L1 retrotransposition in the soma: a field jumping ahead
Mobile DNA volume 9, Article number: 22 (2018)
Retrotransposons are transposable elements (TEs) capable of “jumping” in germ, embryonic and tumor cells and, as is now clearly established, in the neuronal lineage. Mosaic TE insertions form part of a broader landscape of somatic genome variation and hold significant potential to generate phenotypic diversity, in the brain and elsewhere. At present, the LINE-1 (L1) retrotransposon family appears to be the most active autonomous TE in most mammals, based on experimental data obtained from disease-causing L1 mutations, engineered L1 reporter systems tested in cultured cells and transgenic rodents, and single-cell genomic analyses. However, the biological consequences of almost all somatic L1 insertions identified thus far remain unknown. In this review, we briefly summarize the current state-of-the-art in the field, including estimates of L1 retrotransposition rate in neurons. We bring forward the hypothesis that an extensive subset of retrotransposition-competent L1s may be de-repressed and mobile in the soma but largely inactive in the germline. We discuss recent reports of non-canonical L1-associated sequence variants in the brain and propose that the elevated L1 DNA content reported in several neurological disorders may predominantly comprise accumulated, unintegrated L1 nucleic acids, rather than somatic L1 insertions. Finally, we consider the main objectives and obstacles going forward in elucidating the biological impact of somatic retrotransposition.
Transposable elements (TEs) and their mobilization in somatic cells were first described by Barbara McClintock’s celebrated research on Ac/Ds loci in maize . In the intervening 70 years, somatic transposition (“cut-and-paste”) and retrotransposition (“copy-and-paste”) of TEs has been reported throughout the tree of life, including, for example, in plants [2, 3], insects [4,5,6,7], rodents [8,9,10] and primates . By definition, mosaic TE insertions are present in at least one, but not all, cells from an individual. New TE insertions, or the deletion of existing TE insertions , may generate germline as well as somatic mosaicism. Indeed, the primary milieu for heritable LINE-1 (L1) retrotransposition in mammals is the early embryo , where new L1 insertions can enter the germline and contribute genetic diversity to offspring [14,15,16,17] whilst potentially also causing somatic mosaicism in the original host [8, 10, 11, 18]. As embryonic development continues, L1 mobilization appears to become more lineage-restricted, perhaps to the extent that only neurons and their progenitor cells support endogenous L1 activity [19,20,21]. Somatic L1 retrotransposition may therefore be an evolutionary byproduct of TEs being active in the developmental niches most likely to spread new copies of themselves to as many germ cells as possible, combined with an inability to prohibit L1 activity in some committed lineages [20,21,22]. We presently lack compelling evidence to reject the null hypothesis that somatic retrotransposition in normal cells is of little consequence to human biology. Intriguing experimental data do however show that L1 activity is elevated coincident with environmental stimuli [23,24,25] and, more extensively, in psychiatric and neurodevelopmental disorders [26,27,28,29]. As a summary view, we propose that retrotransposons can cause somatic mosaicism in mammals, yet the frequency, spatiotemporal extent, biological impact, and molecular processes regulating this phenomenon remain poorly defined.
Several retrotransposon families are currently mobile in mouse and human [16, 30,31,32,33,34]. In this review, we focus on L1 as the only element proven, by multiple orthogonal approaches, to retrotranspose in somatic cells in vivo . Annotated L1 sequences occupy nearly 20% of the human and mouse reference genomes [36, 37]. Although more than 500,000 L1 copies are found in either species, only ~ 100 and ~ 3000 retrotransposition-competent L1s are found per individual human [38, 39] or mouse [40,41,42,43], respectively. A full-length, retrotransposition-competent (donor) L1 is 6-7kbp in length, contains two open reading frames encoding proteins strictly required for retrotransposition (ORF1p and ORF2p) and is transcriptionally regulated by an internal 5′ promoter [44,45,46,47] (Fig. 1). Retrotransposition requires transcription of a polyadenylated mRNA initiated by the canonical L1 promoter, followed by export of the L1 mRNA to the cytoplasm and translation, yielding ORF1p and ORF2p [48,49,50]. Due to cis preference, the L1 mRNA is bound by ORF1p and ORF2p to form a ribonucleoprotein (RNP) that can re-enter the nucleus [51,52,53,54,55,56,57,58,59,60]. Reverse transcription of the L1 mRNA by ORF2p, primed from a genomic free 3′-OH generated by ORF2p endonuclease activity [44, 45, 58, 61,62,63], followed by removal of the L1 mRNA from the intermediate DNA:RNA hybrid, and second strand DNA synthesis, generates a new L1 insertion. This molecular process, termed target-primed reverse transcription (TPRT), was first established by a seminal study of Bombyx mori R2 retrotransposons . If generated via TPRT, new L1 insertions usually carry specific sequence features, including short target site duplications (TSDs) and a polyadenine (polyA) tail (Fig. 1), and integrate into the genome at a degenerate L1 endonuclease motif [44, 46, 65,66,67]. These TPRT hallmarks can be used to validate somatic L1 insertions . A fraction of new L1 insertions transduce DNA from the genomic flanks of their donor L1 to the integration site, facilitating identification of the donor sequence (Fig. 1) [36, 60, 68,69,70,71,72]. 5′ truncation, internal mutations and the acquisition of repressive epigenetic marks can reduce or abolish the retrotransposition competence of new L1 insertions [47, 69, 73,74,75,76,77]. Finally, L1 can mobilize other cellular RNAs in trans, including those produced by Alu and SVA retrotransposons, adding to L1-driven genome sequence variation [31, 32, 34, 78, 79].
The vast majority of highly active, or “hot”, human donor L1s belong to the L1-Ta subfamily [33, 38, 39, 80,81,82,83] and fewer than 10 hot L1s are present in each individual . These hot elements are usually highly polymorphic, with millions of donor L1 alleles potentially yet to be found in the global population [14, 38, 39, 76, 83,84,85]. Approximately 1 in 150 individuals harbors a new L1 insertion . By contrast, three L1 subfamilies (TF, GF, A), defined by their monomeric 5′ promoter and ORF1 sequences, remain retrotransposition-competent in the mouse germline [16, 17, 40,41,42,43, 87,88,89,90]. At least 1 in 8 pups carries a new L1 insertion in inbred C57BL/6 J mice [13, 18]. As for human L1s, internal mutations can strongly influence the mobility of individual mouse L1s [40, 72, 91, 92]. Although the mouse genome contains many more full-length L1s with intact ORFs than the human genome , it is unknown whether mouse L1 retrotransposition potential is concentrated in a similarly small proportion (< 10%) of elements. The distinct promoter sequences driving L1 transcription in mouse and human, and associated differences in their regulation, may also result in divergent spatiotemporal patterns of L1 expression.
Many, if not most, new L1 insertions are unlikely to generate a phenotype . L1-mediated mutagenesis can nonetheless severely impact the functional products of genes  and, presumably as a result, host cells have multiple layers of regulation that limit L1 retrotransposition (Fig. 1, Table 1), including via epigenetic control of the L1 promoter [20, 27, 96,97,98,99,100,101,102,103,104,105,106,107,108] (for relevant recent reviews on L1 host factors and L1 mutations in disease, please see [109,110,111,112,113,114,115]). Even so, L1 mRNA expression and retrotransposition can occur in the pluripotent cells of the early mouse and human embryo, enabling somatic and germline L1 mosaicism prior to lineage commitment [8, 10, 11, 18, 104, 116,117,118,119,120,121].
Engineered L1 mobilization during neuronal differentiation
Neurons and their precursor cells present an exception to L1 restriction in normal committed lineages . The first experimental evidence of L1 retrotransposition in the neuronal lineage was obtained from an engineered system where a human L1 (L1RP ) tagged with an EGFP reporter gene [116, 123] was introduced into cultivated rat neural cells, and into mice as a transgene (Fig. 2) . Strikingly, GFP+ neurons were found in transgenic mice whilst few, if any, GFP+ cells were found in other somatic cell types . Using a different human L1 (L1.3 [124, 125]) tagged with a similar EGFP cassette, our laboratory has recently recapitulated this result (Bodea et al., unpublished data). The L1-EGFP reporter system has been shown to readily mobilize in embryonic stem cells, neural stem cells, neuronal precursor cells, and post-mitotic neurons [19,20,21, 119, 121], indicating potential for endogenous L1 activity at various points of neuronal differentiation in vivo.
Engineered L1-EGFP insertions lacking an intact EGFP sequence due to severe 5′ truncation, as well as those affected by epigenetic silencing of the heterologous promoter driving EGFP expression [19, 21, 126], can result in GFP− cells where retrotransposition has actually taken place (Fig. 2) . As a further caveat, an EGFP-tagged human L1 introduced as a transgene is also likely not subject to the same host factor control as exerted in its native genome. Engineered L1 reporter systems [9, 10, 46, 71, 90, 127, 128] can still provide proof-of-principle evidence that the L1 machinery may enact retrotransposition of L1 and other TEs [31, 32, 34, 79, 129] in a given spatiotemporal context, although, to our knowledge, Alu or SVA trans mobilization by L1 is yet to be demonstrated in primary neurons or neuronal precursor cells. Engineered L1 systems have nonetheless predicted, with substantial success, L1 activity in cells where endogenous L1 mobilization was later confirmed by genomic assays, as for example in the case of the brain.
What is the frequency of endogenous L1 retrotransposition in neurons?
Endogenous L1 retrotransposition is established to occur in mammalian neurons (for reviews, see [35, 67, 130,131,132]). This conclusion is based on genomic analysis of “bulk” brain tissue [20, 133] and individual neural cells, with the latter requiring whole-genome amplification (WGA) [134,135,136,137] or reprogramming via nuclear transfer followed by clonal cell amplification . Exemplary somatic L1 insertions reported to date include two events carrying 5′ or 3′ transductions [36, 68], which were recovered from individual human cortical neurons through WGA followed by whole-genome sequencing (WGS) . Subsequent insertion site-specific PCR amplification and capillary sequencing revealed structural hallmarks consistent with retrotransposition by TPRT . Analyses employing WGA and targeting human L1-genome junctions have also recovered neuronal L1 insertions [134, 135, 137]. Using an orthogonal approach, and in mouse, Hazen et al. applied WGS to stem cell clones reprogrammed via nuclear transfer of olfactory neuron nuclei, and again found somatic L1 insertions mediated by canonical TPRT . Impressively, this work identified 4 somatic L1 insertions in only 6 reprogrammed neuronal clones, with a false negative rate of at least 50%  as mouse L1 3′ ends are depleted in Illumina sequencing [18, 35]. These and other genomic analyses of neuronal genomes have thus far yielded results highly congruent with experiments employing the L1-EGFP reporter in vitro and in transgenic animals [19,20,21]. Together with somatic L1 insertions that may accumulate earlier in development [11, 18, 136], these data suggest that L1 mosaicism occurs relatively often in the mammalian brain. The expected frequency of L1 retrotransposition in neurons is however debated [35, 132, 134, 137] and depends on multiple factors, such as the methods used for WGA, library preparation and sequencing, how false positive and false negative rates are calculated, how insertions are validated, as well as the species, brain region and neuronal subtype being analyzed. Importantly, L1 insertion mapping strategies only find completed retrotransposition events. Host factors may eliminate TPRT intermediates in neurons before integration is fully executed (Table 1) [29, 139, 140] and, for this reason, the frequency of attempted somatic L1 retrotransposition events may be higher than what is found by studies of either endogenous or engineered L1 mobilization.
