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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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Related in: MedlinePlus

Analysis of 40 protein and DNA HBVc sequences. The 40 sequences detailed in Table 1 were analysed using Neighbor Joining analysis of both protein (panel a) and DNA (panel b) and plotted using TreeView. The bootstrap values (as percentage) are shown in smaller font. The accession number corresponding to each numbered sequence is shown in Table 1. The genotype is indicated by colour coding (Yellow = A, Green = B, Blue = C, Red = D).
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Figure 4: Analysis of 40 protein and DNA HBVc sequences. The 40 sequences detailed in Table 1 were analysed using Neighbor Joining analysis of both protein (panel a) and DNA (panel b) and plotted using TreeView. The bootstrap values (as percentage) are shown in smaller font. The accession number corresponding to each numbered sequence is shown in Table 1. The genotype is indicated by colour coding (Yellow = A, Green = B, Blue = C, Red = D).

Mentions: This phenomenon was analysed in more detail in a subset of 40 full length core protein sequences selected from various sections of the tree illustrated in fig 3 (see Table 1). The phylogenetic relationship between these forty sequences was analysed again, using Neighbour-Joining (a less computation intense method) incorporating a 1000 fold bootstrap replicate in order to validate the tree topology. The results of this analysis are shown in fig 4a. In this smaller subset, genotypes A and D are reasonably well resolved, but genotypes B and C are extensively jumbled. One instance of this is illustrated by two identical sequences (1 and 40 in fig 4) derived from genotypes B and C respectively. The DNA sequences corresponding to each of these forty protein sequences were then obtained from GenBank, and analysed using the same bootstrapped Neighbour-Joining procedure. The tree obtained is shown in fig 4b. As expected, the bootstrap values are in general higher for the DNA tree (since three times as much sequence information is being analysed). The DNA sequences are somewhat more efficient at classifying B and C as separate grouping. In particular the two identical protein sequences (1 and 40 in figure) are well separated and correctly classified by the DNA phylogeny. Overall, however, significant misclassification remains, reflecting either incorrect genotyping, recombination between viral strains [16,17], or simply insufficient discrimination based on these relatively short viral sequences.


Variability and conservation in hepatitis B virus core protein.

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

Analysis of 40 protein and DNA HBVc sequences. The 40 sequences detailed in Table 1 were analysed using Neighbor Joining analysis of both protein (panel a) and DNA (panel b) and plotted using TreeView. The bootstrap values (as percentage) are shown in smaller font. The accession number corresponding to each numbered sequence is shown in Table 1. The genotype is indicated by colour coding (Yellow = A, Green = B, Blue = C, Red = D).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1173110&req=5

Figure 4: Analysis of 40 protein and DNA HBVc sequences. The 40 sequences detailed in Table 1 were analysed using Neighbor Joining analysis of both protein (panel a) and DNA (panel b) and plotted using TreeView. The bootstrap values (as percentage) are shown in smaller font. The accession number corresponding to each numbered sequence is shown in Table 1. The genotype is indicated by colour coding (Yellow = A, Green = B, Blue = C, Red = D).
Mentions: This phenomenon was analysed in more detail in a subset of 40 full length core protein sequences selected from various sections of the tree illustrated in fig 3 (see Table 1). The phylogenetic relationship between these forty sequences was analysed again, using Neighbour-Joining (a less computation intense method) incorporating a 1000 fold bootstrap replicate in order to validate the tree topology. The results of this analysis are shown in fig 4a. In this smaller subset, genotypes A and D are reasonably well resolved, but genotypes B and C are extensively jumbled. One instance of this is illustrated by two identical sequences (1 and 40 in fig 4) derived from genotypes B and C respectively. The DNA sequences corresponding to each of these forty protein sequences were then obtained from GenBank, and analysed using the same bootstrapped Neighbour-Joining procedure. The tree obtained is shown in fig 4b. As expected, the bootstrap values are in general higher for the DNA tree (since three times as much sequence information is being analysed). The DNA sequences are somewhat more efficient at classifying B and C as separate grouping. In particular the two identical protein sequences (1 and 40 in figure) are well separated and correctly classified by the DNA phylogeny. Overall, however, significant misclassification remains, reflecting either incorrect genotyping, recombination between viral strains [16,17], or simply insufficient discrimination based on these relatively short viral sequences.

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