fig 5b. Interestingly, only one position showed a probability of >90 of being positively selected, with two more approaching 50% probability. In contrast 133 out of 140 codons showed a probability of >90% of negative purifying selection. Thus there appears to be only very limited amount of positive selection within the HBV core sequence.


Variability and conservation in hepatitis B virus core protein.

Chain BM, Myers R - BMC Microbiol. (2005)

Synonymous/nonsynonymous mutation rates and selection in HBVc. Panel a shows the distribution of synonymous (dS) and non-synonymous (dN) substitutions (the number of such substations per site), and the ratio dN/dS along the sequence of HBVc. Gaps indicate dS = 0. Panel b shows the posterior probability p+ that dN/dS>1 for each position of HBVc, as calculated by PAML. The probability that dN/dS<1 (purifying selection) is not plotted for clarity but is given by (1- p+).
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Related In: Results  -  Collection

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Figure 5: Synonymous/nonsynonymous mutation rates and selection in HBVc. Panel a shows the distribution of synonymous (dS) and non-synonymous (dN) substitutions (the number of such substations per site), and the ratio dN/dS along the sequence of HBVc. Gaps indicate dS = 0. Panel b shows the posterior probability p+ that dN/dS>1 for each position of HBVc, as calculated by PAML. The probability that dN/dS<1 (purifying selection) is not plotted for clarity but is given by (1- p+).
Mentions: The evolutionary pressures on sequence diversity were analysed in more detail by analysing synonymous (S) /nonsynonymous (N) nucleotide variation within the 40 viral sequences shown in Table 1. The overall distribution pattern of synonymous /nonsynonymous mutation rates is shown in fig 5a. The protein shows evidence of strong purifying selection throughout the sequence, with dN/dS ratios (using a sliding window of 36 base pairs) mostly below 0.1, The apparent dS rate was not homogenous along the length of the gene. The sharp decrease in substitution rate from around position 110 most likely reflects the start of the overlapping open reading frame of the polymerase, and this area was therefore excluded from further analysis. The identification of site-specific positive or neutral selection operating within an area of overall purifying selection has received considerable attention [18-21], and a number of methodologies have been adopted. We applied maximum-likelyhood analysis as implemented using Bayes Empirical Bayes method in the software package PAML [22] and compared a number of models of site-specific selection distribution [18]. The best likelihood value was obtained using model 8 (see Methods) which includes a positive selection subset. The posterior probabilities for the positive (ω = 1.38) classes are plotted in fig 5b. Interestingly, only one position showed a probability of >90 of being positively selected, with two more approaching 50% probability. In contrast 133 out of 140 codons showed a probability of >90% of negative purifying selection. Thus there appears to be only very limited amount of positive selection within the HBV core sequence.

Bottom Line: Polymorphisms were found at 44 out of 185 amino acid positions analysed and were clustered predominantly in those parts of HBVc forming the outer surface and spike on intact capsid.The structural requirements of capsid assembly are likely to play a major role in limiting diversity.The phylogenetic analysis further suggests that immunological selection does not play a major role in driving HBVc diversity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology and Molecular Pathology, University College London, W1T 4JF UK. b.chain@ucl.ac.uk

ABSTRACT

Background: Hepatitis B core protein (HBVc) has been extensively studied from both a structural and immunological point of view, but the evolutionary forces driving sequence variation within core are incompletely understood.

Results: In this study, the observed variation in HBVc protein sequence has been examined in a collection of a large number of HBVc protein sequences from public sequence repositories. An alignment of several hundred sequences was carried out, and used to analyse the distribution of polymorphisms along the HBVc. Polymorphisms were found at 44 out of 185 amino acid positions analysed and were clustered predominantly in those parts of HBVc forming the outer surface and spike on intact capsid. The relationship between HBVc diversity and HBV genotype was examined. The position of variable amino acids along the sequence was examined in terms of the structural constraints of capsid and envelope assembly, and also in terms of immunological recognition by T and B cells.

Conclusion: Over three quarters of amino acids within the HBVc sequence are non-polymorphic, and variation is focused to a few amino acids. Phylogenetic analysis suggests that core protein specific forces constrain its diversity within the context of overall HBV genome evolution. As a consequence, core protein is not a reliable predictor of virus genotype. The structural requirements of capsid assembly are likely to play a major role in limiting diversity. The phylogenetic analysis further suggests that immunological selection does not play a major role in driving HBVc diversity.

Show MeSH
Related in: MedlinePlus