Current estimates of the L1 retrotransposition rate in human neuronal cells range from 0.04 to 13.7 L1 insertions per neuron . In this context, what is a “low” or “high” frequency? If we assume that the typical human brain contains ~ 90 billion neurons , and apply a conservative denominator of the current lowest estimate of 0.04 unique events per neuron, we would still expect at least 3.6 billion somatic L1 insertions per human brain, and many more events may be shared by multiple cells. Should this be considered as a low rate? Firstly, brain cells are far more physiologically and functionally interdependent than myocytes, hepatocytes, fibroblasts and other somatic cell types found in the body. Highly interconnected neuronal networks may hence be disproportionately impacted by mutations in “node” cells [142, 143]. Secondly, rather than occurring randomly throughout the genome, somatic L1 insertions may be found at a significantly higher rate in neuronally expressed genes [21, 133, 137], although at this stage the separation of potential endogenous L1 insertional preference from post-insertion selection and detection bias is challenging. Thirdly, neurodevelopmental disorders may be caused by somatic mutations penetrating less than 10% of neurons from a given brain region [144,145,146] and, moreover, of the two neuronal L1 insertions to undergo lineage tracing thus far, one was found in up to 1.7% of neurons sampled from the cortex . Fourthly, L1 insertions are only one of several types of genomic variant encountered in the brain . These include aneuploidy and other forms of copy number variation (CNV) [148,149,150], as well as single nucleotide variants (SNVs) [151, 152]. Analyses of bulk genomic DNA extracted from brain tissue have elucidated somatic Alu and SVA insertions [133, 153], while a single-cell WGS analysis of a relatively small set of cortical neurons did not find somatic variants attributed to either trans mobilized retrotransposon family . L1 insertions are far larger than an SNV and perhaps carry an average effect size more similar to that of a copy number or structural variant, depending on the genomic and biological context where the variant occurs. These considerations suggest that, with the improving resolution and expanding scale of single-cell genomic analysis applied to brain tissue, somatic L1 insertions causing a neuronal or cognitive phenotype will be identified in the coming years. At present, however, very few neurons, almost exclusively from a handful of neurotypical individuals, have been interrogated for endogenous L1 retrotransposition events. Single-cell genomic experiments that exhaustively survey neuronal subtypes, from numerous individuals and brain regions, are required to define the typical range of neuronal L1 retrotransposition frequency in humans . By also elucidating the genomic locations of new L1 insertions, and their functional effects, these future studies should greatly inform our view of whether L1-driven mosaicism has the potential to be a phenomenon of biological importance, building on foundational evidence now showing that endogenous L1s can jump in the brain.
L1 retrotransposition in non-neuronal brain cells
Somatic L1 insertions have been found in hippocampal glia by recent single-cell genomic analyses [134, 137]. By contrast, experiments based on cultured glial cells and the L1-EGFP system have suggested that retrotransposition in glia is uncommon . One possible explanation for the presence of somatic L1 insertions in glia is that neural stem cells can accommodate retrotransposition events prior to neuronal commitment, leading to occasional L1 insertions in multipotent precursor cells that ultimately commit to the glial lineage . Unlike most neuronal populations, glia can also divide and regenerate in response to injury [154, 155] and this capacity for cell cycling may facilitate retrotransposition [59, 156,157,158]. Comparisons of L1 retrotransposition rate in glia versus neurons are, for these reasons, not straightforward. Even if, on average, they accumulate fewer L1 insertions than neurons , individual glia can oversee more than 100,000 synapses  and impact the functional output of the neurons they support . To speculate, one can therefore envisage a situation where a somatic L1 insertion in a glial cell that supports or protects a large number of neurons could, by extension, alter the functional properties of at least some of those neurons, potentially adding to any direct impact of neuronal L1 insertions . This may be disproportionately likely in pathologic conditions, such as autoimmune diseases where L1 expression in astrocytes for example may be unusually high . It should again be noted, however, that a molecular or biological phenotype is yet to be demonstrated for any somatic L1 insertion arising in a neural cell. Moreover, glial proliferation and regeneration may buffer cells from the potential consequences of somatic L1 insertions, lessening the likelihood of downstream changes to neuronal circuits. Further experimental evidence is required to conclusively demonstrate that somatic L1 insertions can arise in committed glia, as opposed to multipotent progenitor cells. Similarly, L1 retrotransposition is heavily influenced by cellular host factors (Table 1), but we know little about the host factors that regulate L1 in neurons, as compared to those active in glial cells. Thus, it is likely that the L1 mobilization rate in glia and neurons, including neuronal subtypes, may be reliant upon the differential expression of L1 regulatory proteins in these cells.
Somatic retrotransposition outside of the brain?
To our knowledge, no single-cell genomic analysis of somatic retrotransposition has been reported for mammalian organs other than the brain, although a few immortalized skin cells have been surveyed by WGS without a specific search for mosaic TE insertions . This presents a major gap in the field as, at present, we cannot ascertain whether endogenous L1 retrotransposition really is enriched in the brain or occurs, for instance, in liver, heart or skin at a rate resembling that observed for neurons. Bulk sequencing approaches have found isolated examples of likely somatic L1 insertions in normal liver  and gastrointestinal tract [162,163,164,165] tissues of cancer patients, as well as mosaic L1 insertions found in various adult mouse tissues but arising prior to gastrulation . By contrast, a bulk WGS analysis of 10 clonal cell populations expanded from single skin fibroblasts identified no somatic L1 insertions that could be traced to a parental cell . Transgenic L1-EGFP animals also present very few GFP+ cells outside of the brain and gonads [9, 21] and, when employed in vitro, the L1-EGFP reporter retrotransposes consistently in neural progenitor cells and post-mitotic neurons [19,20,21] but not mesenchymal or hematopoietic stem cells .
Taken together, these observations support a model where L1 insertions arising in the early embryo may generate low complexity mosaicism in multiple organs, complemented by ongoing retrotransposition in brain cells. Other adult cell types may also support somatic retrotransposition. However, single-cell genomic analyses of post-mortem, non-brain tissues from human individuals not affected by cancer or other relevant diseases will be required in the future to definitely assess endogenous L1 retrotransposition outside of the brain. That L1 mobilizes frequently in many epithelial tumors [72, 161, 162, 164, 165, 167,168,169,170,171,172,173,174], but rarely in brain tumors [168, 169, 175, 176], suggests that dysplastic epithelial cells may specifically support L1 activity. The discovery of somatic L1 insertions in the pathologically normal cells of organs where tumorigenesis has occurred reinforces this conclusion [161,162,163,164,165] but falls short of demonstrating retrotransposition in a healthy organ. Nonetheless, cancer has provided the only examples thus far of somatic retrotransposition causing a clinical or molecular phenotype [161, 163, 167, 170, 171], and has greatly informed our understanding of L1 regulation in vivo (for relevant reviews, please see [109, 114, 177]).
Transposition in the fly brain
L1 and L1-like retrotransposons are found throughout the eukaryotic tree of life . In animals, somatic TE insertions have been almost exclusively reported in human and rodent tissues and experimental systems . The main exception is Drosophila, where R2, a highly site-specific, L1-like retrotransposon, and gypsy, an endogenous retrovirus found to often integrate into specific genomic hotspots, have been found to mobilize in somatic cells, including neurons [4,5,6,7, 178,179,180] (for a review, see ). Targeted PCR and resequencing, and orthogonal reporter assays, have each indicated retrotransposon integration (e.g. R2 into rRNA genes [64, 182], gypsy into the ovo gene [183, 184]). However, in contrast to mammalian systems, genome-wide attempts to map endogenous TE mobilization in fly somatic cells have to date not corroborated the aforementioned data obtained from reporter assays. For example, Perrat et al. applied a shallow WGS analysis to pooled fly embryos, brain tissue, and pooled olfactory (αβ) neurons purified from mushroom body, generating an estimate of 129 somatic TE insertions per αβ neuron . However, a subsequent and thoughtful WGS analysis of additional αβ neurons, using improved sequencing depth but still incorporating pooled neuronal material, and analyzing the evolutionary age of mobilized TEs, found no evidence for somatic TE transposition in the fly brain . This second study reversed the earlier conclusion of widespread transposon-mediated genomic heterogeneity in the fly brain  and leaves the question of somatic transposition rate in fly unresolved. Interestingly, through additional analyses, the authors also challenged previous findings of increased transposition rate in ageing neurons  and ovaries obtained from dysgenic hybrids  but did not reanalyze the Perrat et al. sequencing data . Given the aforementioned R2 and gypsy experiments [4,5,6,7], we would postulate that a single-cell genomic analysis of fly neurons, with appropriate genotypic controls (i.e. non-brain tissue from the same fly) would identify somatic transposition events. These would likely occur at a lower frequency than first reported by Perrat et al. but, given the extensive array of mobile TE families in the Drosophila genome , perhaps at a higher frequency than seen in mammalian neurons thus far, and with the caveat that somatic transposition in different fly strains may vary greatly in incidence . Aside from the available data obtained from some mammals and insects, it is currently unknown whether TEs can mobilize in the brain (or other somatic tissues) of other animals. The future discovery of somatic retrotransposition in additional species may greatly assist in elucidating any functional consequences of TE-derived mosaicism in neurons.
Donor L1s active in somatic cells: Different LINEs to retrotransposition
As a rule, L1 epigenetic repression is thought to be established during early gastrulation and maintained thereafter to block L1 mobilization (Fig. 3) [19, 20, 117, 119, 190]. DNA methylation of a CpG island  present in the human L1 5′UTR (Fig. 1) is particularly associated with inhibition of L1 expression [98, 103, 192, 193], at least based on relationships between the methylation and transcriptional output of L1 subfamilies, such as L1-Ta [19, 20, 118, 121]. The expression of mouse L1 subfamilies is also inversely correlated with their DNA methylation level [99, 104, 194]. Despite being methylated, full-length L1s are expressed, at varying abundances, in mature somatic tissues [163, 195, 196]. One explanation for this discrepancy is that individual L1s may be regulated in a manner distinct to that of their corresponding L1 subfamily [72, 84]. For example, while genome-wide L1-Ta subfamily mRNA expression may be low in a given context, an individual L1-Ta copy could be highly expressed due to the local demethylation of its promoter. It follows that some donor L1s appear to mobilize in embryonic cells contributing to the germline and in somatic cells at very different efficiencies  and present highly variable levels of transcription and mobilization in various cancer cells [84, 174]. Adding to this heterogeneity, individual donor L1s may have multiple alleles that mobilize at disparate rates [76, 83], can be heterozygous or homozygous at a given genomic locus, potentially impacting their regulation, and be fixed or polymorphic in the global population. Repressive epigenetic marks are also not the only means by which L1s are silenced by the host genome (Table 1) . General rules for the genome-wide regulation of an L1 subfamily likely do not apply equally to all L1s in that family and therefore any mechanistic explanation for somatic L1 retrotransposition may rely on locus-specific resolution of L1 repression or activation [72, 84, 163, 171]. As a result, L1 expression and retrotransposition in the germline and in somatic cells are likely to vary considerably between individuals.
Provided these caveats and considerations, we would propose multiple proven or hypothetical scenarios for L1 to escape epigenetic repression and contribute to somatic genome mosaicism. Firstly, many donor L1s are indeed likely to be active in the early embryo (Fig. 3, red scenario) and then repressed in somatic cells, based on DNA methylation patterns observed for the human L1-Ta family overall [19, 20, 118, 121] and, consistently, for several individual hot L1s . Embryonic L1 insertions arising from these elements can be carried through development to generate somatic mosaicism [11, 18]. Secondly, a given donor L1 may be expressed in the embryo and never fully repressed in mature tissues (Fig. 3, blue scenario). One potential example of this was provided by an L1 on Chromosome 17  that was demethylated and expressed in a colorectal tumor, and also the matched normal colon . This donor L1 is a relatively new polymorphism (minor allele frequency 0.0036), is hot for retrotransposition in vitro  and is therefore likely to still be mobile during embryogenesis or in the committed primordial germline . Thirdly, a donor L1 may be repressed in the embryo but is found in a genomic locus that does not undergo methylation in differentiated tissues (Fig. 3, orange scenario). A likely example of this is an L1 found on Chromosome 22 that is very active in epithelial tumors [72, 171, 174, 197, 198] but almost inactive in the human germline and in cultured cells [39, 85]. Interestingly, this element is intronic to the gene TTC28, which is highly transcribed in epithelial cells and organs where neoplasia often supports retrotransposition of the donor L1 [174, 199] alongside its hypomethylation and transcription in normal and tumor cells [72, 84, 171, 174]. Finally, a donor L1 may be repressed in most contexts (Fig. 3, yellow scenario) but, if located downstream of an active endogenous active promoter, transcription directed by this external promoter may initiate upstream of, and read through into, the L1, thereby generating an intact L1 mRNA. This arrangement could yield somatic L1 insertions with 5′ transductions [36, 69, 73] and may explain one of the examples described above in cortical neurons . In principle, these scenarios present mechanistic bases for individual L1s escaping repression, being transcribed [84, 163, 195, 196], and producing somatic variants that are carried by mature differentiated cells where mobile L1 subfamilies are, overall, marked by epigenetic and transcriptional silencing [19, 20, 22, 27].
