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Alternative titles; symbolsLINE-1.2 RETROTRANSPOSABLE ELEMENT; L1.2Cytogenetic location: 22q11-q12 Genomic coordinates (GRCh38): 22:23,100,000-37,200,000▼ De...

Alternative titles; symbols


Cytogenetic location: 22q11-q12 Genomic coordinates (GRCh38): 22:23,100,000-37,200,000

▼ Description
The LRE1 gene encodes a 'LINE' (long interspersed nuclear element) retrotransposable element (LRE), a mobile DNA sequence with autonomous retrotransposon activity. A retrotransposon is a specific type of transposable element that can be transcribed into RNA, reverse transcribed into cDNA, and then reintegrated as a cDNA into the genome at a new location. LINE-1 does not contain long terminal repeats, has 2 open reading frames, and has an A-rich tract at its 3-prime end. Over 100,000 LINE-1 sequences exist in the human genome; about 3,000 to 4,000 of these are full length, but most are rendered inactive by truncating mutations. LINE-1 retrotransposons comprise about 17% of the human genome (summary by Kazazian and Moran, 1998).

▼ Cloning and Expression
Kazazian et al. (1988) found de novo insertions of an L1 element into exon 14 of the factor VIII gene (F8; 300841) causing hemophilia A (306700) in 2 unrelated patients. Both of these insertions (3.8 and 2.3 kb, respectively) contained 3-prime portions of the L1 sequence. Dombroski et al. (1991) used an oligonucleotide probe complementary to a unique region of the cloned sequence of 1 of these patients to detect hybridizing fragments in the DNA and to isolate a genomic full-length element containing the 2 open reading frames (ORFs) of the L1 consensus sequence. This element, called L1.2A, contained the 2 nucleotide changes found in the insertion in the factor VIII gene of patient JH27 (300841.0022). However, these 2 changes were absent from the DNA in the parents. Dombroski et al. (1991) constructed a genomic DNA library from the mother of JH27 and isolated an allele of L1.2A (L1.2B). L1.2B was the first full-length element with 2 intact ORFs. It contained a 27-bp poly(A) tail and was flanked by a 15-bp target site duplication. The ORF2 of L1.2A encoded reverse transcriptase activity. The L1.2 locus was assigned to chromosome 22 by analysis of somatic cell hybrid DNAs. It was the first retrotransposable element isolated from human DNA. Dombroski et al. (1991) demonstrated that the L1.2 transposable element contains 2 open reading frames.

Mathias et al. (1991) showed that the second open reading frame encodes a protein with reverse transcriptase activity.

Dombroski et al. (1993) isolated the 2 remaining full-length members of the subfamily of L1 elements closely related to the L1.2B present in the genome of the mother of hemophilia patient JH27. Since these elements, L1.3 and L1.4, were very similar in sequence to L1.2B and contained both open reading frames 1 and 2 intact, they were thought also to be active retrotransposable elements. The results suggested that certain L1 subfamilies may contain multiple active elements.

▼ Mapping
Dombroski et al. (1991) mapped the L1.2 locus to chromosome 22 by PCR analysis of DNA from human-rodent cell hybrids. Budarf et al. (1991) localized the assignment to 22q11.1-q11.2 by in situ hybridization. The L1 element on chromosome 22 is presumably present at that location in all humans. Dombroski et al. (1991) found it in the same (i.e., corresponding) location in chimpanzees and gorillas, which means that it has been at the same location in the genome for at least 6 million years.

▼ Gene Function
Mathias et al. (1991) suggested that L1 represents a potential source of the reverse transcriptase activity necessary for dispersion of the many classes of mammalian retroelements. It is possible that the reverse transcriptase coded by LINEs may help Alu sequences move around in the genome.

Feng et al. (1996) identified an endonuclease domain at the N terminus of the second open reading frame of L1. It is highly conserved among poly(A) retrotransposons and resembles the apurinic/apyrimidinic endonucleases. Mutations in conserved amino acid residues of L1 endonuclease abolished its nicking activity and eliminated L1 retrotransposition. Feng et al. (1996) proposed that L1 endonuclease cleaves the target site for L1 insertion and primes reverse transcription.

