L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism

Abstract

Long Interspersed Element 1 (L1) is a retrotransposon that comprises ;17% of the human genome. Despite its abundance in mammalian genomes, relatively little is understood about L1 retrotransposition in vivo. To study the timing and tissue specificity of retrotransposition, we created transgenic mouse and rat models containing human or mouse L1 elements controlled by their endogenous promoters. Here, we demonstrate abundant L1 RNA in both germ cells and embryos. However, the integration events usually occur in embryogenesis rather than in germ cells and are not heritable. We further demonstrate L1 RNA in preimplantation embryos lacking the L1 transgene and L1 somatic retrotransposition events in blastocysts and adults lacking the transgene. Together, these data indicate that L1 RNA transcribed in male or female germ cells can be carried over through fertilization and integrate during embryogenesis, an interesting example of heritability of RNA independent of its encoding DNA. Thus, L1 creates somatic mosaicism during mammalian development, suggesting a role for L1 in carcinogenesis and other disease.[Keywords: Retrotransposon; Line-1; somatic mosaicism; RNA carryover] Supplemental material is available at http://www.genesdev.org.

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

“…Low-level L1 expression does occur in the male and female germlines (Branciforte and Martin 1994;Ostertag and Kazazian Jr. 2001); however, little retrotransposition occurs. Instead, most L1 retrotransposition occurs early in embryogenesis leading to somatic mosaicism (Kano et al 2009). L1 retrotransposition has also been observed in neuronal progenitor cells (Muotri et al 2005) and in the adult hippocampus (Coufal et al 2009;Muotri et al 2009).…”

Reading TE leaves: New approaches to the identification of transposable element insertions

“…For example, researchers interested in the mechanism and impact of retrotransposition have engineered L1 elements to demonstrate retrotransposition in somatic cells Garcia-Perez et al 2007;Coufal et al 2009;Kano et al 2009). By including tumor-derived cell lines in their study, Iskow et al (2010) were able to distinguish germline mutations from those made in somatic cells.…”

ROBO2 gene variants in children with primary nonsyndromic vesicoureteral reflux with or without renal hypoplasia/dysplasia

“…The mutational analysis in this study included only the exons and their intronic boundaries, leaving out the noncoding regions of the gene. Even though ROBO2 content in transposable elements is relatively low (15) taking into account the above, along with the fact that retrotransposons are active during embryogenesis (18), it could be speculated that retrotransposon insertions, in addition to a polymorphism such that found here (IVS5-31), which may affect splicing, could lead to alteration of ROBO2 gene expression in patients with CAKUT. The role of retrotransposons in ROBO2 gene expression therefore needs further investigation.…”

“…Transposable elements are capable of mobilization and integration into new genomic sites, and their activity is generally controlled by various cellular defense mechanisms, such as DNA methylation (16). This control mechanism has been shown to be restricted during development and embryogenesis (18). Deregulated activity of transposable elements has been associated with monogenic and multifactorial genetic diseases (16).…”