An active murine transposon family pair: Retrotransposition of “master” MusD copies and ETn <i>trans</i>-mobilization

Ribet, David; Dewannieux, Marie; Heidmann, Thiérry

doi:10.1101/gr.2924904

Cited by 81 publications

(101 citation statements)

References 23 publications

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“…We rooted the trees between MusD elements that have the highest number of differences between 5 0 and 3 0 LTRs because accumulation of substitutions between 5 0 and 3 0 LTRs that are normally identical is a mark of inactivity and ancient transposition. Our phylogenetic analysis of the non-LTR data set revealed that Dac 1j and Dac 2j transposons group with early MusDs (100% BP), three of which have shown to be active in vitro (Ribet et al 2004). Although the signal of the LTR tree is weaker because of the short sequence length (321 bp) and the phylogenetic trees are not completely congruent, we did not observe striking differences between topologies of LTR and non-LTR trees.…”

Section: Phylogenetic Analysismentioning

confidence: 66%

“…Dac 1j and Dac 2j are the only cases of disease-causing insertions of MusD elements reported to date (Maksakova et al 2006).There are about a hundred MusD elements in the mouse genome, with only a subset of them active. MusD elements carry three genes that are absolutely required for retrotransposition: gag, pro, and pol (Ribet et al 2004). By building a phylogenetic tree with the elements inserted at the Dac loci and other related MusD and ETn sequences, we found that Dac insertions cluster together and in the same branch as the active ETnII elements of the family.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, open reading frames in MusD elements do not seem to be crucial for transposition activity since active ETns do not have any genes needed for transposition (Ribet et al 2004). This suggests that these elements can utilize the proteins needed for transposition produced by other MusD elements in trans.…”

Section: Phylogenetic Analysismentioning

confidence: 99%

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Characterization of mouse Dactylaplasia mutations: a model for human ectrodactyly SHFM3

et al. 2008

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SHFM3 is a limb malformation characterized by the absence of central digits. It has been shown that this condition is associated with tandem duplications of about 500 kb at 10q24. The Dactylaplasia mice display equivalent limb defects and the two corresponding alleles (Dac 1j and Dac 2j ) map in the region syntenic with the duplications in SHFM3. Dac 1j was shown to be associated with an insertion of an unspecified ETn-like mouse endogenous transposon upstream of the Fbxw4 gene. Dac 2j was also thought to be an insertion or a small inversion in intron 5 of Fbxw4, but the breakpoints and the exact molecular lesion have not yet been characterized. Here we report precise mapping and characterization of these alleles. We failed to identify any copy number differences within the SHFM3 orthologous genomic locus between Dac mutant and wildtype littermates, showing that the Dactylaplasia alleles are not associated with duplications of the region, in contrast with the described human SHFM3 cases. We further show that both Dac 1j and Dac 2j are caused by insertions of MusD retroelements that share 98% sequence identity. The differences between the nature of the human and mouse genomic abnormalities argue against models proposed so far that either envisioned SHFM3 as a local trisomy or Dac as a mutant allele of Fbxw4. Instead, both genetic conditions might lead to complex alterations of gene regulation mechanisms that would impair limb morphogenesis. Interestingly, the Dac 2j mutation occurs within a highly conserved element that may represent a regulatory sequence for a neighboring gene.

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Section: Phylogenetic Analysismentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

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Characterization of mouse Dactylaplasia mutations: a model for human ectrodactyly SHFM3

et al. 2008

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“…These insertions were identified as almost identical MusD elements, containing ORFs for gag, pro, and pol proteins of D-type virus. MusD is known to trigger the mobilization of ETn elements, which are the most active murine mobile elements and cause the majority of insertional mutations in mice (4,5,20,21). Although the MusD itself has been shown previously to be autonomous for transposition in a tissue culture assay, no pathegnic MusD insertion has been identified to date (20).…”

Section: Discussionmentioning

confidence: 99%

Genetically regulated epigenetic transcriptional activation of retrotransposon insertion confers mouse dactylaplasia phenotype

Kano

Kurahashi

Toda

2007

Proc. Natl. Acad. Sci. U.S.A.

