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Abstract
Upon cell invasion, retroviruses generate a DNA copy of their RNA genome and integrate retroviral cDNA within host chromosomal DNA. Integration occurs throughout the host cell genome, but target site selection is not random. Each subgroup of retrovirus is distinguished from the others by attraction to particular features on chromosomes. Despite extensive efforts to identify host factors that interact with retrovirion components or chromosome features predictive of integration, little is known about how integration sites are selected. We attempted to identify markers predictive of retroviral integration by exploiting Precision-Recall methods for extracting information from highly skewed datasets to derive robust and discriminating measures of association. ChIPSeq datasets for more than 60 factors were compared with 14 retroviral integration datasets. When compared with MLV, PERV or XMRV integration sites, strong association was observed with STAT1, acetylation of H3 and H4 at several positions, and methylation of H2AZ, H3K4, and K9. By combining peaks from ChIPSeq datasets, a supermarker was identified that localized within 2 kB of 75% of MLV proviruses and detected differences in integration preferences among different cell types. The supermarker predicted the likelihood of integration within specific chromosomal regions in a cell-type specific manner, yielding probabilities for integration into proto-oncogene LMO2 identical to experimentally determined values. The supermarker thus identifies chromosomal features highly favored for retroviral integration, provides clues to the mechanism by which retrovirus integration sites are selected, and offers a tool for predicting cell-type specific proto-oncogene activation by retroviruses.
Highlights
Retroviruses and retrotransposons are of profound importance to eukaryotic biology, evolution, and medicine
To identify markers predictive of retroviral integration site selection, stringent associations were sought between ChIPSeq profiles for more than 60 chromatin-associated factors (Table 1) [63,64,65,66,67,68,69] and 14 retroviral integration site datasets (Table 2) [31,43,70,71,72,73,74,75,76,77]
Following a common convention in the retrovirus integration literature [78], association with a given marker was defined as integration within 2 kB of the nearest marker on the linear sequence of the chromosome
Summary
Retroviruses and retrotransposons are of profound importance to eukaryotic biology, evolution, and medicine These retroelements constitute at least 40% of the mass of mammalian genomes [1] and 75% of the maize genome [2]. Retroelements have the potential to influence local gene expression or to promote recombination and generate deletion mutations [5,6,7]. In some cases they act in trans to catalyze retrotransposition of cellular RNAs, generating pseudogenes or new exons within existing genes [8,9]. It has been suggested that programmed release from retroelement silencing accompanies metazoan development and leads to hypermutation in complex somatic tissues like the brain [11,12]
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