The hepatitis B virus (HBV) is a global health problem that causes different types of
liver diseases. The high mutation rate of HBV, which results from a lack of proofreading activity of the viral polymerase, leads to the actively adaptive evolution of mutant strains under various selection pressures. This study focuses on the positive selection signals in the whole HBV genome and the association of these selection signals with the disease stages and/or viral genotypes. A total of 486 complete HBV genomes from HBV-infected individuals of different illness categories (i.e., acute, chronic, and severe
hepatitis) were analyzed. To obtain a panoramic view of the selection signals,
codon-based maximum likelihood analysis, three-dimensional (3D) mapping, and allele frequency comparison were conducted on genotypes B and C HBV from subjects with different stages of
hepatitis. A total of 95 selected
codons were resolved, and a significantly higher number of positive selection signatures were found in the chronic and severe
hepatitis groups compared with the acute groups. Many of the selected
codons were associated with either a unique disease stage or a specific genotype. The conservation analysis of the selection signals in the viral core
protein (
HBcAg) illustrated the occurrence of selected
codons in the highly diversified regions. The allele-frequency-based analysis identified eight additional
nucleotide substitutions, and the frequencies of these mutations were found to increase with
disease progression. Moreover, we found that three substitutions, including A1762T, G1764A, and A2739C, were nearly fixed. The mapping of all of the selected
codons and
nucleotide substitutions to the functional domains of the
viral proteins suggested that more than 60% of the mutations were subject to selection forces from host immune surveillance,
antiviral therapy, and replication fitness.