Non-canonical L1-associated somatic genome variation
Despite proof of somatic retrotransposition in mammalian brain cells, L1 could impact neuronal phenotype via other routes. For example, a single-cell genomic analysis  of L1 insertions in the human hippocampus identified TPRT-mediated retrotransposition events, corroborating a previous study . The authors also reported examples of somatic genome deletions flanked by germline L1 copies that were detectable in single cells but could also be PCR amplified in bulk hippocampus DNA via digital droplet PCR and PCR reactions performed on very high (500 ng) input template quantities . These deletions were attributed to DNA damage associated with L1 endonuclease activity independent of retrotransposition . Notably, the aforementioned WGS analysis of mouse olfactory neuron clones obtained by nuclear transfer  did not report L1-associated deletions, but also studied fewer neurons from a different species and neuroanatomical region. The frequency and distribution of L1-driven genomic deletion events in humans and other mammals therefore remain to be determined.
More recently, a WGS analysis of bulk human brain tissues  reported thousands of somatic L1 insertions although, surprisingly, the vast majority of these were found nested within L1 insertions annotated on the reference genome. This “L1-within-L1” scenario  presents a significant bioinformatic challenge as sequencing reads can align unreliably to highly repetitive regions , and for this reason insertions into existing younger L1 subfamily (e.g. L1-Ta, L1PA2) copies are usually filtered by TE insertion calling software . Moreover, the putative somatic L1 insertions appeared to not involve L1 ORF2p endonuclease activity , and were 3′ truncated, a feature of L1 integration not encountered for canonical TPRT-mediated L1 insertions in normal cells, where 5′ truncation is instead common [205, 206]. The authors of this study verified a set of nested germline L1 insertions identified by their approach and a publicly available long-read sequencing dataset but, importantly, did not present a similar analysis of long-read sequencing applied to the same brain samples already analyzed by WGS, or sequence matched non-brain tissues . Finally, the proprietary analysis tools required to identify TE insertions in sequencing data generated by this study, and other studies based on the Complete Genomics platform , significantly complicate data sharing and critical re-analysis. L1 may therefore alter the neuronal genome via unexpected pathways, but studies in this area require further investigation and replication, including additional validation and single-cell genomic analyses.
Non-integrated L1 sequences in neural cells
Full-length L1 mRNA transcription can occur in the normal brain [19, 20, 195, 196]. As well as via DNA methylation, the L1 promoter is in this context regulated by a variety of transcription factors, including SOX2 (Fig. 1, Table 1) [20, 22, 27, 47, 69, 105, 207]. An antisense promoter is also present in the human L1 5′UTR , is conserved in primates, and has independent protein-coding potential . This antisense promoter initiates transcription in numerous spatiotemporal contexts and can provide canonical promoters to protein-coding genes [117, 196, 208,209,210,211,212]. 5′ truncated L1s can also act as promoters in the brain, perhaps regulated by the Wnt signaling pathway [22, 196]. Thus, mobile and immobile L1 copies, where the latter are far more numerous, contribute various L1-initiated RNAs to the cellular environment. These can fulfill cis-regulatory roles and act globally to regulate chromatin structure [213, 214]. L1 transcription, protein abundance and mobilization rate may become uncoupled in vitro upon high L1 mRNA expression . The production of diverse sense and antisense L1 RNAs, and their cellular abundance, may therefore in itself impact neuronal phenotype, independent of retrotransposition.
Similarly, L1 DNA sequences not integrated into the host genome, perhaps generated by ectopic reverse transcription primed from other cellular RNAs, aborted retrotransposition events, or another process involving the L1 machinery, may be relevant to cellular function [216,217,218]. Human and mouse L1 CNV assays applying multiplex qPCR to template DNAs extracted from tissue have repeatedly shown variation in L1 DNA content, when brain regions are compared to each other, and when brain samples are compared to non-brain tissue [20, 24, 25, 27, 133, 137, 219]. These studies suggest that i) the hippocampus is a hotspot for L1 CNV and ii) brain tissues are generally enriched for L1 DNA, versus non-brain tissues. As has been proposed previously [112, 220], qPCR-based L1 CNV assays cannot alone demonstrate retrotransposition because they do not discriminate L1 sequences that are, or are not, integrated into the genome. Host factor defenses against retrotransposition very likely include the degradation of single-stranded DNA intermediates produced during TPRT (Table 1) [112, 139] and, where this process is deficient, cells may accumulate single-stranded L1 DNA molecules . Control experiments, such as enzymatically treating qPCR input templates to degrade single-stranded DNA, or selecting only high molecular weight DNA via gel electrophoresis, may reduce, but cannot exclude, the potential for non-integrated L1 DNA to dominate qPCR-based L1 CNV assays . Indeed, these qPCR-based assays can also return absolute L1 CNV values reflecting hundreds of new L1 insertions per cell, depending on normalization approach, when all single-cell genomic analyses performed to date have shown retrotransposed products at a rate far lower than this [35, 67]. It is possible that the qPCR-based assays are simply confounded by unanticipated technical issues and are quantitatively unreliable. In our view, it is more plausible that, alongside L1 RNA expression, neurons can accumulate L1 DNA molecules that are not integrated into the nuclear genome.
The origin, composition and cellular impact of non-integrated L1 DNA sequences remain unclear. They may arise due to a failure to resolve or degrade TPRT intermediates, ectopic L1 reverse transcription where the products are sequestered in the cytosol, or another mechanism by which L1 could form stable, extrachromosomal DNA sequences in vivo [216,217,218, 221,222,223,224,225,226,227]. Are these L1 DNAs predominantly single- or double-stranded? Are they predominantly full-length or heavily truncated? Notably, qPCR assays targeting L1 at its 5′UTR, ORF2 or 3′UTR regions can in some cases generate different L1 CNV results [25, 27], suggesting that the additional L1 DNA sequences are shorter on average than genomic L1 copies of the same subfamily, which supports the hypothesis that interrupted, or unusually inefficient, reverse transcription may be involved in the biogenesis of non-integrated L1 DNA molecules. Along these lines, when the L1 qPCR assay was applied to brain tissue obtained from i) Rett syndrome (RTT) patients, where mutations in the L1 transcriptional repressor MeCP2 (Table 1) [27, 75, 228, 229] cause a severe neurodevelopmental disorder, and ii) an MeCP2-mutant RTT mouse model, significant L1 copy number gain was observed in either species when L1 DNA content was measured at ORF2, when compared to controls . L1 CNV was not, however, observed when measured at the 5′UTR . It is relevant that conditional restoration of MeCP2 function in MeCP2-mutant mice leads to robust reversal of neurological phenotype . In work performed recently in our laboratory, we found that phenotypic reversal in these animals was accompanied by L1 DNA content returning from elevated to wild-type levels after rescue, when measured by qPCR against ORF2 (Morell et al., unpublished data).
These observations altogether suggest that at least some of the additional L1 DNA content reported in RTT brain samples may not be incorporated into the nuclear genome. More broadly, the increased presence of L1 and other TEs in neurological disorders [6, 27,28,29, 231,232,233,234] elucidated by qPCR-based assays therefore may not involve new TE insertions, and any associated potential toxicity  may not be due to retrotransposition. It is tempting to speculate that the accumulation of non-integrated L1 DNA, for example via failed or incomplete elimination of TPRT intermediates [52, 139, 236], could still cause genomic lesions in neuronal genes  or otherwise “distract” host factors which, in addition to guarding against L1 integration, often regulate other cellular processes . L1 activity in the brain is potentially relevant to neuronal physiology and genome stability beyond any impact of somatic retrotransposition, although further experiments are required to demonstrate the biogenesis of non-integrated L1 DNA sequences in neurons and other cells.
Does elevated L1 content in the brain trigger autoimmunity?
Endogenous and exogenous nucleic acids may trigger immune responses mediated by various sensor pathways [for reviews, see [238, 239]]. As well as in RTT, elevated L1 DNA content has been reported in neurological disorders associated with autoimmunity, immunodeficiency and maternal infection, including Aicardi-Goutières syndrome [29, 137, 221], ataxia telangiectasia  and schizophrenia . As for normal individuals, the magnitude of L1 CNV reported in these disorders appears to far exceed what would plausibly be due to somatic retrotransposition and could be due to an accumulation of L1 DNA molecules that are not integrated into the nuclear genome . This scenario would have major implications for the treatment of any condition proven to be caused by L1 activity because the reversal of any associated symptoms would no longer be dependent on the challenging excision of somatic L1 insertions from neuronal genomes. Instead, processes leading to an accumulation of non-integrated single- or double-stranded L1 DNA could be targeted, for example, with reverse transcriptase inhibitors  or through targeted silencing  of heavily transcribed L1 copies .
Aicardi-Goutières syndrome (AGS) is a very rare interferonopathy that provides arguably the best developed example of a neurological phenotype potentially linked to L1-associated autoimmunity. Genetic analyses of AGS patients have revealed mutations most commonly in the genes TREX1, SAMHD1, ADAR1, RNASEH2A, RNASEH2B, RNASEH2C and IFIH1 [239, 243]. Most of these genes encode factors that have been shown to regulate retrotransposon activity (Table 1) [221, 234, 244,245,246,247,248,249,250,251], supporting the hypothesis that the cytosolic accumulation of endogenous nucleic acids in AGS generates an interferon response [239, 252,253,254]. TREX1, for example, is an established exonuclease of aberrant single-stranded intermediates generated during DNA replication . An abundance of single-stranded L1 DNA has been reported in human and mouse TREX1-deficient cells [29, 221], whilst a single-cell genomic analysis of neurons obtained from one AGS patient carrying SAMHD1 mutations indicated that somatic L1 insertions occurred at a rate similar to that of controls . Whilst these experiments suggest L1 might play a role in AGS, the mechanism via which single-stranded L1 DNA could generate an abnormal neuronal phenotype is largely unclear, and it remains plausible that the accumulation of L1 DNA in AGS is a largely inconsequential result of nuclease mutations.
Intriguingly, a recent study demonstrated that media obtained from TREX1-deficient human astrocytes was toxic to healthy neurons, whereas media from TREX1-deficient astrocytes treated with L1 reverse transcriptase inhibitors was significantly less toxic . The authors ascribed this toxicity to an interferon response due to an accumulation of cytosolic single-stranded L1 DNA in astrocytes [29, 256]. By contrast, another recent work found that treatment of TREX1 mutant mice with L1 reverse transcriptase inhibitors had no impact on interferon response or the retrotransposition frequency of an engineered L1 reporter gene in vivo . Previously, different reverse transcriptase inhibitors have been shown to rescue  or not rescue  the lethal myocarditis phenotype of TREX1-deficient mice. These findings raise the prospect that a biochemical mechanism apart from the inhibition of L1 reverse transcriptase activity, perhaps instead targeting inflammation, is responsible for the amelioration of AGS phenotype .
At this stage, the etiological role of TREX1 in controlling L1 and other endogenous retrotransposons in AGS requires further study. It should however be noted that i) the somewhat opposing results detailed above for L1 were obtained using different species and cell types, ii) assays measuring engineered and endogenous L1 activity can provide different results [29, 221, 247, 257], iii) engineered L1 retrotransposition frequency and potentially immunogenic single-stranded L1 DNA content are not equivalent, and iv) host factors and reverse transcriptase inhibitors may act via multiple direct and indirect pathways to limit L1 activity. For example, instead of restricting L1 primarily by exonuclease activity, TREX1 may alter the subcellular localization of L1 ORF1p, and thereby reduce opportunities for cells to accumulate L1 DNA, whether via retrotransposition or another mechanism [221, 247].
