<i>Alu</i> repeat discovery and characterization within human genomes

Hormozdiari, Fereydoun; Alkan, Can; Ventura, Mario; Hajirasouliha, Iman; Malig, Maika; Hach, Faraz; Yörükoğlu, Deniz; Dao, Phuong; Bakhshi, Marzieh; Şahinalp, S. Cenk; Eichler, Evan E.

doi:10.1101/gr.115956.110

Cited by 96 publications

(123 citation statements)

References 43 publications

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“…TIP-chip (23) was used to map insertions (SI Materials and Methods). Previously reported polymorphic Alu elements were collected (10,11,21,22,(24)(25)(26)(27). The LD block for each GWAS signal (P ≤ 10 −8 ) was defined by proxy SNPs to the TAS (r 2 > 0.8) (SI Materials and Methods).…”

Section: Methodsmentioning

confidence: 99%

“…Due to the pace of these discovery efforts, no comprehensive list of all reported polymorphisms has been developed for Alu variants. Therefore, we collated reports of previously identified polymorphic Alu elements (10,11,21,22,(24)(25)(26)(27) to generate a catalog of 13,572 Alu variants distributed throughout the genome. These reports underscore that Alu polymorphisms are a major source of genetic diversity in humans.…”

Section: Significancementioning

confidence: 99%

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Structural variants caused byAluinsertions are associated with risks for many human diseases

Payer

Steranka

Yang

et al. 2017

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

126

102

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Interspersed repeat sequences comprise much of our DNA, although their functional effects are poorly understood. The most commonly occurring repeat is the Alu short interspersed element. New Alu insertions occur in human populations, and have been responsible for several instances of genetic disease. In this study, we sought to determine if there are instances of polymorphic Alu insertion variants that function in a common variant, common disease paradigm. We cataloged 809 polymorphic Alu elements mapping to 1,159 loci implicated in disease risk by genome-wide association study (GWAS) (P < 10−8). We found that Alu insertion variants occur disproportionately at GWAS loci (P = 0.013). Moreover, we identified 44 of these Alu elements in linkage disequilibrium (r2 > 0.7) with the trait-associated SNP. This figure represents a >20-fold increase in the number of polymorphic Alu elements associated with human phenotypes. This work provides a broader perspective on how structural variants in repetitive DNAs may contribute to human disease.

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Section: Methodsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Structural variants caused byAluinsertions are associated with risks for many human diseases

Payer

Steranka

Yang

et al. 2017

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

126

102

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“…[1][2][3] Genomic hypomethylation mainly affects repetitive transposable DNA elements, which comprise 45% of the human genome 4 ; these elements reside mainly in the intergenic and intronic regions of the genome and in noncoding and coding exons of the genome to a much lesser extent. 5 Long interspersed nucleotide element-1 (LINE-1) and ALU are major constituents of interspersed DNA repeats, constituting $17% and 11% of the human genome, respectively. 4 CpG sites located within LINE-1 and ALU are usually methylated in normal somatic tissues, a mechanism that is believed to have evolved as a major defense mechanism to repress these transposable genetic elements.…”

mentioning

confidence: 99%

ALU and LINE‐1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications

Bae

Shin

Kwon

et al. 2012

Intl Journal of Cancer

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Focal CpG island hypermethylation and diffuse genomic hypomethylation signify the changes in the DNA methylation status in cancer cells. ALU and LINE-1 repetitive DNA elements comprise~28% of the human genome. PCR-based measurements of these repetitive DNA elements can be used as a surrogate marker of the genomewide methylation content. Our study aimed to identify the timing of ALU and LINE-1 hypomethylations during multistep gastric carcinogenesis and their prognostic implications in gastric cancer (GC). In our study, we analyzed the methylation statuses of ALU and LINE-1 in 249 cases of gastric biopsy samples and another independent set of 198 cases of advanced GC by pyrosequencing. Regardless of the Helicobacter pylori infection status, a significant decrease in the ALU methylation levels was noted during the transitions from chronic gastritis to intestinal metaplasia and from gastric adenoma to GC. LINE-1 methylation decreased during the transition from intestinal metaplasia to gastric adenoma and no further decrease occurred during the transition from gastric adenoma to GC. A low LINE-1 methylation status was strongly associated with poor prognosis in GC. A multivariate analysis revealed that LINE-1 methylation status was an independent prognostic factor. Our findings suggest that ALU and LINE-1 hypomethylations are early events during multistep gastric carcinogenesis. Furthermore, the LINE-1 methylation status can be used as a molecular biomarker to define a subset of GC patients with poor prognosis.Focal promoter CpG island hypermethylation and generalized genomic hypomethylation signify the changes in the DNA methylation status in human cancer cells. Promoter CpG island hypermethylation is an important mechanism that inactivates tumor suppressor and tumor-related genes; meanwhile, generalized genomic hypomethylation contributes to genomic or chromosomal instability.1-3 Genomic hypomethylation mainly affects repetitive transposable DNA elements, which comprise 45% of the human genome 4 ; these elements reside mainly in the intergenic and intronic regions of the genome and in noncoding and coding exons of the genome to a much lesser extent.5 Long interspersed nucleotide element-1 (LINE-1) and ALU are major constituents of interspersed DNA repeats, constituting $17% and 11% of the human genome, respectively. 4CpG sites located within LINE-1 and ALU are usually methylated in normal somatic tissues, a mechanism that is believed to have evolved as a major defense mechanism to repress these transposable genetic elements.6 Demethylation of transposable elements is hypothesized to facilitate genomic instability by leading to retrotransposition of transposable elements, hypomethylated genome-associated error-prone repair of replication-independent endogenous double-strand breaks, and dysregulation of DNA repair genes. [7][8][9][10][11] In addition to bringing about genomic structural variation, demethylation of transposable element promoters dysregulates gene expression by upregulating the transcription of genes l...