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Dactylaplasia, characterized by missing central digital rays, is an inherited mouse limb malformation that depends on two genetic loci. The first locus, Dac, is an insertional mutation around the dactylin gene that is inherited as a semidominant trait. The second locus is an unlinked modifier, mdac/Mdac, that is polymorphic among inbred strains. Mdac dominantly suppresses the dactylaplasia phenotype in mice carrying Dac. However, little is known about either locus or the nature of their interaction. Here we show that Dac is a LTR retrotransposon insertion caused by the type D mouse endogenous provirus element (MusD). This insertion exhibits different epigenetic states and spatiotemporally expresses depending on the mdac/Mdac modifier background. In dactylaplasia mutants (Dac/؉ mdac/mdac), the LTRs of the insertion contained unmethylated CpGs and active chromatin. Furthermore, MusD elements expressed ectopically at the apical ectodermal ridge of limb buds, accompanying the dactylaplasia phenotype. On the other hand, in Dac mutants carrying Mdac (Dac/؉ Mdac/mdac), the 5 LTR of the insertion was heavily methylated and enriched with inactive chromatin, correlating with inhibition of the dactylaplasia phenotype. Ectopic expression was not observed in the presence of Mdac, which we refined to a 9.4-Mb region on mouse chromosome 13. We report a pathogenic mutation caused by MusD. Our findings indicate that ectopic expression from the MusD insertion correlates with the dactylaplasia phenotype and that Mdac acts as a defensive factor to protect the host genome from pathogenic MusD insertions.dactylin ͉ ectrodactyly ͉ LTR ͉ split hand/split foot malformation ͉ methylation D actylaplasia is an inherited mouse limb malformation that is characterized by missing central digital rays. The Dac mutation is inherited as a semidominant trait, evidenced by missing central digits in the fore-and hindlimbs of heterozygous mice and monodactyly in homozygous mice (1, 2). The Dac locus has been mapped to the distal end of chromosome 19. Two independent Dac mutant alleles, Dac 1J and Dac 2J , arose spontaneously in breeding colonies. Both are insertions residing within the same locus: Dac 1J is located in the region upstream of the dactylin gene, and Dac 2J is located in intron 5 of dactylin (3). Southern blot analysis indicated that both insertions are larger than 4.5 kb; however, ''jumping PCR'' identified only the LTR portion of the insertion (3). Partial PCR products terminating in the 5Ј and 3Ј LTRs cross-prime each other, resulting in amplified products that lack any of the internal sequence between LTRs. Therefore, these insertions were thought to be caused by an early transposon (ETn) element, which is a common mutagen in mice (4, 5).Split hand/split foot malformation (SHFM) in humans is a congenital limb malformation that has an ectrodactyly phenotype analogous to that of the dactylaplasia mouse. SHFM is genetically heterogeneous; to date, five different loci, SHFM1 to SHFM5, have been mapped. Dactylaplasia is a mouse model of S...

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“…In spite of the scarcity of elements with full coding potential, the retroviral-like intracisternal A particle (IAP) and the MusD/Early Transposon (ETn) families are still responsible for approximately 10% of spontaneous mutations in inbred mice (Maksakova et al, 2006. Using ex vivo assays, a few transpositioncompetent elements have been shown to efficiently mobilize the impotent members of their own family in trans, providing an alternative strategy for de novo insertions (Ribet et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

2010

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Retrotransposable elements comprise around 50% of the mammalian genome. Their activity represents a constant threat to the host and has prompted the development of adaptive control mechanisms to protect genome architecture and function. To ensure their propagation, retrotransposons have to mobilize in cells destined for the next generation. Accordingly, these elements are particularly well suited to transcriptional networks associated with pluripotent and germinal states in mammals. The relaxation of epigenetic control that occurs in the early developing germline constitutes a dangerous window in which retrotransposons can escape from host restraint and massively expand. What could be observed as risky behavior may turn out to be an insidious strategy developed by germ cells to sense retrotransposons and hold them back in check. Herein, we review recent insights that have provided a detailed picture of the defense mechanisms that concur toward retrotransposon silencing in mammalian genomes, and in particular in the germline. In this lineage, retrotransposons are hit at multiple stages of their life cycle, through transcriptional repression, RNA degradation and translational control. An organized cross-talk between PIWIinteracting small RNAs (piRNAs) and various nuclear and cytoplasmic accessories provides this potent and multilayered response to retrotransposon unleashing in early germ cells.

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An active murine transposon family pair: Retrotransposition of “master” MusD copies and ETn trans-mobilization

Cited by 81 publications

References 23 publications

Characterization of mouse Dactylaplasia mutations: a model for human ectrodactyly SHFM3

Characterization of mouse Dactylaplasia mutations: a model for human ectrodactyly SHFM3

Genetically regulated epigenetic transcriptional activation of retrotransposon insertion confers mouse dactylaplasia phenotype

Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

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