As for TREX1, RNaseH2 has been alternatively reported as being a negative or positive regulator of L1 retrotransposition [249, 250, 260]. Some eukaryotic TEs encode ribonuclease proteins to facilitate the removal of their template RNA after reverse transcription [261,262,263], and also degrade other cellular DNA:RNA hybrids, supporting a positive role for RNaseH2 in L1 retrotransposition. Alternatively, biochemical assays using the Bombyx mori R2 retrotransposon previously revealed that the RNA in a hybrid DNA:RNA molecule generated during TPRT could be displaced during second strand DNA synthesis without the apparent involvement of a ribonuclease . Ribonuclease mediated degradation of the RNA strand of hybrid L1 DNA:RNA molecules prior to second strand synthesis has been demonstrated in vitro to expose the L1 cDNA to deamination, suggesting that ribonuclease activity may facilitate editing or 5′ truncation of L1 cDNAs in vivo . Nonetheless, we favor the view that the ribonuclease activity of RNaseH2 assists L1 mobility in vivo, even if other RNaseH2 functions are ultimately shown to inhibit retrotransposition. Overall, the available literature points to a potential role for L1 in the etiology and clinical management of AGS and other neurodevelopmental disorders associated with autoimmunity. Significant work is required to reconcile the somewhat opposing results reported for the use of reverse transcriptase inhibitors in disparate AGS experimental models, and to therefore clarify whether L1 activity is a pathogenic or coincidental feature of this disease.
Somatic mosaicism represents an intriguing and underexplored form of genetic and biological variation in mammals. Although L1 retrotransposon-driven mosaicism is now established to occur in brain cells, any impact of this phenomenon upon normal and abnormal neurobiological processes remains undemonstrated. Despite the recent development of tools, including single-cell genome, epigenome and transcriptome sequencing [151, 265,266,267,268,269,270,271,272], in some cases employed in parallel [for a review, see ], as well as CRISPR-Cas9 based genetic and epigenetic engineering [242, 274,275,276,277], conclusive proof is yet to be provided of any individual somatic L1 insertion arising in the neuronal lineage that has generated a molecular, biochemical or behavioral phenotype in vivo. Given the effect size of L1 insertions in genes, and the frequency of endogenous L1 insertions arising during neurodevelopment, adult neurogenesis or in post-mitotic neurons, it is likely that some L1 insertions could induce a biologically relevant neuronal phenotype. We believe such examples will be found in future studies. It is also plausible that L1 may impact neurobiology primarily through mechanisms not involving resolved retrotransposition events, given recent observations from neurological diseases, such as RTT and AGS.
Experiments to test the impact of individual somatic L1 insertions present a major challenge. Work in this area could be greatly accelerated through: i) the development of methods to reliably survey genome structural variation and transcription, genome-wide and from the same cell, using human brain tissue obtained post-mortem, or from tissue obtained during brain surgery [278, 279], or from animal models, ii) the large-scale production of WGS data from individual brain cells, retaining neuronal subtype information, as well as from non-brain cells, and iii) the ability to introduce, via CRISPR-Cas9 or another approach, L1 insertions found in vivo into cultured neurons, organoids or even animal models, to assess their impact upon the transcriptional and regulatory landscapes when established in a homogenous cellular population. Long-read sequencing approaches, such as those developed by PacBio and Oxford Nanopore, which can identify TPRT hallmarks ab initio by resolving L1 integration sites in full, may also prove particularly useful, even if simply applied at high depth to DNA extracted from brain tissue [280,281,282,283,284]. Beyond surveying the spatiotemporal extent and potential immediate functional impact of L1 mosaicism, we also need to be able to modulate endogenous retrotransposition and evaluate the consequences, if any, upon behavior. In neurological disorders where elevated L1 activity is apparent, it would be valuable to assess the impact restricting that activity has upon symptoms. These are long term and challenging experiments. However, neuronal genome mosaicism driven by engineered L1 retrotransposition was first reported in 2005  and has only been definitively shown to be recapitulated by endogenous L1s in vivo quite recently [133,134,135,136,137,138]. Therefore, equipped with foundational knowledge, and improving tools, the field is well positioned to move rapidly towards establishing any functional impact of L1 mosaicism in the soma.
Copy number variation
Clustered regularly interspaced short palindromic repeats
Enhanced green fluorescent protein
- LINE-1 (or L1):
Long interspersed element-1
Open reading frame
Single nucleotide variant
Target-primed reverse transcription
Target site duplication
McClintock B. The origin and behavior of mutable loci in maize. Proc Natl Acad Sci U S A. 1950;36:344–55.
Belzile F, Yoder JI. Pattern of somatic transposition in a high copy ac tomato line. Plant J. 1992;2:173–9.
Raizada MN, Nan GL, Walbot V. Somatic and germinal mobility of the RescueMu transposon in transgenic maize. Plant Cell. 2001;13:1587–608.
Eickbush MT, Eickbush TH. Retrotransposition of R2 elements in somatic nuclei during the early development of Drosophila. Mob DNA. 2011;2:11.
Li W, Prazak L, Chatterjee N, Gruninger S, Krug L, Theodorou D, Dubnau J. Activation of transposable elements during aging and neuronal decline in Drosophila. Nat Neurosci. 2013;16:529–31.
Krug L, Chatterjee N, Borges-Monroy R, Hearn S, Liao WW, Morrill K, Prazak L, Rozhkov N, Theodorou D, Hammell M, Dubnau J. Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS. PLoS Genet. 2017;13:e1006635.
Wood JG, Jones BC, Jiang N, Chang C, Hosier S, Wickremesinghe P, Garcia M, Hartnett DA, Burhenn L, Neretti N, Helfand SL. Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila. Proc Natl Acad Sci U S A. 2016;113:11277–82.
Kano H, Godoy I, Courtney C, Vetter MR, Gerton GL, Ostertag EM, Kazazian HH Jr. L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. Genes Dev. 2009;23:1303–12.
Ostertag EM, DeBerardinis RJ, Goodier JL, Zhang Y, Yang N, Gerton GL, Kazazian HH Jr. A mouse model of human L1 retrotransposition. Nat Genet. 2002;32:655–60.
An W, Han JS, Wheelan SJ, Davis ES, Coombes CE, Ye P, Triplett C, Boeke JD. Active retrotransposition by a synthetic L1 element in mice. Proc Natl Acad Sci U S A. 2006;103:18662–7.
van den Hurk JA, Meij IC, Seleme MC, Kano H, Nikopoulos K, Hoefsloot LH, Sistermans EA, de Wijs IJ, Mukhopadhyay A, Plomp AS, et al. L1 retrotransposition can occur early in human embryonic development. Hum Mol Genet. 2007;16:1587–92.
Tsutsumi M, Imai S, Kyono-Hamaguchi Y, Hamaguchi S, Koga A, Hori H. Color reversion of the albino medaka fish associated with spontaneous somatic excision of the Tol-1 transposable element from the tyrosinase gene. Pigment Cell Res. 2006;19:243–7.
Richardson SR, Faulkner GJ. Heritable L1 Retrotransposition events during development: understanding their origins. Bioessays. 2018;40:e1700189.
Ewing AD, Kazazian HH Jr. Whole-genome resequencing allows detection of many rare LINE-1 insertion alleles in humans. Genome Res. 2011;21:985–90.
Stewart C, Kural D, Stromberg MP, Walker JA, Konkel MK, Stutz AM, Urban AE, Grubert F, Lam HY, Lee WP, et al. A comprehensive map of mobile element insertion polymorphisms in humans. PLoS Genet. 2011;7:e1002236.
Nellaker C, Keane TM, Yalcin B, Wong K, Agam A, Belgard TG, Flint J, Adams DJ, Frankel WN, Ponting CP. The genomic landscape shaped by selection on transposable elements across 18 mouse strains. Genome Biol. 2012;13:R45.
Akagi K, Li J, Stephens RM, Volfovsky N, Symer DE. Extensive variation between inbred mouse strains due to endogenous L1 retrotransposition. Genome Res. 2008;18:869–80.
Richardson SR, Gerdes P, Gerhardt DJ, Sanchez-Luque FJ, Bodea GO, Munoz-Lopez M, Jesuadian JS, Kempen MHC, Carreira PE, Jeddeloh JA, et al. Heritable L1 retrotransposition in the mouse primordial germline and early embryo. Genome Res. 2017;27:1395–405.
Macia A, Widmann TJ, Heras SR, Ayllon V, Sanchez L, Benkaddour-Boumzaouad M, Munoz-Lopez M, Rubio A, Amador-Cubero S, Blanco-Jimenez E, et al. Engineered LINE-1 retrotransposition in nondividing human neurons. Genome Res. 2017;27:335–48.
Coufal NG, Garcia-Perez JL, Peng GE, Yeo GW, Mu Y, Lovci MT, Morell M, O'Shea KS, Moran JV, Gage FH. L1 retrotransposition in human neural progenitor cells. Nature. 2009;460:1127–31.
Muotri AR, Chu VT, Marchetto MC, Deng W, Moran JV, Gage FH. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature. 2005;435:903–10.
Kuwabara T, Hsieh J, Muotri A, Yeo G, Warashina M, Lie DC, Moore L, Nakashima K, Asashima M, Gage FH. Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis. Nat Neurosci. 2009;12:1097–105.
Muotri AR, Zhao C, Marchetto MC, Gage FH. Environmental influence on L1 retrotransposons in the adult hippocampus. Hippocampus. 2009;19:1002–7.
Bachiller S, Del-Pozo-Martin Y, Carrion AM. L1 retrotransposition alters the hippocampal genomic landscape enabling memory formation. Brain Behav Immun. 2017;64:65–70.
Bedrosian TA, Quayle C, Novaresi N, Gage FH. Early life experience drives structural variation of neural genomes in mice. Science. 2018;359:1395–9.
Bundo M, Toyoshima M, Okada Y, Akamatsu W, Ueda J, Nemoto-Miyauchi T, Sunaga F, Toritsuka M, Ikawa D, Kakita A, et al. Increased l1 retrotransposition in the neuronal genome in schizophrenia. Neuron. 2014;81:306–13.
Muotri AR, Marchetto MC, Coufal NG, Oefner R, Yeo G, Nakashima K, Gage FH. L1 retrotransposition in neurons is modulated by MeCP2. Nature. 2010;468:443–6.
Shpyleva S, Melnyk S, Pavliv O, Pogribny I, Jill James S. Overexpression of LINE-1 retrotransposons in autism brain. Mol Neurobiol. 2018;55:1740–9.
Thomas CA, Tejwani L, Trujillo CA, Negraes PD, Herai RH, Mesci P, Macia A, Crow YJ, Muotri AR. Modeling of TREX1-dependent autoimmune disease using human stem cells highlights L1 accumulation as a source of Neuroinflammation. Cell Stem Cell. 2017;21:319–31.
Damert A, Raiz J, Horn AV, Lower J, Wang H, Xing J, Batzer MA, Lower R, Schumann GG. 5′-transducing SVA retrotransposon groups spread efficiently throughout the human genome. Genome Res. 2009;19:1992–2008.
Dewannieux M, Esnault C, Heidmann T. LINE-mediated retrotransposition of marked Alu sequences. Nat Genet. 2003;35:41–8.
Esnault C, Maestre J, Heidmann T. Human LINE retrotransposons generate processed pseudogenes. Nat Genet. 2000;24:363–7.
Mills RE, Bennett EA, Iskow RC, Devine SE. Which transposable elements are active in the human genome? Trends Genet. 2007;23:183–91.
Raiz J, Damert A, Chira S, Held U, Klawitter S, Hamdorf M, Lower J, Stratling WH, Lower R, Schumann GG. The non-autonomous retrotransposon SVA is trans-mobilized by the human LINE-1 protein machinery. Nucleic Acids Res. 2012;40:1666–83.
