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Cell Aug 2022Non-allelic recombination between homologous repetitive elements contributes to evolution and human genetic disorders. Here, we combine short- and long-DNA read...
Non-allelic recombination between homologous repetitive elements contributes to evolution and human genetic disorders. Here, we combine short- and long-DNA read sequencing of repeat elements with a new bioinformatics pipeline to show that somatic recombination of Alu and L1 elements is widespread in the human genome. Our analysis uncovers tissue-specific non-allelic homologous recombination hallmarks; moreover, we find that centromeres and cancer-associated genes are enriched for retroelements that may act as recombination hotspots. We compare recombination profiles in human-induced pluripotent stem cells and differentiated neurons and find that the neuron-specific recombination of repeat elements accompanies chromatin changes during cell-fate determination. Finally, we report that somatic recombination profiles are altered in Parkinson's and Alzheimer's disease, suggesting a link between retroelement recombination and genomic instability in neurodegeneration. This work highlights a significant contribution of the somatic recombination of repeat elements to genomic diversity in health and disease.
Topics: Alu Elements; Genome, Human; Homologous Recombination; Humans; Long Interspersed Nucleotide Elements; Repetitive Sequences, Nucleic Acid; Retroelements
PubMed: 35882231
DOI: 10.1016/j.cell.2022.06.032 -
RNA (New York, N.Y.) Feb 2013Circular RNAs composed of exonic sequence have been described in a small number of genes. Thought to result from splicing errors, circular RNA species possess no known...
Circular RNAs composed of exonic sequence have been described in a small number of genes. Thought to result from splicing errors, circular RNA species possess no known function. To delineate the universe of endogenous circular RNAs, we performed high-throughput sequencing (RNA-seq) of libraries prepared from ribosome-depleted RNA with or without digestion with the RNA exonuclease, RNase R. We identified >25,000 distinct RNA species in human fibroblasts that contained non-colinear exons (a "backsplice") and were reproducibly enriched by exonuclease degradation of linear RNA. These RNAs were validated as circular RNA (ecircRNA), rather than linear RNA, and were more stable than associated linear mRNAs in vivo. In some cases, the abundance of circular molecules exceeded that of associated linear mRNA by >10-fold. By conservative estimate, we identified ecircRNAs from 14.4% of actively transcribed genes in human fibroblasts. Application of this method to murine testis RNA identified 69 ecircRNAs in precisely orthologous locations to human circular RNAs. Of note, paralogous kinases HIPK2 and HIPK3 produce abundant ecircRNA from their second exon in both humans and mice. Though HIPK3 circular RNAs contain an AUG translation start, it and other ecircRNAs were not bound to ribosomes. Circular RNAs could be degraded by siRNAs and, therefore, may act as competing endogenous RNAs. Bioinformatic analysis revealed shared features of circularized exons, including long bordering introns that contained complementary ALU repeats. These data show that ecircRNAs are abundant, stable, conserved and nonrandom products of RNA splicing that could be involved in control of gene expression.
Topics: Alu Elements; Animals; Base Sequence; Cells, Cultured; Computational Biology; Conserved Sequence; Evolution, Molecular; Exons; Exoribonucleases; Gene Expression Regulation; High-Throughput Nucleotide Sequencing; Humans; Male; Mice; Molecular Sequence Data; Nucleotide Motifs; Phosphotransferases; RNA; RNA Splicing; RNA Stability; RNA, Circular; RNA, Small Interfering; Sequence Analysis, RNA; Trans-Splicing
PubMed: 23249747
DOI: 10.1261/rna.035667.112 -
Nature Feb 2024The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes',...
The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes', with a proposed role in contributing to human bipedalism. Yet, the genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Here we present evidence that an individual insertion of an Alu element in the genome of the hominoid ancestor may have contributed to tail-loss evolution. We demonstrate that this Alu element-inserted into an intron of the TBXT gene-pairs with a neighbouring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated multiple mouse models that express both full-length and exon-skipped isoforms of Tbxt, mimicking the expression pattern of its hominoid orthologue TBXT. Mice expressing both Tbxt isoforms exhibit a complete absence of the tail or a shortened tail depending on the relative abundance of Tbxt isoforms expressed at the embryonic tail bud. These results support the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype. Moreover, mice expressing the exon-skipped Tbxt isoform develop neural tube defects, a condition that affects approximately 1 in 1,000 neonates in humans. Thus, tail-loss evolution may have been associated with an adaptive cost of the potential for neural tube defects, which continue to affect human health today.
