Evidence of latent-lytic replication in EBV-positive Burkitt lymphoma from whole genome and transcriptome sequencing

Epstein–Barr virus (EBV) is a ubiquitous human herpesvirus linked to multiple malignancies, but its role in disease remains uncertain. We analysed 410 EBV genomes, including 64 newly sequenced isolates from plasma of East African children with and without Burkitt lymphoma (BL), integrating whole-genome and transcriptomic data. Population genomic analyses revealed marked regional structure with strain-level diversity shaped by both recombination and mutation, particularly within latency and immune-evasion genes ( EBNA-1 , LMP-1 , BCRF1 , BNLF2a ), reflecting selective pressure from host immunity and tumour microenvironment. We identified a BL-associated mutational signature (SBS_EBV3) enriched for T > C and C > T substitutions in G-rich contexts, with limited similarity to known COSMIC signatures (closest match SBS54, cosine similarity 0.74). Transcriptomic profiling demonstrated a mixed latent–lytic expression programme in BL, potentially promoting recombination and mutagenesis. These findings define new features of EBV evolution in BL and highlight opportunities for diagnostics and vaccines targeting both latent and lytic antigens.