Faulkner GJ, Garcia-Perez JL. L1 mosaicism in mammals: extent, effects, and evolution. Trends Genet. 2017;33:802–16.
Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921.
Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M, An P, et al. Initial sequencing and comparative analysis of the mouse genome. Nature. 2002;420:520–62.
Beck CR, Collier P, Macfarlane C, Malig M, Kidd JM, Eichler EE, Badge RM, Moran JV. LINE-1 retrotransposition activity in human genomes. Cell. 2010;141:1159–70.
Brouha B, Schustak J, Badge RM, Lutz-Prigge S, Farley AH, Moran JV, Kazazian HH Jr. Hot L1s account for the bulk of retrotransposition in the human population. Proc Natl Acad Sci U S A. 2003;100:5280–5.
DeBerardinis RJ, Goodier JL, Ostertag EM, Kazazian HH Jr. Rapid amplification of a retrotransposon subfamily is evolving the mouse genome. Nat Genet. 1998;20:288–90.
Goodier JL, Ostertag EM, Du K, Kazazian HH Jr. A novel active L1 retrotransposon subfamily in the mouse. Genome Res. 2001;11:1677–85.
Naas TP, DeBerardinis RJ, Moran JV, Ostertag EM, Kingsmore SF, Seldin MF, Hayashizaki Y, Martin SL, Kazazian HH. An actively retrotransposing, novel subfamily of mouse L1 elements. EMBO J. 1998;17:590–7.
Sookdeo A, Hepp CM, McClure MA, Boissinot S. Revisiting the evolution of mouse LINE-1 in the genomic era. Mob DNA. 2013;4:3.
Feng Q, Moran JV, Kazazian HH Jr, Boeke JD. Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition. Cell. 1996;87:905–16.
Mathias SL, Scott AF, Kazazian HH Jr, Boeke JD, Gabriel A. Reverse transcriptase encoded by a human transposable element. Science. 1991;254:1808–10.
Moran JV, Holmes SE, Naas TP, DeBerardinis RJ, Boeke JD, Kazazian HH Jr. High frequency retrotransposition in cultured mammalian cells. Cell. 1996;87:917–27.
Swergold GD. Identification, characterization, and cell specificity of a human LINE-1 promoter. Mol Cell Biol. 1990;10:6718–29.
Alisch RS, Garcia-Perez JL, Muotri AR, Gage FH, Moran JV. Unconventional translation of mammalian LINE-1 retrotransposons. Genes Dev. 2006;20:210–24.
Dmitriev SE, Andreev DE, Terenin IM, Olovnikov IA, Prassolov VS, Merrick WC, Shatsky IN. Efficient translation initiation directed by the 900-nucleotide-long and GC-rich 5′ untranslated region of the human retrotransposon LINE-1 mRNA is strictly cap dependent rather than internal ribosome entry site mediated. Mol Cell Biol. 2007;27:4685–97.
Lindtner S, Felber BK, Kjems J. An element in the 3′ untranslated region of human LINE-1 retrotransposon mRNA binds NXF1(TAP) and can function as a nuclear export element. RNA. 2002;8:345–56.
Doucet AJ, Hulme AE, Sahinovic E, Kulpa DA, Moldovan JB, Kopera HC, Athanikar JN, Hasnaoui M, Bucheton A, Moran JV, Gilbert N. Characterization of LINE-1 ribonucleoprotein particles. PLoS Genet. 2010;6:e1001150.
Kulpa DA, Moran JV. Cis-preferential LINE-1 reverse transcriptase activity in ribonucleoprotein particles. Nat Struct Mol Biol. 2006;13:655–60.
Kulpa DA, Moran JV. Ribonucleoprotein particle formation is necessary but not sufficient for LINE-1 retrotransposition. Hum Mol Genet. 2005;14:3237–48.
Hohjoh H, Singer MF. Cytoplasmic ribonucleoprotein complexes containing human LINE-1 protein and RNA. EMBO J. 1996;15:630–9.
Martin SL. Ribonucleoprotein particles with LINE-1 RNA in mouse embryonal carcinoma cells. Mol Cell Biol. 1991;11:4804–7.
Martin SL. Characterization of a LINE-1 cDNA that originated from RNA present in ribonucleoprotein particles: implications for the structure of an active mouse LINE-1. Gene. 1995;153:261–6.
Taylor MS, Altukhov I, Molloy KR, Mita P, Jiang H, Adney EM, Wudzinska A, Badri S, Ischenko D, Eng G, et al. Dissection of affinity captured LINE-1 macromolecular complexes. Elife. 2018;7:e30094.
Wei W, Gilbert N, Ooi SL, Lawler JF, Ostertag EM, Kazazian HH, Boeke JD, Moran JV. Human L1 retrotransposition: cis preference versus trans complementation. Mol Cell Biol. 2001;21:1429–39.
Mita P, Wudzinska A, Sun X, Andrade J, Nayak S, Kahler DJ, Badri S, LaCava J, Ueberheide B, Yun CY, et al. LINE-1 protein localization and functional dynamics during the cell cycle. Elife. 2018;7:e30058.
Boeke JD. LINEs and Alus--the polyA connection. Nat Genet. 1997;16:6–7.
Monot C, Kuciak M, Viollet S, Mir AA, Gabus C, Darlix JL, Cristofari G. The specificity and flexibility of l1 reverse transcription priming at imperfect T-tracts. PLoS Genet. 2013;9:e1003499.
Doucet AJ, Wilusz JE, Miyoshi T, Liu Y, Moran JV. A 3’ poly(a) tract is required for LINE-1 Retrotransposition. Mol Cell. 2015;60:728–41.
Boeke JD, Garfinkel DJ, Styles CA, Fink GR. Ty elements transpose through an RNA intermediate. Cell. 1985;40:491–500.
Luan DD, Korman MH, Jakubczak JL, Eickbush TH. Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: a mechanism for non-LTR retrotransposition. Cell. 1993;72:595–605.
Cost GJ, Feng Q, Jacquier A, Boeke JD. Human L1 element target-primed reverse transcription in vitro. EMBO J. 2002;21:5899–910.
Jurka J. Sequence patterns indicate an enzymatic involvement in integration of mammalian retroposons. Proc Natl Acad Sci U S A. 1997;94:1872–7.
Richardson SR, Morell S, Faulkner GJ. L1 retrotransposons and somatic mosaicism in the brain. Annu Rev Genet. 2014;48:1–27.
Moran JV, DeBerardinis RJ, Kazazian HH Jr. Exon shuffling by L1 retrotransposition. Science. 1999;283:1530–4.
Athanikar JN, Badge RM, Moran JV. A YY1-binding site is required for accurate human LINE-1 transcription initiation. Nucleic Acids Res. 2004;32:3846–55.
Pickeral OK, Makalowski W, Boguski MS, Boeke JD. Frequent human genomic DNA transduction driven by LINE-1 retrotransposition. Genome Res. 2000;10:411–5.
Goodier JL, Ostertag EM, Kazazian HH Jr. Transduction of 3′-flanking sequences is common in L1 retrotransposition. Hum Mol Genet. 2000;9:653–7.
Schauer SN, Carreira PE, Shukla R, Gerhardt DJ, Gerdes P, Sanchez-Luque FJ, Nicoli P, Kindlova M, Ghisletti S, Santos AD, et al. L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis. Genome Res. 2018;28:639–53.
Larson PA, Moldovan JB, Jasti N, Kidd JM, Beck CR, Moran JV. Spliced integrated retrotransposed element (SpIRE) formation in the human genome. PLoS Biol. 2018;16:e2003067.
Coufal NG, Garcia-Perez JL, Peng GE, Marchetto MC, Muotri AR, Mu Y, Carson CT, Macia A, Moran JV, Gage FH. Ataxia telangiectasia mutated (ATM) modulates long interspersed element-1 (L1) retrotransposition in human neural stem cells. Proc Natl Acad Sci U S A. 2011;108:20382–7.
Yu F, Zingler N, Schumann G, Stratling WH. Methyl-CpG-binding protein 2 represses LINE-1 expression and retrotransposition but not Alu transcription. Nucleic Acids Res. 2001;29:4493–501.
Lutz SM, Vincent BJ, Kazazian HH Jr, Batzer MA, Moran JV. Allelic heterogeneity in LINE-1 retrotransposition activity. Am J Hum Genet. 2003;73:1431–7.
Grimaldi G, Skowronski J, Singer MF. Defining the beginning and end of KpnI family segments. EMBO J. 1984;3:1753–9.
Taniguchi-Ikeda M, Kobayashi K, Kanagawa M, Yu CC, Mori K, Oda T, Kuga A, Kurahashi H, Akman HO, DiMauro S, et al. Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy. Nature. 2011;478:127–31.
Hancks DC, Goodier JL, Mandal PK, Cheung LE, Kazazian HH Jr. Retrotransposition of marked SVA elements by human L1s in cultured cells. Hum Mol Genet. 2011;20:3386–400.
Myers JS, Vincent BJ, Udall H, Watkins WS, Morrish TA, Kilroy GE, Swergold GD, Henke J, Henke L, Moran JV, et al. A comprehensive analysis of recently integrated human ta L1 elements. Am J Hum Genet. 2002;71:312–26.
Boissinot S, Chevret P, Furano AV. L1 (LINE-1) retrotransposon evolution and amplification in recent human history. Mol Biol Evol. 2000;17:915–28.
Badge RM, Alisch RS, Moran JV. ATLAS: a system to selectively identify human-specific L1 insertions. Am J Hum Genet. 2003;72:823–38.
Seleme MC, Vetter MR, Cordaux R, Bastone L, Batzer MA, Kazazian HH Jr. Extensive individual variation in L1 retrotransposition capability contributes to human genetic diversity. Proc Natl Acad Sci U S A. 2006;103:6611–6.
Philippe C, Vargas-Landin DB, Doucet AJ, van Essen D, Vera-Otarola J, Kuciak M, Corbin A, Nigumann P, Cristofari G. Activation of individual L1 retrotransposon instances is restricted to cell-type dependent permissive loci. Elife. 2016;5:e13926.
Gardner EJ, Lam VK, Harris DN, Chuang NT, Scott EC, Pittard WS, Mills RE, 1000 Genomes Project Consortium, Devine SE. The mobile element locator tool (MELT): population-scale mobile element discovery and biology. Genome Res. 2017;27:1916–29.
Ewing AD, Kazazian HH Jr. High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes. Genome Res. 2010;20:1262–70.
Adey NB, Schichman SA, Graham DK, Peterson SN, Edgell MH, Hutchison CA 3rd. Rodent L1 evolution has been driven by a single dominant lineage that has repeatedly acquired new transcriptional regulatory sequences. Mol Biol Evol. 1994;11:778–89.
Schichman SA, Severynse DM, Edgell MH, Hutchison CA 3rd. Strand-specific LINE-1 transcription in mouse F9 cells originates from the youngest phylogenetic subgroup of LINE-1 elements. J Mol Biol. 1992;224:559–74.
Adey NB, Tollefsbol TO, Sparks AB, Edgell MH, Hutchison CA 3rd. Molecular resurrection of an extinct ancestral promoter for mouse L1. Proc Natl Acad Sci U S A. 1994;91:1569–73.
Newkirk SJ, Lee S, Grandi FC, Gaysinskaya V, Rosser JM, Vanden Berg N, Hogarth CA, Marchetto MCN, Muotri AR, Griswold MD, et al. Intact piRNA pathway prevents L1 mobilization in male meiosis. Proc Natl Acad Sci U S A. 2017;114:E5635–44.
Martin SL, Bushman D, Wang F, Li PW, Walker A, Cummiskey J, Branciforte D, Williams MC. A single amino acid substitution in ORF1 dramatically decreases L1 retrotransposition and provides insight into nucleic acid chaperone activity. Nucleic Acids Res. 2008;36:5845–54.
Kingsmore SF, Giros B, Suh D, Bieniarz M, Caron MG, Seldin MF. Glycine receptor beta-subunit gene mutation in spastic mouse associated with LINE-1 element insertion. Nat Genet. 1994;7:136–41.
