Gene mutations and genomic rearrangements in the mouse as a result of transposon mobilization from chromosomal concatemers

Abstract

Previous studies of the Sleeping Beauty (SB) transposon system, as an insertional mutagen in the germline of mice, have used reverse genetic approaches. These studies have led to its proposed use for regional saturation mutagenesis by taking a forward-genetic approach. Thus, we used the SB system to mutate a region of mouse Chromosome 11 in a forward-genetic screen for recessive lethal and viable phenotypes. This work represents the first reported use of an insertional mutagen in a phenotype-driven approach. The phenotype-driven approach was successful in both recovering visible and behavioral mutants, including dominant limb and recessive behavioral phenotypes, and allowing for the rapid identification of candidate gene disruptions. In addition, a high frequency of recessive lethal mutations arose as a result of genomic rearrangements near the site of transposition, resulting from transposon mobilization. The results suggest that the SB system could be used in a forward-genetic approach to recover interesting phenotypes, but that local chromosomal rearrangements should be anticipated in conjunction with singlecopy, local transposon insertions in chromosomes. Additionally, these mice may serve as a model for chromosome rearrangements caused by transposable elements during the evolution of vertebrate genomes.Citation: Geurts AM, Collier LS, Geurts JL, Oseth LL, Bell ML, et al. (2006) Gene mutations and genomic rearrangements in the mouse as a result of transposon mobilization from chromosomal concatemers. PLoS Genet 2(9): e156.

Whole-Body Sleeping Beauty Mutagenesis Can Cause Penetrant Leukemia/Lymphoma and Rare High-Grade Glioma without Associated Embryonic Lethality

“…The lower number of mobilizing transposons in T2/onc low-copy; Rosa26 -SB11 mice could result in fewer double strand breaks for cellular machinery to repair. Another explanation for embryonic lethality in T2/onc high-copy; Rosa26 -SB11 double transgenics could be the generation of concatomer-associated rearrangements which can accompany SB germline transposition (22). High transposition rates associated with high-copy concatomers could increase the severity of these rearrangements.…”

Functional ability of cytoskeletal β-actin regulator to drive constitutive and ubiquitous expression of a fluorescent reporter throughout the life cycle of transgenic marine medaka Oryzias dancena

“…Fluorescence intensity in F1 transgenics was much stronger in ODM2f than ODM4m, which would be mainly related with the difference in copy number of transgene integrants (i.e., 242 and 34 copies for ODM2f and ODM4m, respectively) between the two transgenic lines (see also Nam et al 1999;Kim et al 2004). Random nonhomologous integration of a repetitive, high copy number of transgene in concatemer(s) has been known to often be prone to transgene rearrangement and transgene silencing, which could frequently lead to transgenic animals that do not faithfully express the introduced transgene (Dorer and Henikoff 1997; Geurts et al 2006). However in contrast with these previous reports, result in this study suggests that both transgenic lines have not experienced significantly the epigenetic modification in their transgene locus until F3 generation.…”

Jumping genes and epigenetics: Towards new species

“…Our exploration of the dynamics of transposable elements (TEs) in natural populations led us to ask how TE mobilization is involved in speciation (Vieira et al, 1999;Rebollo et al, 2008;Fablet et al, 2009). In this short-review we argue that TEs are able to induce speciation through chromosomal rearrangements since, 1) chromosomal rearrangements are able to induce speciation (Noor et al, 2001;Baird et al, 2009;Greig, 2009), 2) bursts of TE transposition can cause chromosomal rearrangements (Geurts et al, 2006;Weil, 2009;Zhang et al, 2009), and 3) bursts of TE transposition may be driven by the selective release of active elements as the result of an epigenetic response to the environment (Lisch, 2009). We also discuss the importance of TE-induced speciation compared to that of other speciation mechanisms.…”