Recent Inserts of Transposable Elements Affect Structure and Functions of Human Genome

Abstract Background Transposable elements (TE) comprise nearly half of the human genome and their insertions have profound effects to human genetic diversification and as well as disease. Despite their abovementioned significance, there is no consensus on the TE subfamilies that remain active in the human genome. In this study, we therefore developed a novel statistical test for recently mobile subfamilies (RMSs), based on patterns of overlap with > 100,000 polymorphic indels. Results Our analysis produced a catalogue of 20 high-confidence RMSs, which excludes many false positives in public databases. Intriguingly though, it includes HERV-K, an LTR subfamily previously thought to be extinct. The RMS catalogue is strongly enriched for contributions to germline genetic disorders (P = 1.1e-10), and thus constitutes a valuable resource for diagnosing disorders of unknown aetiology using targeted TE-insertion screens. Remarkably, RMSs are also highly enriched for somatic insertions in diverse cancers (P = 2.8e-17), thus indicating strong correlations between germline and somatic TE mobility. Using CRISPR/Cas9 deletion, we show that an RMS-derived polymorphic TE insertion increased the expression of RPL17, a gene associated with lower survival in liver cancer. More broadly, polymorphic TE insertions from RMSs were enriched near genes with allele-specific expression, suggesting widespread effects on gene regulation. Conclusions By using a novel statistical test we have defined a catalogue of 20 recently mobile transposable element subfamilies. We illustrate the gene regulatory potential of RMS-derived polymorphic TE insertions, using CRISPR/Cas9 deletion in vitro on a specific candidate, as well as by genome wide analysis of allele-specific expression. Our study presents novel insights into TE mobility and regulatory potential and provides a key resource for human disease genetics and population history studies.

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Impact of transposable elements on the human genome

Annals of Medicine ◽

10.3109/07853890009011771 ◽

2000 ◽

Vol 32 (4) ◽

pp. 264-273 ◽

Cited By ~ 24

Author(s):

Jean Marc Deragon ◽

Pierre Capy

Keyword(s):

Transposable Elements ◽

Human Genome

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"Copy and paste" transposable elements in the human genome.

Journal of Clinical Investigation ◽

10.1172/jci116400 ◽

1993 ◽

Vol 91 (5) ◽

pp. 1859-1860 ◽

Cited By ~ 6

Author(s):

H H Kazazian ◽

A F Scott

Keyword(s):

Transposable Elements ◽

Human Genome ◽

Copy And Paste

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CRISPR-mediated biocontainment

10.1101/2020.02.03.922146 ◽

2020 ◽

Cited By ~ 2

Author(s):

Oscar Castanon ◽

Cory J. Smith ◽

Parastoo Khoshakhlagh ◽

Raphael Ferreira ◽

Marc Güell ◽

...

Keyword(s):

Cell Death ◽

Transposable Elements ◽

Human Genome ◽

Genome Editing ◽

Copy Number ◽

Proof Of Concept ◽

Defense System ◽

Dna Breaks ◽

Repetitive Nature ◽

Mammalian Genomes

AbstractWe have exploited the repetitive nature of transposable elements of the human genome to generate synthetic circuits. Transposable elements such as LINE-1 and Alu have successfully replicated in mammalian genomes throughout evolution to reach a copy number ranging from thousands to more than a million. Targeting these repetitive elements with programmable DNA nucleases such as CRISPR-Cas9 rapidly induce extremely high levels of cell death. We use this genotoxic feature to build synthetic biocontainment circuits: CRISPR defense system (CRISPR-DS) capable of preventing CRISPR genome editing, and we introduce the proof-of-concept of CRISPR Safety-Switch, an inducible, stringent and non-leaky kill-switch capable of clearing out cell lines resistant to DNA breaks.

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Plant transposable elements: Their role in evolution

Bioscience Reports ◽

10.1007/bf01117338 ◽

1988 ◽

Vol 8 (6) ◽

pp. 585-588 ◽

Cited By ~ 1

Author(s):

Heinz Saedler

Keyword(s):

Transposable Elements ◽

Biological Significance ◽

Normal Plant ◽

Wild Type ◽

Induced Mutations ◽

Plant Genomes ◽

Plant Genes ◽

Structure And Functions

Transposable elements (TE) are natural constituents of plant genomes. However, their presence only becomes apparent if they become dislodged from their resident positions in the genome and transpore into another gene, thereby inducing a mutation. Such TE-induced mutations are somatically unstable because they revert to wild type and hence reconstitute the expression of the mutated gene. The frequent somatic excision of the TE results in a variegated phenotype. Since this instability is inherited in a Mendelian manner the variegated phenotype is nuclear determined. By this criterion TE have been shown to occur in more than 30 species belonging to different families and genera. Many questions arise when dealing with TE: their structure and functions, and the biological significance of the activity of elements in the differentiation of a normal plant or in the evolution of plant genes.