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“…In total, these trans retrotransposition events account for at least an additional 10% of human DNA (1). Moreover, several recent studies have further demonstrated that L1-mediated retrotransposition events are responsible for a significant proportion of interindividual genetic variation in the human population (33)(34)(35)(36)(37)(38)(39) and may cause intraindividual variation in the mammalian nervous system (40,41). L1 retrotransposition likely occurs by a mechanism termed target-site primed reverse transcription (TPRT) (42).…”

mentioning

confidence: 99%

Similarities between long interspersed element-1 (LINE-1) reverse transcriptase and telomerase

Kopera¹,

Moldovan²,

Morrish³

et al. 2011

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

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Long interspersed element-1 (LINE-1 or L1) retrotransposons encode two proteins (ORF1p and ORF2p) that contain activities required for conventional retrotransposition by a mechanism termed target-site primed reverse transcription. Previous experiments in XRCC4 or DNA protein kinase catalytic subunit-deficient CHO cell lines, which are defective for the nonhomologous endjoining DNA repair pathway, revealed an alternative endonuclease-independent (ENi) pathway for L1 retrotransposition. Interestingly, some ENi retrotransposition events in DNA protein kinase catalytic subunit-deficient cells are targeted to dysfunctional telomeres. Here we used an in vitro assay to detect L1 reverse transcriptase activity to demonstrate that wild-type or endonuclease-defective L1 ribonucleoprotein particles can use oligonucleotide adapters that mimic telomeric ends as primers to initiate the reverse transcription of L1 mRNA. Importantly, these ribonucleoprotein particles also contain a nuclease activity that can process the oligonucleotide adapters before the initiation of reverse transcription. Finally, we demonstrate that ORF1p is not strictly required for ENi retrotransposition at dysfunctional telomeres. Thus, these data further highlight similarities between the mechanism of ENi L1 retrotransposition and telomerase.L ong interspersed element-1 sequences (LINE-1s or L1s) are abundant non-long terminal repeat (non-LTR) retrotransposons that constitute approximately one-sixth (i.e., ≈17%) of human nuclear DNA (1). An estimated 80-100 full-length, retrotransposition competent L1s (RC-L1s) are present in a typical diploid human genome, and a small number, termed "hot L1s" exhibit high retrotransposition efficiencies in cultured human cells (2). Human RC-L1s are ≈6 kb (3, 4) and encode two proteins (ORF1p and ORF2p) required for retrotransposition (5). ORF1p is a 40-kDa protein (6) with RNA binding (7-12) and nucleic acid chaperone activities (13-15). ORF2p is a 150-kDa protein (16, 17) with endonuclease (EN) (18,19) and reverse transcriptase (RT) (20, 21) activities.The mobilization of RC-L1s can be mutagenic (22); germ line and, less often, somatic L1 insertions have led to ≈65 sporadic cases of disease in humans (reviewed in ref. 23). ORF1p and/or ORF2p also can act in trans to mobilize short interspersed elements [e.g., Alu (24) and SINE-VNTR-Alu (25) elements], certain noncoding RNAs [e.g., U6 snRNA and small nucleolar RNAs (24, 26-29)], and some cellular mRNAs, which leads to the formation of processed pseudogenes (30-32). In total, these trans retrotransposition events account for at least an additional 10% of human DNA (1). Moreover, several recent studies have further demonstrated that L1-mediated retrotransposition events are responsible for a significant proportion of interindividual genetic variation in the human population (33-39) and may cause intraindividual variation in the mammalian nervous system (40, 41). L1 retrotransposition likely occurs by a mechanism termed target-site primed reverse transcription (TPRT) (42)...

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Alu repeat discovery and characterization within human genomes

Cited by 96 publications

References 43 publications

Structural variants caused byAluinsertions are associated with risks for many human diseases

Structural variants caused byAluinsertions are associated with risks for many human diseases

ALU and LINE‐1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications

Similarities between long interspersed element-1 (LINE-1) reverse transcriptase and telomerase

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