Ivancevic AM, Kortschak RD, Bertozzi T, Adelson DL. LINEs between species: evolutionary dynamics of LINE-1 retrotransposons across the eukaryotic tree of life. Genome Biol Evol. 2016;8:3301–22.
Soares ML, Edwards CA, Dearden FL, Ferron SR, Curran S, Corish JA, Rancourt RC, Allen SE, Charalambous M, Ferguson-Smith MA, et al. Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control. Genome Res. 2018;28:345–356.
Kazazian HH Jr, Wong C, Youssoufian H, Scott AF, Phillips DG, Antonarakis SE. Haemophilia a resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature. 1988;332:164–6.
Robbez-Masson L, Tie CHC, Conde L, Tunbak H, Husovsky C, Tchasovnikarova IA, Timms RT, Herrero J, Lehner PJ, Rowe HM. The HUSH complex cooperates with TRIM28 to repress young retrotransposons and new genes. Genome Res. 2018;
Berrens RV, Andrews S, Spensberger D, Santos F, Dean W, Gould P, Sharif J, Olova N, Chandra T, Koseki H, et al. An endosiRNA-based repression mechanism counteracts transposon activation during global DNA demethylation in embryonic stem cells. Cell Stem Cell. 2017;21:694–703. e697
Bourc'his D, Bestor TH. Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature. 2004;431:96–9.
Walter M, Teissandier A, Perez-Palacios R, Bourc'his D. An epigenetic switch ensures transposon repression upon dynamic loss of DNA methylation in embryonic stem cells. Elife. 2016;5:e11418.
Marchetto MCN, Narvaiza I, Denli AM, Benner C, Lazzarini TA, Nathanson JL, Paquola ACM, Desai KN, Herai RH, Weitzman MD, et al. Differential L1 regulation in pluripotent stem cells of humans and apes. Nature. 2013;503:525–9.
Brattas PL, Jonsson ME, Fasching L, Nelander Wahlestedt J, Shahsavani M, Falk R, Falk A, Jern P, Parmar M, Jakobsson J. TRIM28 controls a gene regulatory network based on endogenous retroviruses in human neural progenitor cells. Cell Rep. 2017;18:1–11.
Jacobs FM, Greenberg D, Nguyen N, Haeussler M, Ewing AD, Katzman S, Paten B, Salama SR, Haussler D. An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature. 2014;516:242–5.
Castro-Diaz N, Ecco G, Coluccio A, Kapopoulou A, Yazdanpanah B, Friedli M, Duc J, Jang SM, Turelli P, Trono D. Evolutionally dynamic L1 regulation in embryonic stem cells. Genes Dev. 2014;28:1397–409.
de la Rica L, Deniz O, Cheng KC, Todd CD, Cruz C, Houseley J, Branco MR. TET-dependent regulation of retrotransposable elements in mouse embryonic stem cells. Genome Biol. 2016;17:234.
Hata K, Sakaki Y. Identification of critical CpG sites for repression of L1 transcription by DNA methylation. Gene. 1997;189:227–34.
Liu N, Lee CH, Swigut T, Grow E, Gu B, Bassik MC, Wysocka J. Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators. Nature. 2018;553:228–32.
Li Z, Dai H, Martos SN, Xu B, Gao Y, Li T, Zhu G, Schones DE, Wang Z. Distinct roles of DNMT1-dependent and DNMT1-independent methylation patterns in the genome of mouse embryonic stem cells. Genome Biol. 2015;16:115.
Liang G, Chan MF, Tomigahara Y, Tsai YC, Gonzales FA, Li E, Laird PW, Jones PA. Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol Cell Biol. 2002;22:480–91.
Burns KH. Transposable elements in cancer. Nat Rev Cancer. 2017;17:415–24.
Hancks DC, Kazazian HH Jr. Roles for retrotransposon insertions in human disease. Mob DNA. 2016;7:9.
Chuong EB, Elde NC, Feschotte C. Regulatory activities of transposable elements: from conflicts to benefits. Nat Rev Genet. 2017;18:71–86.
Goodier JL. Restricting retrotransposons: a review. Mob DNA. 2016;7:16.
Kazazian HH Jr, Moran JV. Mobile DNA in health and disease. N Engl J Med. 2017;377:361–70.
Scott EC, Devine SE. The role of somatic L1 Retrotransposition in human cancers. Viruses. 2017;9:e131.
Grassi DA, Jonsson ME, Brattas PL, Jakobsson J. TRIM28 and the control of transposable elements in the brain. Brain Res. 2018;
Prak ET, Dodson AW, Farkash EA, Kazazian HH Jr. Tracking an embryonic L1 retrotransposition event. Proc Natl Acad Sci U S A. 2003;100:1832–7.
Macia A, Munoz-Lopez M, Cortes JL, Hastings RK, Morell S, Lucena-Aguilar G, Marchal JA, Badge RM, Garcia-Perez JL. Epigenetic control of retrotransposon expression in human embryonic stem cells. Mol Cell Biol. 2011;31:300–16.
Klawitter S, Fuchs NV, Upton KR, Munoz-Lopez M, Shukla R, Wang J, Garcia-Canadas M, Lopez-Ruiz C, Gerhardt DJ, Sebe A, et al. Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells. Nat Commun. 2016;7:10286.
Garcia-Perez JL, Marchetto MC, Muotri AR, Coufal NG, Gage FH, O'Shea KS, Moran JV. LINE-1 retrotransposition in human embryonic stem cells. Hum Mol Genet. 2007;16:1569–77.
MacLennan M, Garcia-Canadas M, Reichmann J, Khazina E, Wagner G, Playfoot CJ, Salvador-Palomeque C, Mann AR, Peressini P, Sanchez L, et al. Mobilization of LINE-1 retrotransposons is restricted by Tex19.1 in mouse embryonic stem cells. Elife. 2017;6:e26152.
Wissing S, Munoz-Lopez M, Macia A, Yang Z, Montano M, Collins W, Garcia-Perez JL, Moran JV, Greene WC. Reprogramming somatic cells into iPS cells activates LINE-1 retroelement mobility. Hum Mol Genet. 2012;21:208–18.
Kimberland ML, Divoky V, Prchal J, Schwahn U, Berger W, Kazazian HH Jr. Full-length human L1 insertions retain the capacity for high frequency retrotransposition in cultured cells. Hum Mol Genet. 1999;8:1557–60.
Ostertag EM, Prak ET, DeBerardinis RJ, Moran JV, Kazazian HH Jr. Determination of L1 retrotransposition kinetics in cultured cells. Nucleic Acids Res. 2000;28:1418–23.
Sassaman DM, Dombroski BA, Moran JV, Kimberland ML, Naas TP, DeBerardinis RJ, Gabriel A, Swergold GD, Kazazian HH Jr. Many human L1 elements are capable of retrotransposition. Nat Genet. 1997;16:37–43.
Dombroski BA, Scott AF, Kazazian HH, Jr. Two additional potential retrotransposons isolated from a human L1 subfamily that contains an active retrotransposable element. Proc Natl Acad Sci U S A. 1993;90:6513–17.
Garcia-Perez JL, Morell M, Scheys JO, Kulpa DA, Morell S, Carter CC, Hammer GD, Collins KL, O'Shea KS, Menendez P, Moran JV. Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells. Nature. 2010;466:769–73.
Han JS, Boeke JD. A highly active synthetic mammalian retrotransposon. Nature. 2004;429:314–8.
Xie Y, Rosser JM, Thompson TL, Boeke JD, An W. Characterization of L1 retrotransposition with high-throughput dual-luciferase assays. Nucleic Acids Res. 2011;39:e16.
Garcia-Perez JL, Doucet AJ, Bucheton A, Moran JV, Gilbert N. Distinct mechanisms for trans-mediated mobilization of cellular RNAs by the LINE-1 reverse transcriptase. Genome Res. 2007;17:602–11.
Erwin JA, Marchetto MC, Gage FH. Mobile DNA elements in the generation of diversity and complexity in the brain. Nat Rev Neurosci. 2014;15:497–506.
Singer T, McConnell MJ, Marchetto MC, Coufal NG, Gage FH. LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes? Trends Neurosci. 2010;33:345–54.
Evrony GD, Lee E, Park PJ, Walsh CA. Resolving rates of mutation in the brain using single-neuron genomics. Elife. 2016;5:e12966.
Baillie JK, Barnett MW, Upton KR, Gerhardt DJ, Richmond TA, De Sapio F, Brennan PM, Rizzu P, Smith S, Fell M, et al. Somatic retrotransposition alters the genetic landscape of the human brain. Nature. 2011;479:534–7.
Erwin JA, Paquola AC, Singer T, Gallina I, Novotny M, Quayle C, Bedrosian TA, Alves FI, Butcher CR, Herdy JR, et al. L1-associated genomic regions are deleted in somatic cells of the healthy human brain. Nat Neurosci. 2016;19:1583–91.
Evrony GD, Cai X, Lee E, Hills LB, Elhosary PC, Lehmann HS, Parker JJ, Atabay KD, Gilmore EC, Poduri A, et al. Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell. 2012;151:483–96.
Evrony GD, Lee E, Mehta BK, Benjamini Y, Johnson RM, Cai X, Yang L, Haseley P, Lehmann HS, Park PJ, Walsh CA. Cell lineage analysis in human brain using endogenous retroelements. Neuron. 2015;85:49–59.
Upton KR, Gerhardt DJ, Jesuadian JS, Richardson SR, Sanchez-Luque FJ, Bodea GO, Ewing AD, Salvador-Palomeque C, van der Knaap MS, Brennan PM, et al. Ubiquitous L1 mosaicism in hippocampal neurons. Cell. 2015;161:228–39.
Hazen JL, Faust GG, Rodriguez AR, Ferguson WC, Shumilina S, Clark RA, Boland MJ, Martin G, Chubukov P, Tsunemoto RK, et al. The complete genome sequences, unique mutational spectra, and developmental potency of adult neurons revealed by cloning. Neuron. 2016;89:1223–36.
Richardson SR, Narvaiza I, Planegger RA, Weitzman MD, Moran JV. APOBEC3A deaminates transiently exposed single-strand DNA during LINE-1 retrotransposition. Elife. 2014;3:e02008.
Garcia Perez JL, Alarcon-Riquelme ME. The TREX1 dinosaur bites the brain through the LINE. Cell Stem Cell. 2017;21:287–8.
Herculano-Houzel S, Lent R. Isotropic fractionator: a simple, rapid method for the quantification of total cell and neuron numbers in the brain. J Neurosci. 2005;25:2518–21.
Song S, Sjostrom PJ, Reigl M, Nelson S, Chklovskii DB. Highly nonrandom features of synaptic connectivity in local cortical circuits. PLoS Biol. 2005;3:e68.
Cragg BG. The density of synapses and neurons in normal, mentally defective ageing human brains. Brain. 1975;98:81–90.
Lee JH, Huynh M, Silhavy JL, Kim S, Dixon-Salazar T, Heiberg A, Scott E, Bafna V, Hill KJ, Collazo A, et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet. 2012;44:941–5.
Lim JS, Kim WI, Kang HC, Kim SH, Park AH, Park EK, Cho YW, Kim S, Kim HM, Kim JA, et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med. 2015;21:395–400.
Poduri A, Evrony GD, Cai X, Elhosary PC, Beroukhim R, Lehtinen MK, Hills LB, Heinzen EL, Hill A, Hill RS, et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron. 2012;74:41–8.
McConnell MJ, Moran JV, Abyzov A, Akbarian S, Bae T, Cortes-Ciriano I, Erwin JA, Fasching L, Flasch DA, Freed D, et al. Intersection of diverse neuronal genomes and neuropsychiatric disease: the brain somatic mosaicism network. Science. 2017;356:eaal1641.
Cai X, Evrony GD, Lehmann HS, Elhosary PC, Mehta BK, Poduri A, Walsh CA. Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep. 2015;10:645.
Gole J, Gore A, Richards A, Chiu YJ, Fung HL, Bushman D, Chiang HI, Chun J, Lo YH, Zhang K. Massively parallel polymerase cloning and genome sequencing of single cells using nanoliter microwells. Nat Biotechnol. 2013;31:1126–32.