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Do Small RNAs Interfere With LINE-1?

Journal of Biomedicine and Biotechnology ◽

10.1155/jbb/2006/29049 ◽

2006 ◽

Vol 2006 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Harris S. Soifer

Keyword(s):

Transposable Elements ◽

Human Genome ◽

Small Rnas ◽

Substantial Evidence ◽

Rnai Machinery ◽

Rna Sequences ◽

Direct Role ◽

Long Interspersed Elements ◽

Extensive Analysis ◽

Transposon Activity

Long interspersed elements (LINE-1 or L1) are the most active transposable elements in the human genome. Due to their high copy number and ability to sponsor retrotransposition of nonautonomous RNA sequences, unchecked L1 activity can negatively impact the genome by a number of means. Substantial evidence in lower eukaryotes demonstrates that the RNA interference (RNAi) machinery plays a major role in containing transposon activity. Despite extensive analysis in other eukaryotes, no experimental evidence has been presented that L1-derived siRNAs exist, or that the RNAi plays a significant role in restricting L1 activity in the human genome. This review will present evidence showing a direct role for RNAi in suppressing the movement of transposable elements in other eukaryotes, as well as speculate on the role RNAi might play in protecting the human genome from LINE-1 activity.

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The enhancer activity of long interspersed nuclear element derived microRNA 625 induced by NF-κB

Scientific Reports ◽

10.1038/s41598-021-82735-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hee-Eun Lee ◽

Sang-Je Park ◽

Jae-Won Huh ◽

Hiroo Imai ◽

Heui-Soo Kim

Keyword(s):

Gene Expression ◽

Transposable Elements ◽

Human Genome ◽

Dna Sequences ◽

Binding Sites ◽

Luciferase Assay ◽

Enhancer Activity ◽

Long Interspersed Nuclear Elements ◽

Long Interspersed Nuclear Element ◽

Affect Gene Expression

AbstractTransposable elements (TEs) are DNA sequences that cut or introduced into the genome, and they represent a massive portion of the human genome. TEs generate a considerable number of microRNAs (miRNAs) are derived from TEs (MDTEs). Numerous miRNAs are related to cancer, and hsa-miRNA-625 is a well-known oncomiR derived from long interspersed nuclear elements (LINEs). The relative expression of hsa-miRNA-625-5p differs in humans, chimpanzees, crab-eating monkeys, and mice, and four primers were designed against the 3′UTR of GATAD2B to analyze the different quantities of canonical binding sites and the location of miRNA binding sites. Luciferase assay was performed to score for the interaction between hsa-miRNA-625 and the 3′UTR of GATAD2B, while blocking NF-κB. In summary, the different numbers of canonical binding sites and the locations of miRNA binding sites affect gene expression, and NF-κB induces the enhancer activity of hsa-miRNA-625-5p by sharing the binding sites.

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The Testis as a Conduit for Genomic Plasticity: an advanced interdisciplinary workshop

Biochemical Society Transactions ◽

10.1042/bst0350605 ◽

2007 ◽

Vol 35 (3) ◽

pp. 605-608 ◽

Cited By ~ 4

Author(s):

D. Miller ◽

M. Brinkworth ◽

D. Iles

Keyword(s):

Dna Methylation ◽

Transposable Elements ◽

Germ Cell ◽

Human Genome ◽

Regulatory Control ◽

Evidence Based ◽

Genomic Plasticity ◽

Windows Of Opportunity ◽

New Locations ◽

Control Of Expression

The premise for this unusual amalgamation of reproductive biologists, molecular geneticists and evolutionary biologists rested on the evidence-based assumption that reproductive tissues could be ideal environments for the expression and transmission of transposable elements that can move into new locations in the genome. These elements include DNA transposons and retrotransposons that, together, make up over 40% of the human genome. The testis may be a particularly good niche for their expression because of the unique dynamic of spermatogenesis, where the methylation–demethylation status of germ cell DNA is at its most plastic. Hence windows of opportunity can arise that may release transposable elements from the tight regulatory control of expression imposed on them by bulk DNA methylation. As the testis is where most mutations become embedded in the germline, the meeting included a number of keynote presentations that aimed to examine the potential for transposable elements to heritably alter the genome and effect variation independently of the usual Mendelian mechanisms. In essence, could the testis be one of the favoured sites where genomic plasticity makes its mark?

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