Coevolution of Sites under Immune Selection Shapes Epstein–Barr Virus Population Structure

Abstract

Epstein–Barr virus (EBV) is one of the most common viral infections in humans and persists within its host for life. EBV therefore represents an extremely successful virus that has evolved complex strategies to evade the host’s innate and adaptive immune response during both initial and persistent stages of infection. Here, we conducted a comparative genomics analysis on 223 whole genome sequences of worldwide EBV strains. We recover extensive genome-wide linkage disequilibrium (LD) despite pervasive genetic recombination. This pattern is explained by the global EBV population being subdivided into three main subpopulations, one primarily found in East Asia, one in Southeast Asia and Oceania, and the third including most of the other globally distributed genomes we analyzed. Additionally, sites in LD were overrepresented in immunogenic genes. Taken together, our results suggest that host immune selection and local adaptation to different human host populations has shaped the genome-wide patterns of genetic diversity in EBV.

Evolution and Genetic Diversity of Primate Cytomegaloviruses

“…Conversely, despite abundant recombination, EBV shows extensive genome-wide LD [85]. Because sites in LD are enriched in EBV genes that encode immunogenic proteins, Wegner and coworkers suggested that viral population structure is determined by local adaptation to human populations [85]. In summary, these data suggest that, although a wider sampling of HCMV diversity may in the future reveal some level of geographic clustering, most HCMV stains derive from a highly recombining panmictic population distributed worldwide.…”

“…Another notable difference among human herpesviruses is the degree of geographic structuring of viral populations. At one extreme stand VZV and EBV, which display a clear spatial distribution of genetic diversity [82][83][84][85]. For instance, VZV clades 1, 3, and 6 are mainly transmitted in Europe, North America, and Australia, whereas clade 2 is primarily Asian [83].…”

“…Recent analyses, however, indicated that HCMV and HSV-1 have a different recombination pattern compared to EBV. In particular, the two former viruses are essentially freely recombining, with only limited regions of linkage disequilibrium (LD) throughout their genomes [85,87]. Conversely, despite abundant recombination, EBV shows extensive genome-wide LD [85].…”

“…In particular, the two former viruses are essentially freely recombining, with only limited regions of linkage disequilibrium (LD) throughout their genomes [85,87]. Conversely, despite abundant recombination, EBV shows extensive genome-wide LD [85]. Because sites in LD are enriched in EBV genes that encode immunogenic proteins, Wegner and coworkers suggested that viral population structure is determined by local adaptation to human populations [85].…”

The influence of human genetic variation on Epstein-Barr virus sequence diversity

“…Another group investigated the co-evolution of worldwide EBV strains [34] and found extensive linkage disequilibrium (LD) throughout EBV genomes. Furthermore, they observed that genes in strong LD were enriched in immunogenic genes, suggesting adaptive immune selection and epistasis.…”