McConnell MJ, Lindberg MR, Brennand KJ, Piper JC, Voet T, Cowing-Zitron C, Shumilina S, Lasken RS, Vermeesch JR, Hall IM, Gage FH. Mosaic copy number variation in human neurons. Science. 2013;342:632–7.
Chen C, Xing D, Tan L, Li H, Zhou G, Huang L, Xie XS. Single-cell whole-genome analyses by linear amplification via transposon insertion (LIANTI). Science. 2017;356:189–94.
Lodato MA, Woodworth MB, Lee S, Evrony GD, Mehta BK, Karger A, Lee S, Chittenden TW, D'Gama AM, Cai X, et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science. 2015;350:94–8.
Kurnosov AA, Ustyugova SV, Nazarov VI, Minervina AA, Komkov AY, Shugay M, Pogorelyy MV, Khodosevich KV, Mamedov IZ, Lebedev YB. The evidence for increased L1 activity in the site of human adult brain neurogenesis. PLoS One. 2015;10:e0117854.
Burda JE, Sofroniew MV. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron. 2014;81:229–48.
Gallo V, Deneen B. Glial development: the crossroads of regeneration and repair in the CNS. Neuron. 2014;83:283–308.
Kubo S, Seleme MC, Soifer HS, Perez JL, Moran JV, Kazazian HH Jr, Kasahara N. L1 retrotransposition in nondividing and primary human somatic cells. Proc Natl Acad Sci U S A. 2006;103:8036–41.
Shi X, Seluanov A, Gorbunova V. Cell divisions are required for L1 retrotransposition. Mol Cell Biol. 2007;27:1264–70.
Xie Y, Mates L, Ivics Z, Izsvak Z, Martin SL, An W. Cell division promotes efficient retrotransposition in a stable L1 reporter cell line. Mob DNA. 2013;4:10.
Bushong EA, Martone ME, Jones YZ, Ellisman MH. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci. 2002;22:183–92.
Han X, Chen M, Wang F, Windrem M, Wang S, Shanz S, Xu Q, Oberheim NA, Bekar L, Betstadt S, et al. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell. 2013;12:342–53.
Shukla R, Upton KR, Munoz-Lopez M, Gerhardt DJ, Fisher ME, Nguyen T, Brennan PM, Baillie JK, Collino A, Ghisletti S, et al. Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell. 2013;153:101–11.
Doucet-O'Hare TT, Rodic N, Sharma R, Darbari I, Abril G, Choi JA, Young Ahn J, Cheng Y, Anders RA, Burns KH, et al. LINE-1 expression and retrotransposition in Barrett's esophagus and esophageal carcinoma. Proc Natl Acad Sci U S A. 2015;112:E4894–900.
Scott EC, Gardner EJ, Masood A, Chuang NT, Vertino PM, Devine SE. A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer. Genome Res. 2016;26:745–55.
Doucet-O'Hare TT, Sharma R, Rodic N, Anders RA, Burns KH, Kazazian HH Jr. Somatically acquired LINE-1 insertions in normal esophagus undergo clonal expansion in esophageal squamous cell carcinoma. Hum Mutat. 2016;37:942–54.
Ewing AD, Gacita A, Wood LD, Ma F, Xing D, Kim MS, Manda SS, Abril G, Pereira G, Makohon-Moore A, et al. Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution. Genome Res. 2015;25:1536–45.
Saini N, Roberts SA, Klimczak LJ, Chan K, Grimm SA, Dai S, Fargo DC, Boyer JC, Kaufmann WK, Taylor JA, et al. The impact of environmental and endogenous damage on somatic mutation load in human skin fibroblasts. PLoS Genet. 2016;12:e1006385.
Helman E, Lawrence MS, Stewart C, Sougnez C, Getz G, Meyerson M. Somatic retrotransposition in human cancer revealed by whole-genome and exome sequencing. Genome Res. 2014;24:1053–63.
Iskow RC, McCabe MT, Mills RE, Torene S, Pittard WS, Neuwald AF, Van Meir EG, Vertino PM, Devine SE. Natural mutagenesis of human genomes by endogenous retrotransposons. Cell. 2010;141:1253–61.
Lee E, Iskow R, Yang L, Gokcumen O, Haseley P, Luquette LJ 3rd, Lohr JG, Harris CC, Ding L, Wilson RK, et al. Landscape of somatic retrotransposition in human cancers. Science. 2012;337:967–71.
Miki Y, Nishisho I, Horii A, Miyoshi Y, Utsunomiya J, Kinzler KW, Vogelstein B, Nakamura Y. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Res. 1992;52:643–5.
Nguyen THM, Carreira PE, Sanchez-Luque FJ, Schauer SN, Fagg AC, Richardson SR, Davies CM, Jesuadian JS, Kempen MHC, Troskie RL, et al. L1 retrotransposon heterogeneity in ovarian tumor cell evolution. Cell Rep. 2018;23:3730–40.
Rodic N, Steranka JP, Makohon-Moore A, Moyer A, Shen P, Sharma R, Kohutek ZA, Huang CR, Ahn D, Mita P, et al. Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma. Nat Med. 2015;21:1060–4.
Solyom S, Ewing AD, Rahrmann EP, Doucet T, Nelson HH, Burns MB, Harris RS, Sigmon DF, Casella A, Erlanger B, et al. Extensive somatic L1 retrotransposition in colorectal tumors. Genome Res. 2012;22:2328–38.
Tubio JMC, Li Y, Ju YS, Martincorena I, Cooke SL, Tojo M, Gundem G, Pipinikas CP, Zamora J, Raine K, et al. Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science. 2014;345:1251343.
Achanta P, Steranka JP, Tang Z, Rodic N, Sharma R, Yang WR, Ma S, Grivainis M, Huang CRL, Schneider AM, et al. Somatic retrotransposition is infrequent in glioblastomas. Mob DNA. 2016;7:22.
Carreira PE, Ewing AD, Li G, Schauer SN, Upton KR, Fagg AC, Morell S, Kindlova M, Gerdes P, Richardson SR, et al. Evidence for L1-associated DNA rearrangements and negligible L1 retrotransposition in glioblastoma multiforme. Mob DNA. 2016;7:21.
Carreira PE, Richardson SR, Faulkner GJ. L1 retrotransposons, cancer stem cells and oncogenesis. FEBS J. 2014;281:63–73.
Guo C, Jeong HH, Hsieh YC, Klein HU, Bennett DA, De Jager PL, Liu Z, Shulman JM. Tau activates transposable elements in Alzheimer's disease. Cell Rep. 2018;23:2874–80.
Jones BC, Wood JG, Chang C, Tam AD, Franklin MJ, Siegel ER, Helfand SL. A somatic piRNA pathway in the Drosophila fat body ensures metabolic homeostasis and normal lifespan. Nat Commun. 2016;7:13856.
Sousa-Victor P, Ayyaz A, Hayashi R, Qi Y, Madden DT, Lunyak VV, Jasper H. Piwi is required to limit exhaustion of aging somatic stem cells. Cell Rep. 2017;20:2527–37.
Dubnau J. The retrotransposon storm and the dangers of a Collyer's genome. Curr Opin Genet Dev. 2018;49:95–105.
Burke WD, Calalang CC, Eickbush TH. The site-specific ribosomal insertion element type II of Bombyx mori (R2Bm) contains the coding sequence for a reverse transcriptase-like enzyme. Mol Cell Biol. 1987;7:2221–30.
Dej KJ, Gerasimova T, Corces VG, Boeke JD. A hotspot for the Drosophila gypsy retroelement in the ovo locus. Nucleic Acids Res. 1998;26:4019–25.
Labrador M, Sha K, Li A, Corces VG. Insulator and Ovo proteins determine the frequency and specificity of insertion of the gypsy retrotransposon in Drosophila melanogaster. Genetics. 2008;180:1367–78.
Perrat PN, DasGupta S, Wang J, Theurkauf W, Weng Z, Rosbash M, Waddell S. Transposition-driven genomic heterogeneity in the Drosophila brain. Science. 2013;340:91–5.
Treiber CD, Waddell S. Resolving the prevalence of somatic transposition in Drosophila. Elife. 2017;6:e28297.
Khurana JS, Wang J, Xu J, Koppetsch BS, Thomson TC, Nowosielska A, Li C, Zamore PD, Weng Z, Theurkauf WE. Adaptation to P element transposon invasion in Drosophila melanogaster. Cell. 2011;147:1551–63.
Kaminker JS, Bergman CM, Kronmiller B, Carlson J, Svirskas R, Patel S, Frise E, Wheeler DA, Lewis SE, Rubin GM, et al. The transposable elements of the Drosophila melanogaster euchromatin: a genomics perspective. Genome Biol. 2002;3:RESEARCH0084.
Kofler R, Hill T, Nolte V, Betancourt AJ, Schlotterer C. The recent invasion of natural Drosophila simulans populations by the P-element. Proc Natl Acad Sci U S A. 2015;112:6659–63.
Friedli M, Turelli P, Kapopoulou A, Rauwel B, Castro-Diaz N, Rowe HM, Ecco G, Unzu C, Planet E, Lombardo A, et al. Loss of transcriptional control over endogenous retroelements during reprogramming to pluripotency. Genome Res. 2014;24:1251–9.
Bird A, Taggart M, Frommer M, Miller OJ, Macleod D. A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell. 1985;40:91–9.
Bestor TH, Edwards JR, Boulard M. Notes on the role of dynamic DNA methylation in mammalian development. Proc Natl Acad Sci U S A. 2015;112:6796–9.
Grandi FC, Rosser JM, Newkirk SJ, Yin J, Jiang X, Xing Z, Whitmore L, Bashir S, Ivics Z, Izsvak Z, et al. Retrotransposition creates sloping shores: a graded influence of hypomethylated CpG islands on flanking CpG sites. Genome Res. 2015;25:1135–46.
Booth MJ, Branco MR, Ficz G, Oxley D, Krueger F, Reik W, Balasubramanian S. Quantitative sequencing of 5-methylcytosine and 5-hydroxymethylcytosine at single-base resolution. Science. 2012;336:934–7.
Belancio VP, Roy-Engel AM, Pochampally RR, Deininger P. Somatic expression of LINE-1 elements in human tissues. Nucleic Acids Res. 2010;38:3909–22.
Faulkner GJ, Kimura Y, Daub CO, Wani S, Plessy C, Irvine KM, Schroder K, Cloonan N, Steptoe AL, Lassmann T, et al. The regulated retrotransposon transcriptome of mammalian cells. Nat Genet. 2009;41:563–71.
Pitkanen E, Cajuso T, Katainen R, Kaasinen E, Valimaki N, Palin K, Taipale J, Aaltonen LA, Kilpivaara O. Frequent L1 retrotranspositions originating from TTC28 in colorectal cancer. Oncotarget. 2014;5:853–9.
Paterson AL, Weaver JM, Eldridge MD, Tavare S, Fitzgerald RC, Edwards PA, Consortium OC. Mobile element insertions are frequent in oesophageal adenocarcinomas and can mislead paired-end sequencing analysis. BMC Genomics. 2015;16:473.
GTEX Consortium. Genetic effects on gene expression across human tissues. Nature. 2017;550:204–13.
Gasior SL, Wakeman TP, Xu B, Deininger PL. The human LINE-1 retrotransposon creates DNA double-strand breaks. J Mol Biol. 2006;357:1383–93.
Jacob-Hirsch J, Eyal E, Knisbacher BA, Roth J, Cesarkas K, Dor C, Farage-Barhom S, Kunik V, Simon AJ, Gal M, et al. Whole-genome sequencing reveals principles of brain retrotransposition in neurodevelopmental disorders. Cell Res. 2018;28:187–203.
Levy A, Schwartz S, Ast G. Large-scale discovery of insertion hotspots and preferential integration sites of human transposed elements. Nucleic Acids Res. 2010;38:1515–30.