Topics: Animals; Humans; Mice; Alternative Splicing; Alu Elements; Disease Models, Animal; Evolution, Molecular; Genome; Hominidae; Introns; Neural Tube Defects; Phenotype; Protein Isoforms; T-Box Domain Proteins; Tail; Exons
PubMed: 38418917
DOI: 10.1038/s41586-024-07095-8 -
Genomics & Informatics Sep 2016Transposable elements are one of major sources to cause genomic instability through various mechanisms including insertion, insertion-mediated genomic deletion, and... (Review)
Review
Transposable elements are one of major sources to cause genomic instability through various mechanisms including insertion, insertion-mediated genomic deletion, and recombination-associated genomic deletion. Among them is element which is the most abundant element, composing ~10% of the human genome. The element emerged in the primate genome 65 million years ago and has since propagated successfully in the human and non-human primate genomes. element is a non-autonomous retrotransposon and therefore retrotransposed using L1-enzyme machinery. The 'master gene' model has been generally accepted to explain element amplification in primate genomes. According to the model, different subfamilies of elements are created by mutations on the master gene and most elements are amplified from the hyperactive master genes. element is frequently involved in genomic rearrangements in the human genome due to its abundance and sequence identity between them. The genomic rearrangements caused by elements could lead to genetic disorders such as hereditary disease, blood disorder, and neurological disorder. In fact, elements are associated with approximately 0.1% of human genetic disorders. The first part of this review discusses mechanisms of amplification and diversity among different subfamilies. The second part discusses the particular role of elements in generating genomic rearrangements as well as human genetic disorders.
PubMed: 27729835
DOI: 10.5808/GI.2016.14.3.70 -
Viruses Jan 2021Although mobile genetic elements, or transposons, have played an important role in genome evolution, excess activity of mobile elements can have detrimental... (Review)
Review
Although mobile genetic elements, or transposons, have played an important role in genome evolution, excess activity of mobile elements can have detrimental consequences. Already, the enhanced expression of transposons-derived nucleic acids can trigger autoimmune reactions that may result in severe autoinflammatory disorders. Thus, cells contain several layers of protective measures to restrict transposons and to sense the enhanced activity of these "intragenomic pathogens". This review focuses on our current understanding of immunogenic patterns derived from the most active elements in humans, the retrotransposons long interspersed element (LINE)-1 and Alu. We describe the role of known pattern recognition receptors in nucleic acid sensing of LINE-1 and Alu and the possible consequences for autoimmune diseases.
Topics: Alu Elements; Animals; Disease Susceptibility; Genetic Predisposition to Disease; Host-Pathogen Interactions; Humans; Long Interspersed Nucleotide Elements; Retroelements
PubMed: 33445593
DOI: 10.3390/v13010094 -
Experimental Biology and Medicine... May 2022SINE-VNTR-Alus (SVAs) are the youngest retrotransposon family in the human genome. Their ongoing mobilization has generated genetic variation within the human... (Review)
Review
SINE-VNTR-Alus (SVAs) are the youngest retrotransposon family in the human genome. Their ongoing mobilization has generated genetic variation within the human population. At least 24 insertions to date, detailed in this review, have been associated with disease. The predominant mechanisms through which this occurs are alterations to normal splicing patterns, exonic insertions causing loss-of-function mutations, and large genomic deletions. Dissecting the functional impact of these SVAs and the mechanism through which they cause disease provides insight into the consequences of their presence in the genome and how these elements could influence phenotypes. Many of these disease-associated SVAs have been difficult to characterize and would not have been identified through routine analyses. However, the number identified has increased in recent years as DNA and RNA sequencing data became more widely available. Therefore, as the search for complex structural variation in disease continues, it is likely to yield further disease-causing SVA insertions.
Topics: Alu Elements; Genome, Human; Humans; Minisatellite Repeats; Retroelements
PubMed: 35387528
DOI: 10.1177/15353702221082612 -
RNA Biology Nov 2021Alu RNA are implicated in the poor prognosis of several human disease states. These RNA are transcription products of primate specific transposable elements called Alu...
Alu RNA are implicated in the poor prognosis of several human disease states. These RNA are transcription products of primate specific transposable elements called Alu elements. These elements are extremely abundant, comprising over 10% of the human genome, and 100 to 1000 cytoplasmic copies of Alu RNA per cell. Alu RNA do not have a single universal functional role aside from selfish self-propagation. Despite this, Alu RNA have been found to operate in a diverse set of translational and transcriptional mechanisms. This review will focus on the current knowledge of Alu RNA involved in human disease states and known mechanisms of action. Examples of Alu RNA that are transcribed in a variety of contexts such as introns, mature mRNA, and non-coding transcripts will be discussed. Past and present challenges in studying Alu RNA, and the future directions of Alu RNA in basic and clinical research will also be examined.
