Novel non-canonical genetic rearrangements termed "complex structural variations" in HBV genome.

BACKGROUNDS AND AIMS: Chronic hepatitis B virus (HBV) infection is an important worldwide public health issue. Further knowledge on the characteristics of HBV will facilitate its eradication. Genome structural variations (SVs) are defined by its canonical form such as duplication, deletion, and insertion. However, recent studies have reported complex SVs that cannot be explained by those canonical SVs. A HBV strain (UK2) with an unusual genome structure rearrangement that was completely different from known mutations or rearrangements was previously reported. Thus, this study was conducted to confirm the rearrangement in UK2 as a novel complex SV, and to find additional HBV strains with complex SVs. Further, the contribution of complex SVs in hepadnavirus variability was investigated.

METHODS: The genome rearrangement pattern in UK2 was analyzed. Further, a search of online databases retrieved additional HBV strains which were candidates to harbor complex SVs. The architecture of each rearrangement in the candidate strains was analyzed by bioinformatical tools. In addition, alignment of woolly monkey hepatitis virus (WMHV) and HBV from human and non-human primates was performed to investigate the contribution of complex SVs to variability of hepadnavirus.

RESULTS: The rearrangement in UK2 was confirmed as a complex SV. An additional 15 HBV strains were retrieved from databases, and confirmed as harboring complex SVs. Complex combinations of deletion, insertion, and duplication characterized the novel rearrangements. The complex SVs in six strains (37.5%) were composed of deletion, insertion, and duplication. The complex SVs in another six strains (37.5%) consisted of deletion and insertion, followed by insertions and duplication in three strains (18.8%), and deletion and duplication in one strain (6.3%). In addition, unique preS1 promoter insertions, which contained the hepatocyte nuclear factor 1 binding site, were observed in seven (43.8%) of 16 strains. Further, analysis of the genetic sequences of WMHV and HBV from human and non-human primates showed that complex combinations of deletions and insertions accounted for their genetic differences.

CONCLUSIONS: Non-canonical genetic rearrangements termed complex SVs were observed in HBV. Further, complex SVs accounted for the genetic differences of WMHV and HBV from human and non-human primates.