Mobile elements create structural variation: Analysis of a complete human genome

Xing, Jinchuan; Zhang, Yuhua; Han, Kyudong; Salem, Abdel Halim; Sen, Shurjo K.; Huff, Chad; Zhou, Qiong; Kirkness, Ewen F.; Lévy, Samuel; Batzer, Mark A.; Jorde, Lynn B.

doi:10.1101/gr.091827.109

Cited by 266 publications

(306 citation statements)

References 80 publications

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“…The frequency of L1 insertion in the human germline has been recently estimated by genomic mapping of dimorphic L1 loci between individuals. De novo insertions appear to be very infrequent (e.g., approximately 1 insertion in every 100-300 live births) (66)(67)(68). Accordingly, our limited understanding of the developmental timing of new L1 insertions comes from isolated case reports of pathological insertions in humans (69,70).…”

Section: Discussionmentioning

confidence: 99%

Intact piRNA pathway prevents L1 mobilization in male meiosis

Newkirk

Lee

Grandi

et al. 2017

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

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The PIWI-interacting RNA (piRNA) pathway is essential for retrotransposon silencing. In piRNA-deficient mice, L1-overexpressing male germ cells exhibit excessive DNA damage and meiotic defects. It remains unknown whether L1 expression simply highlights piRNA deficiency or actually drives the germ-cell demise. Specifically, the sheer abundance of genomic L1 copies prevents reliable quantification of new insertions. Here, we developed a codon-optimized L1 transgene that is controlled by an endogenous mouse L1 promoter. Importantly, DNA methylation dynamics of a single-copy transgene were indistinguishable from those of endogenous L1s. Analysis of Mov10l1 −/− testes established that de novo methylation of the L1 transgene required the intact piRNA pathway. Consistent with loss of DNA methylation and programmed reduction of H3K9me2 at meiotic onset, the transgene showed 1,400-fold increase in RNA expression and consequently 70-fold increase in retrotransposition in postnatal day 14 Mov10l1 −/− germ cells compared with the wildtype. Analysis of adult Mov10l1 −/− germ-cell fractions indicated a stage-specific increase of retrotransposition in the early meiotic prophase. However, extrapolation of the transgene data to endogenous L1s suggests that it is unlikely insertional mutagenesis alone accounts for the Mov10l1 −/− phenotype. Indeed, pharmacological inhibition of reverse transcription did not rescue the meiotic defect. Cumulatively, these results establish the occurrence of productive L1 mobilization in the absence of an intact piRNA pathway but leave open the possibility of processes preceding L1 integration in triggering meiotic checkpoints and germ-cell death. Additionally, our data suggest that many heritable L1 insertions originate from individuals with partially compromised piRNA defense.LINE-1 reporter transgene | meiotic arrest | PIWI-interacting RNA | retrotransposition | spermatogenesis T he bulk of mammalian genomes are made up of transposable elements, the majority of which are retrotransposons (1). Retrotransposons are classified into long-interspersed elements (LINEs), short-interspersed elements (SINEs), and LTR retrotransposons, which collectively account for 43% and 37% of the human and mouse genomes, respectively (2). Retrotransposons amplify in the genome through an RNA intermediate, a process termed retrotransposition. LINEs are autonomous elements. An intact, full-length LINE-1 (L1) encodes two ORFs (i.e., ORF1 and ORF2); both are required for L1 mobilization (3). SINEs are nonautonomous elements and rely on L1's proteins for propagation in the genome (4). LTR retrotransposons are autonomous but appear to be inactivated in the human genome (5). Retrotransposition endangers the integrity of both somatic and germline genomes through insertional mutagenesis. In somatic tissues, both elevated L1 expression and retrotransposition have been strongly associated with many types of human cancers (6, 7). In a few cases, specific retrotransposition events (i.e., insertions) have been determined to drive t...

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Section: Discussionmentioning

confidence: 99%

Intact piRNA pathway prevents L1 mobilization in male meiosis

Newkirk

Lee

Grandi

et al. 2017

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

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“…The sequences directly neighboring the intact Alu termini suggested overlapping intronic regions as the target for retrotransposition in both cases. The fact that they reside in one and the same AT-rich stretch (Figures 1c′-c′′), together with the general rarity of germline Alu retrotransposition 15 made us hypothesize that a single insertion, rather than two independent ones, may be part of an explanation (Figure 2a-a′′). To test this hypothesis we used three highly polymorphic microsatellites to construct haplotypes for the SPAST locus in both families.…”

Section: Two Intragenic Spast Deletions That Involve Distinct Exons Cmentioning

confidence: 99%

A polymorphic Alu insertion that mediates distinct disease-associated deletions

et al. 2016

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Large deletions that are associated with insertions of Alu-derived sequence represent a rare, but potentially unique class of alterations. Whether they form by a one-step mechanism or by a primary insertion step followed by an independent secondary deletion step is not clear. We resolved two disease-associated SPAST deletions, which involve distinct exons by long range PCR. Alu-derived sequence was observed between the breakpoints in both cases. The intronic regions that represent the targets of potentially involved Alu retrotransposition events overlapped. Microsatellite-and SNP-based haplotyping indicated that both deletions originated on one and the same founder allele. Our data suggest that the deletions are best explained by two-step insertion-deletion scenarios for which a single Alu retrotransposition event represents the shared primary step. This Alu then mediated one of the deletions by non-homologous end joining and the other by non-allelic homologous recombination. Our findings thus strongly argue for temporal separation of insertion and deletion in Alu insertion-associated deletions. They also suggest that certain Alu integrations confer a general increase in local genomic instability, and that this explains why they are usually not detected during the probably short time that precedes the rearrangements they mediate.

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“…The most recent estimate prior to this work was one new insertion for every 225 births (Xing et al 2009). Ewing and Kazazian (2010b) and Huang et al (2010) both essentially doubled this value to between one in 140 births and one in 108 births, respectively.…”

Section: Human Applications: Variationmentioning

confidence: 99%

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

Ray¹,

Batzer²

2011

Genome Res.

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Transposable elements (TEs) are a tremendous source of genome instability and genetic variation. Of particular interest to investigators of human biology and human evolution are retrotransposon insertions that are recent and/or polymorphic in the human population. As a consequence, the ability to assay large numbers of polymorphic TEs in a given genome is valuable. Five recent manuscripts each propose methods to scan whole human genomes to identify, map, and, in some cases, genotype polymorphic retrotransposon insertions in multiple human genomes simultaneously. These technologies promise to revolutionize our ability to analyze human genomes for TE-based variation important to studies of human variability and human disease. Furthermore, the approaches hold promise for researchers interested in nonhuman genomic variability. Herein, we explore the methods reported in the manuscripts and discuss their applications to aspects of human biology and the biology of other organisms.

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Mobile elements create structural variation: Analysis of a complete human genome

Cited by 266 publications

References 80 publications

Intact piRNA pathway prevents L1 mobilization in male meiosis

Intact piRNA pathway prevents L1 mobilization in male meiosis

A polymorphic Alu insertion that mediates distinct disease-associated deletions

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

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