Moran et al. (1996) showed that both the previously isolated human L1 elements, L1.2 and LRE2, can actively retrotranspose in cultured mammalian cells. When stably expressed from an episome in HeLa cells, both elements retrotransposed into a variety of chromosomal locations at a high frequency. The retrotransposed products resembled endogenous L1 insertions, since they were variably 5-prime truncated, ended in poly(A) tracts, and were flanked by target-site duplications or short deletions. Point mutations in conserved domains of the L1.2-encoded proteins reduced retrotransposition by 100- to 1,000-fold. Remarkably, L1.2 also retrotransposed in a mouse cell line, suggesting a potential role for L1-based vectors in random insertional mutagenesis.

Sassaman et al. (1997) demonstrated that many human L1 elements are capable of retrotransposition in HeLa cells. They reported studies bringing to 7 the number of characterized active human L1 elements. Based on these and other data, they estimated that 30 to 60 active L1 elements reside in the average diploid human genome. Boeke (1997) reviewed the significance of the fact that LINEs and Alu elements have in common the presence of poly(A) tails of varying length, as well as other shared structural features. A puzzling aspect of L1 retrotransposition is that the transposition machinery behaves in a cis-acting manner. The estimate of Sassaman et al. (1997) that 20 to 60 functional L1 elements are to be found in the diploid genome indicates that in spite of the large number of L1 elements that are transcriptionally active, only a remarkably small subset (less than 0.01%) are able to transpose, i.e., are capable of causing mutations. In humans and mice, only L1 elements encoding intact open reading frames are transpositionally competent. This implies the existence of a mechanism ensuring cis-action. Human L1 contains 2 ORFs; ORF1 encodes an RNA-binding protein and ORF2 encodes an endonuclease-reverse transcriptase protein. Several observations suggested to Boeke (1997) that during or immediately after its translation, nascent L1 ORF2 protein interacts with the poly(A) tail of its own mRNA. Binding to the poly(A) at the 3-prime end of L1 RNA is likely to be required for retrotransposition.

Long interspersed elements are abundant retrotransposons in mammalian genomes that probably retrotranspose by target site-primed reverse transcription (TPRT). During TPRT, the LINE-1 endonuclease cleaves genomic DNA, freeing a 3-prime hydroxyl that serves as a primer for reverse transcription of LINE-1 RNA by LINE-1 reverse transcriptase. The nascent LINE-1 cDNA joins to genomic DNA, generating LINE-1 structural hallmarks. Morrish et al. (2002) described a pathway for LINE-1 retrotransposition in Chinese hamster ovary (CHO) cells that acts independently of endonuclease but is dependent upon reverse transcriptase. Further results suggested that LINE-1s integrate into DNA lesions, resulting in retrotransposon-mediated DNA repair in mammalian cells.

Eickbush (2002), commenting on the fact that LINE-1 elements can insert at sites of double-stranded DNA breaks, raised the question of whether they promote the repair process or take advantage of potential priming sites offered by such breaks without contributing to repair. The answer was not clear, and Eickbush (2002) marveled that so little is known of the insertional mechanism that accounts for nearly half of our own genome.

In cultured human cells, Goodier et al. (2004) determined that full-length ORF2 protein was predominantly cytoplasmic, while carboxy terminal-deleted ORF2 protein localized additionally to the nucleolus. ORF1 protein appeared in the cytoplasm with a speckled pattern and colocalized with ORF2 protein in nucleoli in a subset of cells.

LINE-1 (L1) elements are the most abundant autonomous retrotransposons in the human genome, accounting for about 17% of human DNA. Han et al. (2004) demonstrated that inserting L1 sequences on a transcript significantly decreases RNA expression and therefore protein expression. This decreased RNA concentration does not result from major effects on the transcription initiation rate or RNA stability. Rather, the poor L1 expression is primarily due to inadequate transcription elongation. Because L1 is an abundant and broadly distributed mobile element, Han et al. (2004) speculated that the inhibition of transcription elongation by L1 might profoundly affect expression of endogenous human genes. They proposed a model in which L1 affects gene expression genomewide by acting as a 'molecular rheostat' of target genes. Bioinformatic data are consistent with the hypothesis that L1 can serve as an evolutionary fine tuner of the human transcriptome.

Using an in vitro self-selection technique, Salehi-Ashtiani et al. (2006) identified a self-cleaving ribozyme associated with a LINE-1 retrotransposon.

