Abstract
BackgroundTransposable elements (TEs) make up > 50% of the human genome, and the majority of retrotransposon insertions are truncated and many are located in introns. However, the effects of retrotransposition on the host genes remain incompletely known.ResultsWe report here that insertion of a chimeric L1 (cL1), but not IAP solo LTR, into intron 6 of Axin1 using CRIPSR/Cas9 induced the kinky tail phenotype with ~ 80% penetrance in heterozygous AxincL1 mice. Both penetrant (with kinky tails) and silent (without kinky tails) AxincL1 mice, regardless of sex, could transmit the phenotype to subsequent generations with similar penetrance (~ 80%). Further analyses revealed that a longer Axin1 transcript isoform containing partial cL1-targeted intron was present in penetrant, but absent in silent and wild type mice, and the production of this unique Axin1 transcript appeared to correlate with altered levels of an activating histone modification, H3K9ac.ConclusionsThe mechanism for AxincL1 mice is different from those previously identified in mice with spontaneous retrotransposition of IAP, e.g., AxinFu and Avy, both of which have been associated with DNA methylation changes. Our data suggest that Axin1 locus is sensitive to genetic and epigenetic alteration by retrotransposons and thus, ideally suited for studying the effects of new retrotransposition events on target gene function in mice.
Highlights
Transposable elements (TEs) make up > 50% of the human genome, and the majority of retrotransposon insertions are truncated and many are located in introns
Insertion of a chimeric L1, not the IAP solo LTR, into intron 6 of Axin1 induced the kinky tail phenotype To test whether an IAP solo LTR can induce the kinky tail phenotype, we first inserted a 335 bp IAP solo LTR flanked by two loxP sites in reverse orientation into intron 6 of Axin1 using CRISPR/CRISPR associated protein 9 (Cas9) (Additional file 1: Figure S1A and supplemental notes)
All homozygous (Axin1cL1/cL1) mice showed kinky tails and displayed neuronal abnormalities characterized by motor discordances, whereas ~ 80% of the heterozygous (Axin1+/cL1) mice showed the kinky tail phenotype and the remaining heterozygous mice had normal tails (Fig. 1 b and c). These results suggest that a chimeric L1/mammalian apparent LTR retrotransposon (MaLR) sequence, rather than IAP solo LTR, can cause the kinky tail phenotype once inserted into intron 6 of Axin1 in mice
Summary
Transposable elements (TEs) make up > 50% of the human genome, and the majority of retrotransposon insertions are truncated and many are located in introns. The vast majority of human TEs are retrotransposons, which replicate via a RNA-based process termed retrotransposition [2]. The vast majority of TEs in the genome are truncated or rearranged, leaving behind 3′ fragments of L1 s or single (“solo”) LTRs of ERVs, in which ORFs critical for TE replication are lacking [2, 3, 20, 21]. Most of the TE insertions described to date in cancers are intronic or intergenic [22, 23] It remains to be investigated the extent to which TE insertions affect the expression of their host coding genes and genomic activities near the insertion sites
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