Faulkner GJ, Forrest AR, Chalk AM, Schroder K, Hayashizaki Y, Carninci P, Hume DA, Grimmond SM. A rescue strategy for multimapping short sequence tags refines surveys of transcriptional activity by CAGE. Genomics. 2008;91:281–8.
Ewing AD. Transposable element detection from whole genome sequence data. Mob DNA. 2015;6:24.
Morrish TA, Gilbert N, Myers JS, Vincent BJ, Stamato TD, Taccioli GE, Batzer MA, Moran JV. DNA repair mediated by endonuclease-independent LINE-1 retrotransposition. Nat Genet. 2002;31:159–65.
Gilbert N, Lutz S, Morrish TA, Moran JV. Multiple fates of L1 retrotransposition intermediates in cultured human cells. Mol Cell Biol. 2005;25:7780–95.
Yang N, Zhang L, Zhang Y, Kazazian HH Jr. An important role for RUNX3 in human L1 transcription and retrotransposition. Nucleic Acids Res. 2003;31:4929–40.
Speek M. Antisense promoter of human L1 retrotransposon drives transcription of adjacent cellular genes. Mol Cell Biol. 2001;21:1973–85.
Denli AM, Narvaiza I, Kerman BE, Pena M, Benner C, Marchetto MC, Diedrich JK, Aslanian A, Ma J, Moresco JJ, et al. Primate-specific ORF0 contributes to retrotransposon-mediated diversity. Cell. 2015;163:583–93.
Pinson ME, Pogorelcnik R, Court F, Arnaud P, Vaurs-Barriere C. CLIFinder: identification of LINE-1 chimeric transcripts in RNA-seq data. Bioinformatics. 2018;34:688–90.
Criscione SW, Theodosakis N, Micevic G, Cornish TC, Burns KH, Neretti N, Rodic N. Genome-wide characterization of human L1 antisense promoter-driven transcripts. BMC Genomics. 2016;17:463.
Nigumann P, Redik K, Matlik K, Speek M. Many human genes are transcribed from the antisense promoter of L1 retrotransposon. Genomics. 2002;79:628–34.
Jachowicz JW, Bing X, Pontabry J, Boskovic A, Rando OJ, Torres-Padilla ME. LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo. Nat Genet. 2017;49:1502–10.
Percharde M, Lin CJ, Yin Y, Guan J, Peixoto GA, Bulut-Karslioglu A, Biechele S, Huang B, Shen X, Ramalho-Santos M. A LINE1-Nucleolin partnership regulates early development and ESC identity. Cell. 2018.
An W, Dai L, Niewiadomska AM, Yetil A, O'Donnell KA, Han JS, Boeke JD. Characterization of a synthetic human LINE-1 retrotransposon ORFeus-Hs. Mob DNA. 2011;2:2.
Dhellin O, Maestre J, Heidmann T. Functional differences between the human LINE retrotransposon and retroviral reverse transcriptases for in vivo mRNA reverse transcription. EMBO J. 1997;16:6590–602.
Segal-Bendirdjian E, Heidmann T. Evidence for a reverse transcription intermediate for a marked line transposon in tumoral rat cells. Biochem Biophys Res Commun. 1991;181:863–70.
Shimizu A, Nakatani Y, Nakamura T, Jinno-Oue A, Ishikawa O, Boeke JD, Takeuchi Y, Hoshino H. Characterisation of cytoplasmic DNA complementary to non-retroviral RNA viruses in human cells. Sci Rep. 2014;4:5074.
Giorgi G, Virgili M, Monti B, Del Re B. Long INterspersed nuclear elements (LINEs) in brain and non-brain tissues of the rat. Cell Tissue Res. 2018;
Goodier JL. Retrotransposition in tumors and brains. Mob DNA. 2014;5:11.
Stetson DB, Ko JS, Heidmann T, Medzhitov R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell. 2008;134:587–98.
Han JS, Shao S. Circular retrotransposition products generated by a LINE retrotransposon. Nucleic Acids Res. 2012;40:10866–77.
Moldovan JB, Moran JV. The zinc-finger antiviral protein ZAP inhibits LINE and Alu Retrotransposition. PLoS Genet. 2015;11:e1005121.
Goodier JL, Zhang L, Vetter MR, Kazazian HH Jr. LINE-1 ORF1 protein localizes in stress granules with other RNA-binding proteins, including components of RNA interference RNA-induced silencing complex. Mol Cell Biol. 2007;27:6469–83.
Balaj L, Lessard R, Dai L, Cho YJ, Pomeroy SL, Breakefield XO, Skog J. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun. 2011;2:180.
Hu S, Li J, Xu F, Mei S, Le Duff Y, Yin L, Pang X, Cen S, Jin Q, Liang C, Guo F. SAMHD1 inhibits LINE-1 Retrotransposition by promoting stress granule formation. PLoS Genet. 2015;11:e1005367.
Jones RB, Song H, Xu Y, Garrison KE, Buzdin AA, Anwar N, Hunter DV, Mujib S, Mihajlovic V, Martin E, et al. LINE-1 retrotransposable element DNA accumulates in HIV-1-infected cells. J Virol. 2013;87:13307–20.
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23:185–8.
Guy J, Hendrich B, Holmes M, Martin JE, Bird A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet. 2001;27:322–6.
Guy J, Gan J, Selfridge J, Cobb S, Bird A. Reversal of neurological defects in a mouse model of Rett syndrome. Science. 2007;315:1143–7.
Tarallo V, Hirano Y, Gelfand BD, Dridi S, Kerur N, Kim Y, Cho WG, Kaneko H, Fowler BJ, Bogdanovich S, et al. DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell. 2012;149:847–59.
Kaneko H, Dridi S, Tarallo V, Gelfand BD, Fowler BJ, Cho WG, Kleinman ME, Ponicsan SL, Hauswirth WW, Chiodo VA, et al. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature. 2011;471:325–30.
Li W, Lee MH, Henderson L, Tyagi R, Bachani M, Steiner J, Campanac E, Hoffman DA, von Geldern G, Johnson K, et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med. 2015;7:307ra153.
Ahmad S, Mu X, Yang F, Greenwald E, Park JW, Jacob E, Zhang CZ, Hur S. Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation. Cell. 2018;172:797–810.
Wallace NA, Belancio VP, Deininger PL. L1 mobile element expression causes multiple types of toxicity. Gene. 2008;419:75–81.
Wissing S, Montano M, Garcia-Perez JL, Moran JV, Greene WC. Endogenous APOBEC3B restricts LINE-1 retrotransposition in transformed cells and human embryonic stem cells. J Biol Chem. 2011;286:36427–37.
Madabhushi R, Gao F, Pfenning AR, Pan L, Yamakawa S, Seo J, Rueda R, Phan TX, Yamakawa H, Pao PC, et al. Activity-induced DNA breaks govern the expression of neuronal early-response genes. Cell. 2015;161:1592–605.
Wu J, Chen ZJ. Innate immune sensing and signaling of cytosolic nucleic acids. Annu Rev Immunol. 2014;32:461–88.
Crow YJ, Manel N. Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol. 2015;15:429–40.
Kempen MHC, Bodea GO, Faulkner GJ. Neuronal genome plasticity: retrotransposons, environment and disease. In: Cristofari G, editor. Human retrotransposons in health and disease. New York: Springer; 2017. p. 107–25.
Dai L, Huang Q, Boeke JD. Effect of reverse transcriptase inhibitors on LINE-1 and Ty1 reverse transcriptase activities and on LINE-1 retrotransposition. BMC Biochem. 2011;12:18.
Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP, Lim WA. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell. 2013;152:1173–83.
Crow YJ, Chase DS, Lowenstein Schmidt J, Szynkiewicz M, Forte GM, Gornall HL, Oojageer A, Anderson B, Pizzino A, Helman G, et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A. 2015;167A:296–312.
Zhao K, Du J, Han X, Goodier JL, Li P, Zhou X, Wei W, Evans SL, Li L, Zhang W, et al. Modulation of LINE-1 and Alu/SVA retrotransposition by Aicardi-Goutieres syndrome-related SAMHD1. Cell Rep. 2013;4:1108–15.
Orecchini E, Doria M, Antonioni A, Galardi S, Ciafre SA, Frassinelli L, Mancone C, Montaldo C, Tripodi M, Michienzi A. ADAR1 restricts LINE-1 retrotransposition. Nucleic Acids Res. 2017;45:155–68.
Herrmann A, Wittmann S, Thomas D, Shepard CN, Kim B, Ferreiros N, Gramberg T. The SAMHD1-mediated block of LINE-1 retroelements is regulated by phosphorylation. Mob DNA. 2018;9:11.
Li P, Du J, Goodier JL, Hou J, Kang J, Kazazian HH Jr, Zhao K, Yu XF. Aicardi-Goutieres syndrome protein TREX1 suppresses L1 and maintains genome integrity through exonuclease-independent ORF1p depletion. Nucleic Acids Res. 2017;45:4619–31.
Liddicoat BJ, Piskol R, Chalk AM, Ramaswami G, Higuchi M, Hartner JC, Li JB, Seeburg PH, Walkley CR. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science. 2015;349:1115–20.
Bartsch K, Knittler K, Borowski C, Rudnik S, Damme M, Aden K, Spehlmann ME, Frey N, Saftig P, Chalaris A, Rabe B. Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy. Hum Mol Genet. 2017;26:3960–72.
Choi J, Hwang SY, Ahn K. Interplay between RNASEH2 and MOV10 controls LINE-1 retrotransposition. Nucleic Acids Res. 2018;46:1912–26.
Chung H, Calis JJA, Wu X, Sun T, Yu Y, Sarbanes SL, Dao Thi VL, Shilvock AR, Hoffmann HH, Rosenberg BR, Rice CM. Human ADAR1 prevents endogenous RNA from triggering translational shutdown. Cell. 2018;172:811–24.
Kasher PR, Jenkinson EM, Briolat V, Gent D, Morrissey C, Zeef LA, Rice GI, Levraud JP, Crow YJ. Characterization of samhd1 morphant zebrafish recapitulates features of the human type I interferonopathy Aicardi-Goutieres syndrome. J Immunol. 2015;194:2819–25.
Herzner AM, Hagmann CA, Goldeck M, Wolter S, Kubler K, Wittmann S, Gramberg T, Andreeva L, Hopfner KP, Mertens C, et al. Sequence-specific activation of the DNA sensor cGAS by Y-form DNA structures as found in primary HIV-1 cDNA. Nat Immunol. 2015;16:1025–33.
Volkman HE, Stetson DB. The enemy within: endogenous retroelements and autoimmune disease. Nat Immunol. 2014;15:415–22.
Yang YG, Lindahl T, Barnes DE. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell. 2007;131:873–86.
Akwa Y, Hassett DE, Eloranta ML, Sandberg K, Masliah E, Powell H, Whitton JL, Bloom FE, Campbell IL. Transgenic expression of IFN-alpha in the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration. J Immunol. 1998;161:5016–26.
Achleitner M, Kleefisch M, Hennig A, Peschke K, Polikarpova A, Oertel R, Gabriel B, Schulze L, Lindeman D, Gerbaulet A, et al. Lack of Trex1 causes systemic autoimmunity despite the presence of antiretroviral drugs. J Immunol. 2017;199:2261–9.
Beck-Engeser GB, Eilat D, Wabl M. An autoimmune disease prevented by anti-retroviral drugs. Retrovirology. 2011;8:91.
Fowler BJ, Gelfand BD, Kim Y, Kerur N, Tarallo V, Hirano Y, Amarnath S, Fowler DH, Radwan M, Young MT, et al. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science. 2014;346:1000–3.
Benitez-Guijarro M, Lopez-Ruiz C, Tarnauskaite Z, Murina O, Mian Mohammad M, Williams TC, Fluteau A, Sanchez L, Vilar-Astasio R, Garcia-Canadas M, et al. RNase H2, mutated in Aicardi-Goutieres syndrome, promotes LINE-1 retrotransposition. EMBO J. 2018.
Lankenau DH, Huijser P, Jansen E, Miedema K, Hennig W. Micropia: a retrotransposon of Drosophila comb