Morrish et al. (2002) reported an efficient, endonuclease-independent L1 retrotransposition pathway (ENi) in certain Chinese hamster ovary cell lines that are defective in the nonhomologous end-joining (NHEJ) pathway of DNA double-strand break repair. Morrish et al. (2007) characterized ENi retrotransposition events generated in V3 CHO cells, which are deficient in DNA-dependent protein kinase catalytic subunit activity and have both dysfunctional telomeres and an NHEJ defect. Notably, about 30% of ENi retrotransposition events insert in an orientation-specific manner adjacent to a perfect telomere repeat (5-prime-TTAGGG-3-prime). Similar insertions were not detected among ENi retrotransposition events generated in controls or in XR-1 CHO cells deficient for XRCC4 (194363), an NHEJ factor that is required for DNA ligation but has no known function in telomere maintenance. Furthermore, transient expression of a dominant-negative allele of human TERF2 (602027) in XRCC4-deficient XR-1 cells, which disrupts telomere capping, enabled telomere-associated ENi retrotransposition events. Morrish et al. (2007) concluded that L1s containing a disabled endonuclease can use dysfunctional telomeres as an integration substrate. These findings highlighted similarities between the mechanism of endonuclease-independent L1 retrotransposition and the action of telomerase (see 187270), because both processes can use a 3-prime OH for priming reverse transcription at either internal DNA lesions or chromosome ends. Thus, Morrish et al. (2007) proposed that endonuclease-independent L1 retrotransposition is an ancestral mechanism of RNA-mediated DNA repair associated with non-long-terminal-repeat retrotransposons that may have been used before the acquisition of an endonuclease domain.

In living and fixed cells, Goodier et al. (2010) assayed tagged ribonucleoprotein particles (RNPs) generated from constructs expressing retrotransposition-competent L1s. The proteins ORF1 and ORF2 and L1 RNA colocalized in cytoplasmic foci, which are often associated with markers of cytoplasmic stress granules. Mutation analyses revealed that ORF1 could direct L1 RNP distribution within the cell. The nonautonomous retrotransposons Alu and SVA each manifested unique features of subcellular RNA distribution, despite a requirement for the L1 integration machinery. In nuclei, Alu RNA formed small round foci partially associated with marker proteins for coiled bodies (suborganelles involved in the processing of noncoding RNAs). SVA RNA patterning was distinctive, being cytoplasmic but without prominent foci and concentrated in large nuclear aggregates that often ringed nucleoli. Such variability predicted significant differences in the life cycles of these elements.

Van Meter et al. (2014) reported that the longevity-regulating protein SIRT6 (606211) is a powerful repressor of L1 activity. Specifically, SIRT6 binds to the 5-prime UTR of L1 loci, where it mono-ADP ribosylates the nuclear corepressor protein KAP1 (601742) and facilitates KAP1 interaction with the heterochromatin factor HP1-alpha (HP1; 604478), thereby contributing to the packaging of L1 elements into transcriptionally repressive heterochromatin. During the course of aging, and also in response to DNA damage, however, Van Meter et al. (2014) found that SIRT6 is depleted from L1 loci, allowing the activation of these previously silenced retroelements.

De Cecco et al. (2019) demonstrated that during cellular senescence, L1 retrotransposable elements become transcriptionally derepressed and activated a type I interferon (IFN-I) response. The IFN-I interferon response is a phenotype of late senescence and contributes to the maintenance of the senescence-associated secretory phenotype. The IFN-I response is triggered by cytoplasmic L1 cDNA, and is antagonized by inhibitors of the L1 reverse transcriptase. Treatment of aged mice with the nucleoside reverse transcriptase inhibitor lamivudine downregulated IFN-I activation and age-associated inflammation (inflammaging) in several tissues. De Cecco et al. (2019) proposed that the activation of retrotransposons is an important component of sterile inflammation that is a hallmark of aging, and that L1 reverse transcriptase is a relevant target for the treatment of age-associated disorders.

▼ Molecular Genetics
To determine the frequency of L1-mediated transduction in the human genome, Goodier et al. (2000) studied 66 previously uncharacterized L1 sequences from the GenBank database. Fifteen (23%) of these L1s had transposed flanking DNA with an average transduction length of 207 nucleotides. Given that there are approximately 400,000 L1 elements, the authors estimated that insertion of transduced sequences alone may have enlarged the diploid human genome as much as 19 Mb or 0.6%. They also examined 24 full-length mouse L1s and found 2 long transduced sequences. The authors concluded that L1 retrotransposition in vivo commonly transduces sequences flanking the 3-prime end of the element.

