Profiling Genome-Wide Recombination in Epstein Barr Virus Reveals Type-Specific Patterns and Associations with Endemic-Burkitt Lymphoma

Abstract Background Endemic Burkitt lymphoma (eBL) is potentiated through the interplay of Epstein Barr virus (EBV) and holoendemic Plasmodium falciparum malaria. To better understand EBV’s biology and role in eBL, we characterized genome-wide recombination sites and patterns as a source of genetic diversity in EBV genomes in our well-defined population of eBL cases and controls from Western Kenya. Methods EBV genomes representing 54 eBL cases and 32 healthy children from the same geographic region in Western Kenya that we previously sequenced were analyzed. Whole-genome multiple sequence alignment, recombination analyses, and phylogenetic inference were made using multiple alignment with fast Fourier transform, recombination detection program 4, and molecular evolutionary genetics analysis. Results We identified 28 different recombination events and 71 (82.6%) of the 86 EBV genomes analyzed contained evidence of one or more recombinant segments. Associated recombination breakpoints were found to occur in a total of 42 different genes, with only 7 (16.67%) being latent genes. Recombination events were major drivers of clustering within genome-wide phylogenetic trees. The occurrence of recombination segments was comparable between genomes from male and female participants and across age groups. More recombinant segments were found in EBV type 1 genomes (p = 6.4e − 06) and the genomes from the eBLs (p = 0.037). Two recombination events were enriched in the eBLs; event 47 (OR = 4.07, p = 0.038) and event 50 (OR = 14.24, p = 0.012). Conclusions EBV genomes have extensive evidence of recombination likely acquired progressively and cumulatively over time. Recombination patterns display a heterogeneous occurrence rate across the genome with enrichment in lytic genes. Overall, recombination appears to be a major evolutionary force impacting EBV diversity and genome structure with evidence of the association of specific recombinants with eBL.