Latent infection with Kaposi’s sarcoma-associated herpesvirus enhances retrotransposition of long interspersed element-1

Long interspersed element 1 (LINE-1 or L1) retrotransposons have markedly affected the human genome. L1s must retrotranspose in the germ line or during early development to ensure their evolutionary success, yet the extent to which this process affects somatic cells is poorly understood. We previously demonstrated that engineered human L1s can retrotranspose in adult rat hippocampus progenitor cells in vitro and in the mouse brain in vivo. Here we demonstrate that neural progenitor cells isolated from human fetal brain and derived from human embryonic stem cells support the retrotransposition of engineered human L1s in vitro. Furthermore, we developed a quantitative multiplex polymerase chain reaction that detected an increase in the copy number of endogenous L1s in the hippocampus, and in several regions of adult human brains, when compared to the copy number of endogenous L1s in heart or liver genomic DNAs from the same donor. These data suggest that de novo L1 retrotransposition events may occur in the human brain and, in principle, have the potential to contribute to individual somatic mosaicism.

Mobile DNAs, also known as transposons or 'jumping genes', are widespread in nature and comprise an estimated 45% of the human genome. Transposons are divided into two general classes based on their transposition intermediate (DNA or RNA). Only one subclass, the non-LTR retrotransposons, which includes the Long INterspersed Element-1 (LINE-1 or L1), is currently active in humans as indicated by 96 disease-causing insertions. The autonomous LINE-1 is capable of retrotransposing not only a copy of its own RNA in cis but also other RNAs (Alu, SINE-VNTR-Alu (SVA), U6) in trans to new genomic locations through an element encoded reverse transcriptase. L1 can also retrotranspose cellular mRNAs, resulting in processed pseudogene formation. Here, we highlight recent reports that update our understanding of human L1 retrotransposition and their role in disease. Finally we discuss studies that provide insights into the past and current activity of these retrotransposons, and shed light on not just when, but where, retrotransposition occurs and its part in genetic variation. Copyright © 2012 Elsevier Ltd. All rights reserved.

Retrotransposons, mainly LINEs, SINEs, and endogenous retroviruses, make up roughly 40% of the mammalian genome and have played an important role in genome evolution. Their prevalence in genomes reflects a delicate balance between their further expansion and the restraint imposed by the host. In any human genome only a small number of LINE1s (L1s) are active, moving their own and SINE sequences into new genomic locations and occasionally causing disease. Recent insights and new technologies promise answers to fundamental questions about the biology of transposable elements.