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Driven by advances in deep sequencing technologies, recent studies have systematically characterized EBV genomic landscapes in diverse clinical specimens, uncovering distinct geographic patterns in strain distribution. However, a comprehensive understanding of how EBV genomic variation contributes to disease pathogenesis remains incomplete. This review aims to consolidate current knowledge on EBV genomic variation and its role in disease development. First, we delineate the evolutionary origins of EBV genetic variations, focusing on key factors such as replication errors, recombination, and immune\u2010driven selection. Next, we summarize the association between EBV subtypes and diseases, with evidence linking specific genetic variations to malignancies, infectious mononucleosis, and multiple sclerosis. At the mechanistic level, EBV genomic variation may influence pathogenesis through three interconnected mechanisms: viral functional changes, viral\u2013host interactions, and molecular mimicry. Finally, this review explores how genomic insights into EBV can inform clinical applications, including early diagnostic biomarkers and next\u2010generation therapies targeting lineage\u2010specific variations, such as mRNA vaccines and small molecules that disrupt latency. These advances highlight the critical role of EBV genomics in understanding disease mechanisms and developing precision interventions to address the global burden of EBV\u2010related diseases.<\/jats:p>","DOI":"10.1002\/jmv.70883","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T09:08:58Z","timestamp":1776071338000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["EBV Genome Variations and Association With Diseases"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7246-5136","authenticated-orcid":false,"given":"Xueer","family":"Lin","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Center Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingtong","family":"Liang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Center Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuting","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Center Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinyao","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Center Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Center Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Center Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(64)91524-7"},{"key":"e_1_2_15_3_1","unstructured":"IARC. \u201c Epstein\u2010Barr Virus and Kaposi's Sarcoma Herpesvirus\/Human Herpesvirus 8. 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