Abstract
Lymphoblastoid cell lines (LCLs) are commonly used in molecular genetics, supplying DNA for the HapMap and 1000 Genomes Projects, used to test chemotherapeutic agents, and informing the basis of a number of population genetics studies of gene expression. The process of transforming human B cells into LCLs requires the presence of Epstein-Barr virus (EBV), a double-stranded DNA virus which through B-cell immortalisation maintains an episomal virus genome in every cell of an LCL at variable copy numbers. Previous studies have reported that EBV alters host-gene expression and EBV copy number may be under host genetic control. We performed a genome-wide association study of EBV genome copy number in LCLs and found the phenotype to be highly heritable, although no individual SNPs achieved a significant association with EBV copy number. The expression of two host genes (CXCL16 and AGL) was positively correlated and expression of ADARB2 was negatively correlated with EBV copy number in a genotype-independent manner. This study shows an association between EBV copy number and the gene expression profile of LCLs, and suggests that EBV copy number should be considered as a covariate in future studies of host gene expression in LCLs.
Highlights
Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus
A comparison of EpsteinBarr virus copy number in 62 adult and paediatric Lymphoblastoid cell lines (LCLs) found considerable inter-individual variation in EBV copy number that correlated with expression of immediate-early viral lytic genes BRLF1 and BZLF1, suggesting that spontaneous lytic reactivation is the cause of high EBV genome copy numbers in a subset of LCLs
We examined the trait of EBV copy number in different populations (Figure 1 B), and found significant differences in the mean EBV copy number between the populations (ANOVA p,2.2610216)
Summary
Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus. Following primary infection EBV establishes lifelong persistent infection through latent infection of memory B cells where the virus genome is transcriptionally silent [1,2]. A comparison of EpsteinBarr virus copy number in 62 adult and paediatric LCLs found considerable inter-individual variation in EBV copy number that correlated with expression of immediate-early viral lytic genes BRLF1 and BZLF1, suggesting that spontaneous lytic reactivation is the cause of high EBV genome copy numbers in a subset of LCLs. After the addition of acyclovir, a drug which inhibits viral reactivation, Davies et al showed EBV genome copy numbers fall in LCLs, and return to previous high levels after the removal of acyclovir [8]. After the addition of acyclovir, a drug which inhibits viral reactivation, Davies et al showed EBV genome copy numbers fall in LCLs, and return to previous high levels after the removal of acyclovir [8] This suggests that spontaneous lytic reactivation may be under the control of cell-intrinsic factors. We have hypothesised that high EBV copy number in LCLs is the result of poor host cell control of the EBV latentlytic cycle switch, and may be under the control of host genetic factors
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