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Heterogeneity of the Epstein-Barr virus major internal repeat reveals evolutionary mechanisms of EBV and a functional defect in the prototype EBV strain B95-8.

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Title: Heterogeneity of the Epstein-Barr virus major internal repeat reveals evolutionary mechanisms of EBV and a functional defect in the prototype EBV strain B95-8.
Authors: Ba abdullah, M
Palermo, RD
Palser, A
Grayson, NE
Kellam, P
Correia, S
Szymula, A
White, RE
Item Type: Journal Article
Abstract: Epstein-Barr virus (EBV) is a ubiquitous pathogen of humans that can cause several types of lymphoma and carcinoma. Like other herpesviruses, EBV has diversified both through co-evolution with its host, and genetic exchange between virus strains. Sequence analysis of the EBV genome is unusually challenging, because of the large number and length of repeat regions within the virus. Here we describe the sequence assembly and analysis of the large internal repeat of EBV (IR1 or BamW repeats) from over 70 strains. Diversity of the latency protein EBNA-LP resides predominantly within the exons downstream of IR1. The integrity of the putative BWRF1 ORF is retained in over 80% of strains, and deletions truncating IR1 always spare BWRF1. Conserved regions include the IR1 latency promoter (Wp), and one zone upstream of and two within BWRF1. IR1 is heterogeneous in 70% of strains, and this heterogeneity arises from sequence exchange between strains as well as spontaneous mutation, with inter-strain recombination more common in tumour-derived viruses. This genetic exchange often incorporates regions of <1kb, and allelic gene conversion changes the frequency of small regions within the repeat, but not close to the flanks. These observations suggest that IR1 — and by extension EBV — diversifies through both recombination and breakpoint repair, while concerted evolution of IR1 is driven by gene conversion of small regions. Finally, the prototype EBV strain B95-8 contains four non-consensus variants within a single IR1 repeat unit, including a STOP codon in EBNA-LP. Repairing IR1 improves EBNA-LP levels and the quality of transformation by the B95-8 BAC.
Issue Date: 13-Sep-2017
Date of Acceptance: 3-Sep-2017
URI: http://hdl.handle.net/10044/1/50596
DOI: https://dx.doi.org/10.1128/JVI.00920-17
ISSN: 1098-5514
Publisher: American Society for Microbiology
Journal / Book Title: Journal of Virology
Volume: 91
Issue: 23
Copyright Statement: Copyright © 2017 Ba abdullah et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Sponsor/Funder: Medical Research Council (MRC)
King Abdulaziz City for Science and Technology (KA
Funder's Grant Number: MR/L008432/1
N/A
Keywords: B95-8
DNA sequencing
EBNA-LP
Epstein-Barr virus
genome analysis
human herpesviruses
internal repeat
viral evolution
virus mutation
06 Biological Sciences
07 Agricultural And Veterinary Sciences
11 Medical And Health Sciences
Virology
Publication Status: Published
Article Number: e00920-17
Appears in Collections:Department of Medicine (up to 2019)