Abstract
Hepatitis B virus (HBV) is classified into several genotypes, correlated with different geographic distributions, clinical outcomes and susceptible human populations. It is crucial to investigate the evolutionary significance behind the diversification of HBV genotypes, because it improves our understanding of their pathological differences and pathogen-host interactions. Here, we performed comprehensive analysis of HBV genome sequences collected from public database. With a stringent criteria, we generated a dataset of 2992 HBV genomes from eight major genotypes. In particular, we applied a specified classification of non-synonymous and synonymous variants in overlapping regions, to distinguish joint and independent gene evolutions. We confirmed the presence of selective constraints over non-synonymous variants in consideration of overlapping regions. We then performed the McDonald-Kreitman test and revealed adaptive evolutions of non-synonymous variants during genotypic differentiation. Remarkably, we identified strong positive selection that drove the differentiation of PreS1 domain, which is an essential regulator involved in viral transmission. Our study presents novel evidences for the adaptive evolution of HBV genotypes, which suggests that these viruses evolve directionally for maintenance or improvement of successful infections.
Highlights
The hepatitis B virus (HBV) is one of the most prevalent viral infections worldwidely[1, 2] and is known as a leading cause of liver diseases
Among the 8 major genotypes (A–H), genotypes A and D primarily spread in Europe and Africa, genotypes B and C are commonly found in Asia, genotype E is prevalent in central and western Africa, genotypes F and H are restricted to Latin America and Alaska, and genotype G is reported in Europe and the United States[10, 11]
To study the genotypic diversity of Hepatitis B virus (HBV), we constructed a dataset of 6765 HBV genome sequences, which is approximately the entire public collection after exclusion of redundancy and poor quality (See Materials and Methods)
Summary
The hepatitis B virus (HBV) is one of the most prevalent viral infections worldwidely[1, 2] and is known as a leading cause of liver diseases. The underlying assumption using dN/dS ratio to imply positive or negative selection is to treat dS as the neutrally evolving rate[21], which is in conflict with the fact that synonymous sites of overlapping genes often cause non-synonymous alterations of another ORF. Further support to this statement is the decreased synonymous substitution rate observed in overlapping vs non-overlapping regions of HBV5. Alternative methods considering the inconsistency of genotypic evolutions will provide novel information to the standing questions
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