300: Population-scale WGS links MHC class II antigen presentation to persistent Epstein–Barr virus (EBV) DNA

Nyeo SS et al., Nature, doi:10.1038/s41586-025-10020-2 - Population-scale WGS reanalysis quantifies persistent EBV DNA and shows MHC class II–mediated antigen presentation predicts EBV DNAemia and links to autoimmune and respiratory disease. Key terms: Epstein–Barr virus, MHC class II, whole-genome sequencing, HLA, antigen presentation.

Study Highlights:
Using whole-genome sequencing from UK Biobank (n≈490,560) and All of Us (n≈245,394), the authors extracted chrEBV-mapping reads, masked low-mappability regions, and defined EBV DNAemia (>1.2 genomes per 10^4 cells) in 9.7–11.9% of donors. They performed PheWAS, GWAS and ExWAS and identified 22 genome-wide significant loci and 686 missense variants across 148 genes with heritability enrichment in immune regulatory regions and B cells/antigen-presenting cells. Single-cell module scoring, pathway analyses and NetMHCpan/NetMHCIIpan peptide-presentation modeling implicated variable antigen processing and MHC class II presentation as primary determinants of EBV persistence, with stronger predicted presentation linked to lower EBV DNAemia. EBV DNAemia was reproducibly associated with autoimmune, respiratory, neurological and cardiovascular phenotypes across cohorts.

Conclusion:
Reanalysis of population-scale WGS demonstrates that host genetic variation—predominantly in antigen processing and MHC class II peptide presentation—modulates persistent EBV DNA in blood and associates with multiple complex diseases.

Music:
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Article title:
Population-scale sequencing resolves determinants of persistent EBV DNA

First author:
Nyeo SS

Journal:
Nature, doi:10.1038/s41586-025-10020-2

DOI:
10.1038/s41586-025-10020-2

Reference:
Nyeo SS, Cumming EM, Burren OS, Pagadala MS, Gutierrez JC, Ali TA, Kida LC, Chen Y, Chu H, Hu F, Zou XZ, Hollis B, Fabre MA, MacArthur S, Wang Q, Ludwig LS, Dey KK, Petrovski S, Dhindsa RS & Lareau CA. Population-scale sequencing resolves determinants of persistent EBV DNA. Nature. 2026 Feb 19;650:664–672. https://doi.org/10.1038/s41586-025-10020-2

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the spoken content for core EBV DNAemia measurement, population-scale findings, genetic architecture (GWAS/ExWAS), MHC class II/HLA roles, peptide presentation modeling, cell-type enrichment, phenotype associations, viral genome considerations, and replication across UKB and AoU.
- transcript topics: Definition and measurement of EBV DNAemia from population-scale WGS; Population-scale prevalence in UKB and AoU, threshold and binarization; Genome-wide and exome-wide association results (22 loci; 686 missense variants in 148 genes); Role of MHC class II and HLA variation in EBV DNAemia; Specific HLA alleles: HLA-A*03:01 risk; HLA-DRB1*12:01 protection; NetMHC/NetMHCIIpan predictions and HBR-based antigen presentation

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- EBV DNAemia is quantified from chrEBV reads in population-scale WGS; threshold set at 1.2 EBV genomes per 10^4 human cells
- UKB prevalence of EBV DNAemia: 9.7% (47,452 individuals); AoU replication prevalence: 11.9%
- Genome-wide analysis identified 22 independent loci associated with EBV DNAemia; 686 missense variants across 148 genes
- Heritability enriched in immune regulatory regions; pronounced enrichment in B cells and antigen-presenting cells
- HLA region drives strongest genetic associations; HLA-A*03:01 increases risk; HLA-DRB1*12:01 is protective
- Predicted EBV epitope presentation strength by MHC class II alleles correlates with lower EBV DNAemia; class II alleles show strongest associations

QC result: Pass.