Although LINE-1 retrotransposons comprise 17% of the human genome, in an exhaustive search of the human genome working draft sequence (95% complete), Brouha et al. (2003) found only 90 L1s with intact open reading frames (ORFs). They demonstrated that 38 of 86 L1s (44%) are polymorphic as to their presence or absence in human populations. They cloned 82 (91%) of the 90 L1s and found that 40 of the 82 (49%) were active in a cultured cell retrotransposition assay. Remarkably, 84% of assayed retrotransposition capability was present in 6 highly active L1s, referred to as hot L1s. The data indicated that most L1 retrotransposition in the human population stems from hot L1s, with the remaining elements playing a lesser role in genome plasticity.

Lutz et al. (2003) demonstrated that L1.2 is present at an intermediate insertion allele frequency in worldwide human populations and that common alleles (L1.2A and L1.2B) exhibit an approximately 16-fold difference in their ability to retrotranspose in cultured human HeLa cells. They showed that 2 amino acid substitutions (S1259L and I1220M) downstream of the conserved cysteine-rich motif in L1 ORF2 are largely responsible for the observed reduction in L1.2A retrotransposition efficiency. Thus, common L1 alleles can vary widely in their retrotransposition potential. Lutz et al. (2003) proposed that such allelic heterogeneity can influence the potential L1 mutational load present in an individual genome.

Baillie et al. (2011) applied a high-throughput method to identify numerous L1, Alu, and SVA germline mutations, as well as 7,743 putative somatic L1 insertions, in the hippocampus and caudate nucleus of 3 individuals. Surprisingly, the authors also found 13,692 somatic Alu insertions and 1,350 SVA insertions. The results demonstrated that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Baillie et al. (2011) concluded that somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiologic processes.

Disease Associations

Kazazian and Moran (1998) reviewed the 'master' human mobile element, the L1 retrotransposon. They predicted that new insight is likely to lead to important practical applications for these intriguing mobile elements. They referred to 6 retrotransposed L1 insertions in addition to the original 2 found to disrupt the factor VIII gene, resulting in hemophilia A: 1 was also in factor VIII, causing no deleterious effects (Woods-Samuels et al., 1989); 3 were in the Duchenne muscular dystrophy gene (DMD; 300377); 1 was in the APC gene (611731), causing colon cancer (Miki et al., 1992); and another was in the beta-globin gene (HBB; 141900). Ostertag and Kazazian (2001) stated that there were 13 reported cases of L1 insertions resulting in human disease.

Mirabello et al. (2010) studied global methylation at L1 elements in DNA from 152 patients with testicular germ cell tumors (TGCT) and 314 unaffected family members from 101 multiple-case testicular cancer (273300) families. Analysis of the correlation of L1 methylation levels among parent-child pairs independent of affection status revealed a strong positive association only between mother-daughter (r = 0.48; p = 0.0002) and father-daughter (r = 0.31; p = 0.021) pairs, suggesting gender-specific inheritance of methylation. Incorporating cancer status into the analysis revealed a strong correlation in L1 methylation levels only among affected father-son pairs (r = 0.49; p = 0.03). There was a marginally significant inverse association between lower L1 methylation levels and increased risk of testicular cancer compared with healthy male relatives (p = 0.049). Mirabello et al. (2010) stated that their findings suggested that heritability of L1 methylation might be gender-specific, and that transgenerational inheritance of L1 methylation levels might be associated with testicular cancer risk.

