The Phylogeographic Diversity of EBV and Admixed Ancestry in the Americas⁻Another Model of Disrupted Human-Pathogen Co-Evolution

Abstract

Epstein-Barr virus (EBV) is an etiological agent for gastric cancer with significant worldwide variations. Molecular characterizations of EBV have shown phylogeographical variations among healthy populations and in EBV-associated diseases, particularly the cosegregated BamHI-I fragment and XhoI restriction site of exon 1 of the LMP-1 gene. In the Americas, both cosegregated variants are present in EBV carriers, which aligns with the history of Asian and European human migration to this continent. Furthermore, novel recombinant variants have been found, reflecting the genetic makeup of this continent. However, in the case of EBV-associated gastric cancer (EBV-associated GC), the cosegregated European BamHI-"i" fragment and XhoI restriction site strain prevails. Thus, we propose that a disrupted coevolution between viral phylogeographical strains and mixed human ancestry in the Americas might explain the high prevalence of this particular gastric cancer subtype. This cosegregated region contains two relevant transcripts for EBV-associated GC, the BARF-1 and miR-BARTs. Thus, genome-wide association studies (GWAS) or targeted sequencing of both transcripts may be required to clarify their role as a potential source of this disrupted coevolution.

Keywords: Epstein-Barr Virus; gastric cancer; human ancestry; viral phylogeography.

Figure 1

Genomic map of Epstein-Barr virus (EBV) genome with major phylogeographic variants. (A) Diagram shows the location of open reading frames for EBV latent proteins on the BamHI restriction map of the prototype EBV B95-8 genome. The BamHI fragments are named according to size and are indicated by capital letters, with A being the largest. Lowercase letters indicate variations in size within these fragments. TR refers to the terminal repeats at each end of the genome. Below is a schematic representation of viral miR-BARTs in sequence order with deletion indicated within the BamHI-A fragment of the EBV genome in the B95-8 strain. N_het is used to indicate heterogeneity in this region according to the number of TRs within different virus isolates. (B) Schematic representation of the genomic location of BamHI-I and BamHI-A fragments with TR. Within the exon 1 of LMP1 gene is the XhoI restriction site. The region containing the BamHI-I and XhoI restriction site is 21,277 nucleotides long and contains several relevant transcripts (miR-BARTS and BARF-1) for EBV transformation abilities. Figure is adapted from References [39] (with permission to use part of the figure) and [40] (localization of miR-BARTs).

Figure 2

Human heritage and EBV strains in the healthy population and EBV-associated GC in Chile and Peru. (A) Human ancestries and Asian, European and recombinant viral strains identified in the healthy population of Chile and Peru. (B) Distribution and geographical origin of viral strains among EBV-associated GC patients in Chile and Peru, showing the predominance of the European BamHI-”i” fragment and XhoI restriction site strain. In the case of the healthy population, EBV strains were examined from throat washing specimens, and in the case of gastric cancer patients, from paraffin-embedded tumor specimens.