Mutations and CpG islands among hepatitis B virus genotypes in Europe

Abstract

BackgroundHepatitis B virus (HBV) genotypes have a distinct geographical distribution and influence disease progression and treatment outcomes. The purpose of this study was to investigate the distribution of HBV genotypes in Europe, the impact of mutation of different genotypes on HBV gene abnormalities, the features of CpG islands in each genotype and their potential role in epigenetic regulation.ResultsOf 383 HBV isolates from European patients, HBV genotypes A-G were identified, with the most frequent being genotype D (51.96%) in 12 countries, followed by A (39.16%) in 7 countries, and then E (3.66%), G (2.87%), B (1.57%), F (0.52%) and C (0.26%). A higher rate of mutant isolates were identified in those with genotype D (46.7%) followed by G (45.5%), and mutations were associated with structural and functional abnormalities of HBV genes. Conventional CpG island I was observed in genotypes A, B, C, D and E. Conventional islands II and III were detected in all A-G genotypes. A novel CpG island IV was found in genotypes A, D and E, and island V was only observed in genotype F. The A-G genotypes lacked the novel CpG island VI. “Split” CpG island I in genotypes D and E and “split” island II in genotypes A, D, E, F and G were observed. Two mutant isolates from genotype D and one from E were found to lack both CpG islands I and III.ConclusionsHBV genotypes A-G were identified in European patients. Structural and functional abnormalities of HBV genes were caused by mutations leading to the association of genotypes D and G with increased severity of liver disease. The distribution, length and genetic traits of CpG islands were different between genotypes and their biological and clinical significances warrant further study, which will help us better understand the potential role of CpG islands in epigenetic regulation of the HBV genome.

Characteristics of CpG Islands and their quasispecies of full-length hepatitis B virus genomes from patients at different phases of infection

“…Consistent with the previous studies (Zhang et al 2013 ; Zhong et al 2015 ; Hou et al 2015 ), CGI and split CGII were much more common in HBV genotype B compared to genotype C. Nevertheless, 30 clones in genotype C from two patients (one CHB patient and one ACLF patient) contained CGI, while among the 16 clones in genotype B from a CHB patient, only three clones contained CGI.…”

“…Although the function of CGI remains unclear, its absence might induce less methylation of the first CpG-rich region in HBV genotype C (Zhang et al 2013 ), and likely to be associated with the progressive liver diseases caused by HBV genotype C. To note, as shown in the present study, 30 clones in genotype C from two patients (one CHB patient and one ACLF patient) contained CGI, while among the 16 clones in genotype B from a CHB patient, only three clones contained CGI. Different from the previous studies (Hou et al 2015 ; Zhang et al 2013 ; Zhong et al 2015 ), data from HBV quasispecies emphasize that, distribution of CpG islands does not abide by genotypes strictly.…”

“…Different distribution of CpG islands which can affect their methylation status and HBV gene expression, might further lead to different clinical outcomes of HBV infection. Previous studies have shown that distribution of CpG islands differed across HBV genotypes (Hou et al 2015 ; Zhang et al 2013 ; Zhong et al 2015 ). However, all of the nucleotide sequences mentioned in those studies were searched from Genbank at the National Center for Biotechnology Information.…”

Differences in Cpg Island Distribution Between Subgenotypes of the Hepatitis B Virus Genotype

“…The absence of CpG island I is common in genotypes A, C, F, G and H, and new CpG islands are common in genotypes B, C, E, F, H, but rare in A, D, and G [ 21 , 22 ]. However, the findings of the present study showed that there were significant differences between specific subtypes, and that every subtype may possess a different CpG island distribution within the same genotype ( Figure 1B ).…”

“…Currently, six CpG islands, including three newly identified CpG islands (IV, V, and VI), are generally accepted to exist. These CpG islands are located at the transcription start site or are located upstream and downstream of the promoters [ 20 – 22 ]. Host DNA methyltransferase mediates CpG methylation, and methylated HBV CpG islands limit their regulation of viral protein expression [ 23 , 24 ].…”