Dataset Information

Subgenotyping of genotype C hepatitis B virus: correcting misclassifications and identifying a novel subgenotype.

ABSTRACT:

Background

More than ten subgenotypes of genotype C Hepatitis B virus (HBV) have been reported, including C1 to C16 and two C/D recombinant subgenotypes (CD1 and CD2), however, inconsistent designations of these subgenotypes still exist.

Methodology/principal findings

We performed a phylogenetic analysis of all full-length genotype C HBV genome sequences to correct the misclassifications of HBV subgenotypes and to study the influence of recombination on HBV subgenotyping. Our results showed that although inclusion of the recombinant sequences changed the topology of the phylogenetic tree, it did not affect the subgenotyping of the non-recombinant sequences, except subgenotype C2. In addition, most of the subgenotypes have been properly designated. However, several misclassifications of HBV subgenotypes have been identified and corrected. For example, C11 proposed by Utsumi and colleagues in 2011 was found to be grouped with C12 proposed by Mulyanto and colleagues. Two sequences, GQ358157 and GU721029, previously designated as C6 have been re-designated as C12 and C7, respectively. Moreover, a quasi-subgenotype C2 was proposed, which included the old C2, several previously unclassified sequences and previously designated C14. In particular, we identified a novel subgenotype, tentative C14, which was well supported by phylogenetic analysis and sequence divergence of >4%.

Conclusions/significance

A number of misclassifications in the subgenotyping of genotype C HBV have been identified in this study. After correcting the misclassifications, we proposed a better classification for the subgenotyping of genotype C HBV, in which a novel quasi-subgenotype C2 and a novel subgenotype, tentative C14, were described. Based on this large-scale analysis, we propose that a novel subgenotype should only be reported after a complete comparison of all relevant sequences rather than a few representative sequences only.

SUBMITTER: Shi W

PROVIDER: S-EPMC3471840 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Subgenotyping of genotype C hepatitis B virus: correcting misclassifications and identifying a novel subgenotype.

Shi Weifeng W Zhu Chaodong C Zheng Weimin W Zheng Wei W Ling Cheng C Carr Michael J MJ Higgins Desmond G DG Zhang Zhong Z

PloS one 20121015 10

<h4>Background</h4>More than ten subgenotypes of genotype C Hepatitis B virus (HBV) have been reported, including C1 to C16 and two C/D recombinant subgenotypes (CD1 and CD2), however, inconsistent designations of these subgenotypes still exist.<h4>Methodology/principal findings</h4>We performed a phylogenetic analysis of all full-length genotype C HBV genome sequences to correct the misclassifications of HBV subgenotypes and to study the influence of recombination on HBV subgenotyping. Our resu ...[more]

PMID: 23077582

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Project description:Hepatitis B virus (HBV) is a highly variable DNA virus due to its unique life cycle, which involves an error-prone reverse transcriptase. The high substitution rate drives the evolution of HBV by generating genetic variants upon which selection operates. HBV mutants with clinical implications have been documented worldwide, indicating the potential for spreading and developing their own epidemiology. However, the prevalence of such mutants among the different HBV genotypes and subgenotypes has not been systematically analyzed. In the current study, we performed large-scale analysis of 6,479 full-length HBV genome sequences from genotypes A-H, with the aim of gaining comprehensive insights into the relationships of relevant mutations associated with immune escape, antiviral resistance and hepatocellular carcinoma (HCC) development with HBV (sub)genotypes and geographic regions. Immune escape mutations were detected in 10.7% of the sequences, the most common being I/T126S (1.8%), G145R (1.2%), M133T (1.2%), and Q129R (1.0%). HBV genotype B showed the highest rate of escape mutations (14.7%) while genotype H had no mutations (P < 0.001). HCC-associated mutations were detected in 33.7% of the sequences, with significantly higher frequency of C1653T, T1753V and A1762T/G1764A in genotype G than C (P < 0.001). The overall frequencies of lamivudine-, telbivudine-, adefovir-, and entecavir-resistant mutants were 7.3, 7.2, 0.5, and 0.2%, respectively, while only 0.05% showed reduced susceptibility to tenofovir. In particular, the highest frequency of lamivudine-resistant mutations was observed in genotype G and the lowest frequency in genotype E (32.5 and 0.3%; P < 0.001). The prevalence of HBV mutants was also biased by geographic location, with North America identified as one of the regions with the highest rates of immune escape, antiviral resistance, and HCC-associated mutants. The collective findings were discussed in light of natural selection and the known characteristics of HBV (sub)genotypes. Our data provide relevant information on the prevalence of clinically relevant HBV mutations, which may contribute to further improvement of diagnostic procedures, immunization programs, therapeutic protocols, and disease prognosis.

Project description:The focus of this study was the computational analysis of hepatitis B virus (HBV) genotype D subgenotype D1 in Pakistan, China, and India. In total, 54 complete genome sequences of HBV genotype D subgenotype D1 were downloaded from National Center for Biotechnology Information (NCBI). Of these, 6 complete genome sequences were from Pakistan, 14 were from China, and 34 were from India. Sequence alignment showed less than 4% divergence in these sequences. C and X genes showed divergence of less than 3%. Comparison over the S gene showed more than 97% similarity among the nucleotide sequences of genotype D subgenotype D1. The identity and similarity matrix of 54 nucleotide sequences of HBV genotype D subgenotype D1 from Pakistan, China, and India revealed more than 93% identity and 93% similarity. Phylogenetic analysis highlighted that complete genome isolates of HBV circulating in Pakistan had the closest evolutionary relationship with its neighboring countries China and India. China's (HQ833466) and Pakistan's (AB583680.1) isolates shared the same ancestor. Gene structure analysis showed that "P" gene exons were the longest, about three-fourth of the genome size, whereas gene "S" had the second longest coding regions with 2 exons and 1 intron. However, "C" and "X" genes had 1 smallest exon. X proteins had proven role in spreading of the HBV infection diseases. For HBx analysis, 1 X protein sequence of HBV genotype D subgenotype D1 belonging to each country was obtained. Homology models of the 3 X proteins generated using SWISS-MODEL revealed GMQE (Global Model Quality Estimation) = 0.1. Global and local quality estimate scores including Z-scores for Qualitative Model Energy Analysis (QMEAN) C-beta, all-atom, solvation, and torsion energy scores were similar indicating good quality, accuracy, and reliability of the predicted models. Three-dimensional (3D) visualization showed similar structures and Ramachandran plots showed a high percentage of protein residues into the favorable region for X protein models.

Dataset Information

Subgenotyping of genotype C hepatitis B virus: correcting misclassifications and identifying a novel subgenotype.

Background

Methodology/principal findings

Conclusions/significance

Publications

Subgenotyping of genotype C hepatitis B virus: correcting misclassifications and identifying a novel subgenotype.

Similar Datasets

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