Using RT-PCR analysis, Bundo et al. (2014) found significantly increased L1 ORF2 content in postmortem prefrontal cortex samples from 13 patients with schizophrenia (181500) compared to 13 controls. A tendency toward copy number increase was also observed in mood disorders, including major depression (MDD; 608516) and bipolar disorder (MAFD1; 125480). In a second cohort of 35 schizophrenic patients and 34 samples, neuronal L1 ORF2 was specifically increased in neuronal cells in schizophrenia compared to controls. In a mouse model of prenatal environmental risk, L1 copy number was increased in prefrontal cortex of offspring in response to immune activation in the pregnant mother. Similarly, increased L1 copy number was observed in prefrontal tissue from neonatal macaques treated with immune activation. Increased L1 was demonstrated in neurons from prefrontal cortex of patients and in induced pluripotent stem (iPS) cell-derived neurons containing 22q11 deletions. Whole-genome sequencing in 3 patients with schizophrenia showed that brain-specific L1 insertion localized preferentially to synapse- and schizophrenia-related genes compared to 3 controls, although the number of brain-specific L1 insertions did not differ significantly. The results suggested that the hyperactive L1 retrotransposition into critical genes during neural development, triggered by genetic and/or environmental factors, may contribute to the pathophysiology of schizophrenia.

▼ Evolution
To understand their role in human evolution, Ovchinnikov et al. (2002) endeavored to delineate the L1 elements that have amplified since the emergence of the hominid lineage. They used an approach based on shared sequence variants to trace backwards from the then-amplifying Ta subfamily. The groups of insertions they identified accounted for much of the evolution of human L1s. Ovchinnikov et al. (2002) identified an L1 subfamily that amplified both before and after the divergence of humans from their closest extant relatives. Progressively more modern groups of L1s included greater numbers of insertions. These data were considered consistent with the hypothesis that the rate of L1 amplification has been increasing during recent human evolution.

Marchetto et al. (2013) described the generation and initial characterization of induced pluripotent stem (iPS) cells from chimpanzees and bonobos as tools to explore factors that may have contributed to great ape evolution. Comparative gene expression analysis of human and nonhuman primate iPS cells revealed differences in the regulation of L1 transposons. A force of change in mammalian evolution, L1 elements are retrotransposons that have remained active during primate evolution. Decreased levels of L1-restricting factors APOBEC3B (607110) and PIWIL2 (610312) in nonhuman primate iPS cells correlated with increased L1 mobility and endogenous L1 mRNA levels. Moreover, results from the manipulation of APOBEC3B and PIWIL2 levels in iPS cells supported a causal inverse relationship between levels of these proteins and L1 retrotransposition. Finally, Marchetto et al. (2013) found increased copy numbers of species-specific L1 elements in the genome of chimpanzees compared to humans, supporting the idea that increased L1 mobility in nonhuman primates is not limited to iPS cells in culture and may have also occurred in the germline or embryonic cells developmentally upstream to germline specification during primate evolution. Marchetto et al. (2013) proposed that differences in L1 mobility may have differentially shaped the genomes of humans and nonhuman primates and could have continuing adaptive significance.

▼ Nomenclature
Brosius and Gould (1992), who referred to the gene discovered by Dombroski et al. (1991) as the LINE-1 master gene, proposed a 'genomenclature' which would provide a comprehensive and, as they pointed out, respectful taxonomy for pseudogenes and other so-called junk DNA. They proposed a general terminology that might aid the integrated study of evolution and molecular biology. They designated as a 'nuon' any stretch of nucleic acid sequence that may be identifiable by any criterion. Since pseudogenes and dispersed repetitive elements constitute a vast repertoire of sequences with the capacity to shape an organism during evolution, they proposed that this potential to contribute sequences for future use be reflected in the terms 'potonuons' or 'potogenes.' If such a potonuon has been co-opted into a variant or novel function, an evolutionary process termed 'exaptation,' they employed the term 'xaptonuon.' If a potonuon remains without function (nonactive nuon), it is a 'nonaptation' and they termed it 'naptonuon.' They gave a number of examples for potonuons and xaptonuons. They even used the term 'xaptoprotein' for examples involving crystallins of the eye lens which, although having structural roles in the refractive properties of the lens, are identical to housekeeping enzymes (see 123660).

▼ Animal Model
Using transgenic mice and rats expressing human or mouse L1 elements controlled by their endogenous promoters, Kano et al. (2009) demonstrated abundant L1 RNA expression in both germ cells and embryos. However, integration events usually occurred during embryogenesis rather than in germ cells and were not heritable. L1 RNA was detected in preimplantation embryos lacking the L1 transgene, and L1 somatic retrotranspositions events were detected in blastocysts and adults lacking the transgene. Kano et al. (2009) concluded that L1 RNA transcribed in male or female germ cells can be carried over through fertilization and integrate during embryogenesis to create somatic mosaicism.

Tags: 22q11, 22q12



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