Topics: Alternative Splicing; Alu Elements; Animals; Biomarkers; Disease Susceptibility; Exons; Gene Expression Regulation; Humans; Introns; MicroRNAs; RNA; RNA Editing; RNA Folding; RNA Interference; RNA Stability; RNA, Circular; RNA, Untranslated; Structure-Activity Relationship
PubMed: 34672903
DOI: 10.1080/15476286.2021.1989201 -
PloS One 2022Epigenetic changes that cause genomic instability may be the basis of pathogenic processes of age-associated noncommunicable diseases (NCDs). Essential hypertension is...
INTRODUCTION
Epigenetic changes that cause genomic instability may be the basis of pathogenic processes of age-associated noncommunicable diseases (NCDs). Essential hypertension is one of the most common NCDs. Alu hypomethylation is an epigenetic event that is commonly found in elderly individuals. Epigenomic alterations are also found in age-associated NCDs such as osteoporosis and diabetes mellitus. Alu methylation prevents DNA from being damaged. Therefore, Alu hypomethylated DNA accumulates DNA damage and, as a result, causes organ function deterioration. Here, we report that Alu hypomethylation is a biomarker for essential hypertension.
RESULTS
We investigated Alu methylation levels in white blood cells from normal controls, patients with prehypertension, and patients with hypertension. The hypertension group possessed the lowest Alu methylation level when classified by systolic blood pressure and diastolic blood pressure (P = 0.0002 and P = 0.0088, respectively). In the hypertension group, a higher diastolic blood pressure and a lower Alu methylation level were observed (r = -0.6278). Moreover, we found that changes in Alu hypomethylation in the four years of follow-up in the same person were directly correlated with increased diastolic blood pressure.
CONCLUSIONS
Similar to other age-associated NCDs, Alu hypomethylation is found in essential hypertension and is directly correlated with severity, particularly with diastolic blood pressure. Therefore, Alu hypomethylation may be linked with the molecular pathogenesis of high blood pressure and can be used for monitoring the clinical outcome of this disease.
Topics: Aged; Alu Elements; DNA; DNA Methylation; Essential Hypertension; Humans; Hypertension
PubMed: 35802708
DOI: 10.1371/journal.pone.0270004 -
Epigenomics Feb 2018Global DNA hypomethylation promoting genomic instability leads to cancer and deterioration of human health with age.
UNLABELLED
Global DNA hypomethylation promoting genomic instability leads to cancer and deterioration of human health with age.
AIM
To invent a biotechnology that can reprogram this process.
METHODS
We used Alu siRNA to direct Alu interspersed repetitive sequences methylation in human cells. We evaluated the correlation between DNA damage and Alu methylation levels.
RESULTS
We observed an inverse correlation between Alu element methylation and endogenous DNA damage in white blood cells. Cells transfected with Alu siRNA exhibited high Alu methylation levels, increased proliferation, reduced endogenous DNA damage and improved resistance to DNA damaging agents.
CONCLUSION
Alu methylation stabilizes the genome by preventing accumulation of DNA damage. Alu siRNA could be useful for evaluating reprograming of the global hypomethylation phenotype in cancer and aging cells.
Topics: Aging; Alu Elements; DNA Damage; DNA Methylation; Genomic Instability; Humans; Interspersed Repetitive Sequences; RNA, Small Interfering
PubMed: 29336607
DOI: 10.2217/epi-2017-0096 -
Communications Biology Jan 2022Alu is a primate-specific repeat element in the human genome and has been increasingly appreciated as a regulatory element in many biological processes. But the...
Alu is a primate-specific repeat element in the human genome and has been increasingly appreciated as a regulatory element in many biological processes. But the appreciation of Alu has been limited in tumorigenesis, especially for brain tumor. To investigate the relevance of Alu to the gliomagenesis, we studied Alu element-associated post-transcriptional processes and the RNA expression of the element by performing RNA-seq for a total of 41 pairs of neurotypical and diverse glioma brain tissues. We find that A-to-I editing and circular RNA levels, as well as Alu RNA expression, are decreased overall in gliomas, compared to normal tissue. Interestingly, grade 2 oligodendrogliomas are least affected in A-to-I editing and circular RNA levels among gliomas, whereas they have a higher proportion of down-regulated Alu subfamilies, compared to the other gliomas. These findings collectively imply a unique pattern of Alu-associated transcriptomes in grade 2 oligodendroglioma, providing an insight to gliomagenesis from the perspective of an evolutionary genetic element.
Topics: Alu Elements; Gene Expression Regulation, Neoplastic; Genome, Human; Glioma; Humans; Oligodendroglioma
PubMed: 35042936
DOI: 10.1038/s42003-022-03011-w