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Abstract
DNA sequences from retroviruses, retrotransposons, DNA transposons, and parvoviruses can all become integrated into the human genome. Accumulation of such sequences accounts for at least 40% of our genome today. These integrating elements are also of interest as gene-delivery vectors for human gene therapy. Here we present a comprehensive bioinformatic analysis of integration targeting by HIV, MLV, ASLV, SFV, L1, SB, and AAV. We used a mathematical method which allowed annotation of each base pair in the human genome for its likelihood of hosting an integration event by each type of element, taking advantage of more than 200 types of genomic annotation. This bioinformatic resource documents a wealth of new associations between genomic features and integration targeting. The study also revealed that the length of genomic intervals analyzed strongly affected the conclusions drawn—thus, answering the question “What genomic features affect integration?” requires carefully specifying the length scale of interest.
Highlights
The exons of human genes comprise only about 1.5% of the total genome sequence [1,2]
Datasets Studied The integration site collections studied are listed in Table
Addition of other genomic features to a model based on score.20 alone using Bayes model averaging (BMA) showed little or no further improvement in receiver operator characteristic (ROC) areas
Summary
The exons of human genes comprise only about 1.5% of the total genome sequence [1,2]. Fragments of genomic parasites—integrating viruses and transposons—comprise a much larger fraction, at least 40%. These elements are highly dynamic—new elements insert and occasionally excise, and repeated sequences provide portable regions of sequence homology that act as substrates for homologous recombination. Integration of new DNA can result in changes in gene activity or formation of new genes [3,4]. Integrating DNA elements are important in human gene therapy as delivery vehicles for new sequences. Recent setbacks in gene therapy, emphasize the importance of integration target site selection. In an otherwise quite successful gene therapy trial treating human X-SCID, the gene therapy vector used integrated near a proto-oncogene and caused leukemia in three of the patients treated [5,6]
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