Additional file 2 of Coordinates and intervals in graph-based reference genomes

Example of gene notation. Example of representation of genes on an alternative locus on GRCh38 (txt). (TXT 4 kb

Additional file 1 of Coordinates and intervals in graph-based reference genomes

Definitions and experiment details. Formal definitions of terms used in the article and details on the section Genes on GRCh38 (pdf). (PDF 181 kb

EBNA2/RBPJ overlap with MS regions.

<p>Results of EBNA2/RBPJ peak overlap with MS associated regions, defined as SNP position ± 50kb</p><p>O/E: factor of observed <i>vs</i> expected overlap</p><p>EBNA2 = Epstein-Barr nuclear antigen 2; RBPJ = Recombination signal-binding protein for immunoglobulin Kappa J region; DHS = DNase I hypersensitive sites; MHC = Major histocompatibility complex; MS = multiple sclerosis.</p><p>EBNA2/RBPJ overlap with MS regions.</p

EBNA2 Binds to Genomic Intervals Associated with Multiple Sclerosis and Overlaps with Vitamin D Receptor Occupancy

<div><p>Epstein-Barr virus (EBV) is a non-heritable factor that associates with multiple sclerosis (MS). However its causal relationship with the disease is still unclear. The virus establishes a complex co-existence with the host that includes regulatory influences on gene expression. Hence, if EBV contributes to the pathogenesis of MS it may do so by interacting with disease predisposing genes. To verify this hypothesis we evaluated EBV nuclear antigen 2 (EBNA2, a protein that recent works by our and other groups have implicated in disease development) binding inside MS associated genomic intervals. We found that EBNA2 binding occurs within MS susceptibility sites more than expected by chance (factor of observed <i>vs</i> expected overlap [O/E] = 5.392-fold, p < 2.0e-05). This remains significant after controlling for multiple genomic confounders. We then asked whether this observation is significant per se or should also be viewed in the context of other disease relevant gene-environment interactions, such as those attributable to vitamin D. We therefore verified the overlap between EBNA2 genomic occupancy and vitamin D receptor (VDR) binding sites. EBNA2 shows a striking overlap with VDR binding sites (O/E = 96.16-fold, p < 2.0e-05), even after controlling for the chromatin accessibility state of shared regions (p <0.001). Furthermore, MS susceptibility regions are preferentially targeted by both EBNA2 and VDR than by EBNA2 alone (enrichment difference = 1.722-fold, p = 0.0267). Taken together, these findings demonstrate that EBV participates in the gene-environment interactions that predispose to MS.</p></div

Histogram plots of VDR, RBPJ and DNase peak distribution centered on EBNA2 peak position.

<p>In similar analyses, when the position of two factors (e.g., co-factors) across the genome tends to coincide, the correspondent graph shows a clear middle-point peak, as seen for the relation between EBNA2 and RBPJ (plot in the middle). Refer to the text for interpretation.</p

EBNA2-VDR joint binding inside MS and other disease-associated regions.

<p>Overlap results for EBNA2-VDR joint occupancy track within MS regions and excess enrichment relatively to EBNA2 exclusive peaks.</p><p>O/E: factor of observed <i>vs</i> expected overlap; ¹: EED for EBNA2-VDR peaks (case) relatively to control (EBNA2 exclusive peaks) inside MS regions.</p><p>EBNA2 = Epstein-Barr nuclear antigen 2; VDR = Vitamin D receptor; MS = multiple sclerosis; DHS = DNase I hypersensitive sites</p><p>EBNA2-VDR joint binding inside MS and other disease-associated regions.</p

EBNA2-VDR joint binding inside RA and SLE associated regions.

<p>Overlap results for EBNA2-VDR joint occupancy track within RA and SLE regions, and excess enrichment of case-control analysis</p><p>O/E: factor of observed <i>vs</i> expected overlap; ¹: EED for EBNA2-VDR joint occupancy track on MS regions (case) relatively to control regions (RA, SLE).</p><p>EBNA2 = Epstein-Barr nuclear antigen 2; VDR = Vitamin D receptor; RA = Rheumatoid arthritis; SLE = Systemic lupus erythematosus; MHC = Major histocompatibility complex.</p><p>EBNA2-VDR joint binding inside RA and SLE associated regions.</p