title: Selection pressure-driven evolution of the Epstein-Barr virus-encoded oncogene LMP1 in virus isolates from Southeast Asia.
abstract: The geographically constrained distribution of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) in southeast Asian populations suggests that both viral and host genetics may influence disease risk. Although susceptibility loci have been mapped within the human genome, the role of viral genetics in the focal distribution of NPC remains an enigma. Here we report a molecular phylogenetic analysis of an NPC-associated viral oncogene, LMP1, in a large panel of EBV isolates from southeast Asia and from Papua New Guinea, Africa, and Australia, regions of the world where NPC is and is not endemic, respectively. This analysis revealed that LMP1 sequences show a distinct geographic structure, indicating that the southeast Asian isolates have evolved as a lineage distinct from those of Papua New Guinea, African, and Australian isolates. Furthermore, a likelihood ratio test revealed that the C termini of the LMP1 sequences of the southeast Asian lineage are under significant positive selection pressure, particularly at some sites within the C-terminal activator regions. We also present evidence that although the N terminus and transmembrane region of LMP1 have undergone recombination, the C-terminal region of the gene has evolved without any history of recombination. Based on these observations, we speculate that selection pressure may be driving the LMP1 sequences in virus isolates from southeast Asia towards a more malignant phenotype, thereby influencing the endemic distribution of NPC in this region.
authors.affiliation: Tumour Immunology Laboratory, Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, and Department of Molecular and Cellular Pathology, University of Queensland, Brisbane, Australia 4029.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Burrows
authors.forename: Lindell
authors.initials: L
authors.lastname: Bromham
authors.forename: Megan
authors.initials: M
authors.lastname: Woolfit
authors.forename: Gwenaël
authors.initials: G
authors.lastname: Piganeau
authors.forename: Judy
authors.initials: J
authors.lastname: Tellam
authors.forename: Geoff
authors.initials: G
authors.lastname: Connolly
authors.forename: Natasha
authors.initials: N
authors.lastname: Webb
authors.forename: Leith
authors.initials: L
authors.lastname: Poulsen
authors.forename: Leanne
authors.initials: L
authors.lastname: Cooper
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
authors.forename: Denis J
authors.initials: DJ
authors.lastname: Moss
authors.forename: Sofia M
authors.initials: SM
authors.lastname: Haryana
authors.forename: Mun
authors.initials: M
authors.lastname: Ng
authors.forename: John M
authors.initials: JM
authors.lastname: Nicholls
authors.forename: Rajiv
authors.initials: R
authors.lastname: Khanna
mesh_terms: D000595:Amino Acid Sequence; D001210:Asia, Southeastern; D002460:Cell Line; D020031:Epstein-Barr Virus Infections / Q000821:virology; D019143:Evolution, Molecular; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008214:Lymphocytes; D008969:Molecular Sequence Data; D009303:Nasopharyngeal Neoplasms / Q000821:virology*; D010802:Phylogeny; D012641:Selection, Genetic; D014763:Viral Matrix Proteins / Q000235:genetics*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins