Research

20 pages, 4156 KiB

Open AccessArticle

Large Deletions, Cleavage of the Telomeric Repeat Sequence, and Reverse Transcriptase-Mediated DNA Damage Response Associated with Long Interspersed Element-1 ORF2p Enzymatic Activities

by Kristine J. Kines, Mark Sokolowski, Cecily DeFreece, Afzaal Shareef, Dawn L. deHaro and Victoria P. Belancio

Genes 2024, 15(2), 143; https://doi.org/10.3390/genes15020143 - 23 Jan 2024

Viewed by 961

Abstract

L1 elements can cause DNA damage and genomic variation via retrotransposition and the generation of endonuclease-dependent DNA breaks. These processes require L1 ORF2p protein that contains an endonuclease domain, which cuts genomic DNA, and a reverse transcriptase domain, which synthesizes cDNA. The complete [...] Read more.

L1 elements can cause DNA damage and genomic variation via retrotransposition and the generation of endonuclease-dependent DNA breaks. These processes require L1 ORF2p protein that contains an endonuclease domain, which cuts genomic DNA, and a reverse transcriptase domain, which synthesizes cDNA. The complete impact of L1 enzymatic activities on genome stability and cellular function remains understudied, and the spectrum of L1-induced mutations, other than L1 insertions, is mostly unknown. Using an inducible system, we demonstrate that an ORF2p containing functional reverse transcriptase is sufficient to elicit DNA damage response even in the absence of the functional endonuclease. Using a TK/Neo reporter system that captures misrepaired DNA breaks, we demonstrate that L1 expression results in large genomic deletions that lack any signatures of L1 involvement. Using an in vitro cleavage assay, we demonstrate that L1 endonuclease efficiently cuts telomeric repeat sequences. These findings support that L1 could be an unrecognized source of disease-promoting genomic deletions, telomere dysfunction, and an underappreciated source of chronic RT-mediated DNA damage response in mammalian cells. Our findings expand the spectrum of biological processes that can be triggered by functional and nonfunctional L1s, which have impactful evolutionary- and health-relevant consequences. Full article

(This article belongs to the Special Issue Mobile-Element-Related Genetic Variation)

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17 pages, 4557 KiB

Open AccessArticle

Identification of microRNAs Derived from Transposable Elements in the Macaca mulatta (Rhesus Monkey) Genome

by Eun Gyung Park, Yun Ju Lee, Jae-Won Huh, Sang-Je Park, Hiroo Imai, Woo Ryung Kim, Du Hyeong Lee, Jung-min Kim, Hae Jin Shin and Heui-Soo Kim

Genes 2023, 14(11), 1984; https://doi.org/10.3390/genes14111984 - 24 Oct 2023

Viewed by 997

Abstract

Transposable elements (TEs) are mobile DNA entities that can move within the host genome. Over long periods of evolutionary time, TEs are typically silenced via the accumulation of mutations in the genome, ultimately resulting in their immobilization. However, they still play an important [...] Read more.

Transposable elements (TEs) are mobile DNA entities that can move within the host genome. Over long periods of evolutionary time, TEs are typically silenced via the accumulation of mutations in the genome, ultimately resulting in their immobilization. However, they still play an important role in the host genome by acting as regulatory elements. They influence host transcription in various ways, one of which as the origin of the generation of microRNAs (miRNAs), which are so-called miRNAs derived from TEs (MDTEs). miRNAs are small non-coding RNAs that are involved in many biological processes by regulating gene expression at the post-transcriptional level. Here, we identified MDTEs in the Macaca mulatta (rhesus monkey) genome, which is phylogenetically close species to humans, based on the genome coordinates of miRNAs and TEs. The expression of 5 out of 17 MDTEs that were exclusively registered in M. mulatta from the miRBase database (v22) was examined via quantitative polymerase chain reaction (qPCR). Moreover, Gene Ontology analysis was performed to examine the functional implications of the putative target genes of the five MDTEs. Full article

(This article belongs to the Special Issue Mobile-Element-Related Genetic Variation)

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18 pages, 3091 KiB

Open AccessArticle

Assessing the Expression of Long INterspersed Elements (LINEs) via Long-Read Sequencing in Diverse Human Tissues and Cell Lines

by Karleena Rybacki, Mingyi Xia, Mian Umair Ahsan, Jinchuan Xing and Kai Wang

Genes 2023, 14(10), 1893; https://doi.org/10.3390/genes14101893 - 29 Sep 2023

Viewed by 1534

Abstract

Transposable elements, such as Long INterspersed Elements (LINEs), are DNA sequences that can replicate within genomes. LINEs replicate using an RNA intermediate followed by reverse transcription and are typically a few kilobases in length. LINE activity creates genomic structural variants in human populations [...] Read more.

Transposable elements, such as Long INterspersed Elements (LINEs), are DNA sequences that can replicate within genomes. LINEs replicate using an RNA intermediate followed by reverse transcription and are typically a few kilobases in length. LINE activity creates genomic structural variants in human populations and leads to somatic alterations in cancer genomes. Long-read RNA sequencing technologies, including Oxford Nanopore and PacBio, can directly sequence relatively long transcripts, thus providing the opportunity to examine full-length LINE transcripts. This study focuses on the development of a new bioinformatics pipeline for the identification and quantification of active, full-length LINE transcripts in diverse human tissues and cell lines. In our pipeline, we utilized RepeatMasker to identify LINE-1 (L1) transcripts from long-read transcriptome data and incorporated several criteria, such as transcript start position, divergence, and length, to remove likely false positives. Comparisons between cancerous and normal cell lines, as well as human tissue samples, revealed elevated expression levels of young LINEs in cancer, particularly at intact L1 loci. By employing bioinformatics methodologies on long-read transcriptome data, this study demonstrates the landscape of L1 expression in tissues and cell lines. Full article

(This article belongs to the Special Issue Mobile-Element-Related Genetic Variation)

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14 pages, 1412 KiB

Open AccessArticle

Homoplasy of Retrotransposon Insertions in Toothed Whales

by Liliya Doronina, Lynn Ogoniak and Jürgen Schmitz

Genes 2023, 14(9), 1830; https://doi.org/10.3390/genes14091830 - 21 Sep 2023

Cited by 2 | Viewed by 1315

Abstract

Retrotransposon insertion patterns facilitate a virtually homoplasy-free picture of phylogenetic history. Still, a few most likely random parallel insertions or deletions result in rare cases of homoplasy in primates. The following question arises: how frequent is retrotransposon homoplasy in other phylogenetic clades? Here, [...] Read more.

Retrotransposon insertion patterns facilitate a virtually homoplasy-free picture of phylogenetic history. Still, a few most likely random parallel insertions or deletions result in rare cases of homoplasy in primates. The following question arises: how frequent is retrotransposon homoplasy in other phylogenetic clades? Here, we derived genome insertion data of toothed whales to evaluate the extension of homoplasy in a representative laurasiatherian group. Among more than a thousand extracted and aligned retrotransposon loci, we detected 37 cases of precise parallel insertions in species that are separated by over more than 10 million years, a time frame which minimizes the effects of incomplete lineage sorting. We compared the phylogenetic signal of insertions with the flanking sequences of these loci to further exclude potential polymorphic loci derived by incomplete lineage sorting. We found that the phylogenetic signals of retrotransposon insertion patterns exhibiting true homoplasy differ from the signals of their flanking sequences. In toothed whales, precise parallel insertions account for around 0.18–0.29% of insertion cases, which is about 12.5 times the frequency of such insertions among Alus in primates. We also detected five specific deletions of retrotransposons on various lineages of toothed whale evolution, a frequency of 0.003%, which is slightly higher than such occurrences in primates. Overall, the level of retrotransposon homoplasy in toothed whales is still marginal compared to the phylogenetic diagnostic retrotransposon presence/absence signal. Full article

(This article belongs to the Special Issue Mobile-Element-Related Genetic Variation)

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12 pages, 2154 KiB

Open AccessArticle

Extensive Independent Amplification of Platy-1 Retroposons in Tamarins, Genus Saguinus

by Jessica M. Storer, Jerilyn A. Walker, Thomas O. Beckstrom and Mark A. Batzer

Genes 2023, 14(7), 1436; https://doi.org/10.3390/genes14071436 - 13 Jul 2023

Viewed by 784

Abstract

Platy-1 retroposons are short interspersed elements (SINEs) unique to platyrrhine primates. Discovered in the common marmoset (Callithrix jacchus) genome in 2016, these 100 bp mobile element insertions (MEIs) appeared to be novel drivers of platyrrhine evolution, with over 2200 full-length members [...] Read more.

Platy-1 retroposons are short interspersed elements (SINEs) unique to platyrrhine primates. Discovered in the common marmoset (Callithrix jacchus) genome in 2016, these 100 bp mobile element insertions (MEIs) appeared to be novel drivers of platyrrhine evolution, with over 2200 full-length members across 62 different subfamilies, and strong evidence of ongoing proliferation in C. jacchus. Subsequent characterization of Platy-1 elements in Aotus, Saimiri and Cebus genera, suggested that the widespread mobilization detected in marmoset (family Callithrichidae) was perhaps an anomaly. Two additional Callithrichidae genomes are now available, a scaffold level genome assembly for Saguinus imperator (tamarin; SagImp_v1) and a chromosome-level assembly for Saguinus midas (Midas tamarin; ASM2_v1). Here, we report that each tamarin genome contains over 11,000 full-length Platy-1 insertions, about 1150 are shared by both Saguinus tamarins, 7511 are unique to S. imperator, and another 8187 are unique to S. midas. Roughly 325 are shared among the three callithrichids. We identified six new Platy-1 subfamilies derived from Platy-1-8, with the youngest new subfamily, Platy-1-8c_Saguinus, being the primary source of the Saguinus amplification burst. This constitutes the largest expansion of Platy-1 MEIs reported to date and the most extensive independent SINE amplification between two closely related species. Full article

(This article belongs to the Special Issue Mobile-Element-Related Genetic Variation)

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12 pages, 1813 KiB

Open AccessArticle

Human Endogenous Retrovirus-H-Derived miR-4454 Inhibits the Expression of DNAJB4 and SASH1 in Non-Muscle-Invasive Bladder Cancer

by Eun Gyung Park, Du Hyeong Lee, Woo Ryung Kim, Yun Ju Lee, Woo Hyeon Bae, Jung-min Kim, Hae Jin Shin, Hongseok Ha, Joo Mi Yi, Ssang Goo Cho, Yung Hyun Choi, Sun Hee Leem, Hee Jae Cha, Sang Woo Kim and Heui Soo Kim

Genes 2023, 14(7), 1410; https://doi.org/10.3390/genes14071410 - 07 Jul 2023

Cited by 1 | Viewed by 1608

Abstract

Although most human endogenous retroviruses (HERVs) have been silenced and lost their ability to translocate because of accumulated mutations during evolution, they still play important roles in human biology. Several studies have demonstrated that HERVs play pathological roles in numerous human diseases, especially [...] Read more.

Although most human endogenous retroviruses (HERVs) have been silenced and lost their ability to translocate because of accumulated mutations during evolution, they still play important roles in human biology. Several studies have demonstrated that HERVs play pathological roles in numerous human diseases, especially cancer. A few studies have revealed that long non-coding RNAs that are transcribed from HERV sequences affect cancer progression. However, there is no study on microRNAs derived from HERVs related to cancer. In this study, we identified 29 microRNAs (miRNAs) derived from HERV sequences in the human genome. In particular, we discovered that miR-4454, which is HERV-H-derived miRNA, was upregulated in non-muscle-invasive bladder cancer (NMIBC) cells. To figure out the effects of upregulated miR-4454 in NMIBC, genes whose expression was downregulated in NMIBC, as well as tumor suppressor genes, were selected as putative target genes of miR-4454. The dual-luciferase assay was used to determine the negative relationship between miR-4454 and its target genes, DNAJB4 and SASH1, and they were confirmed to be promising target genes of miR-4454. Taken together, this study suggests that the upregulation of miR-4454 derived from HERV-H in NMIBC reduces the expression of the tumor suppressor genes, DNAJB4 and SASH1, to promote NMIBC progression. Full article

(This article belongs to the Special Issue Mobile-Element-Related Genetic Variation)

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20 pages, 3573 KiB

Open AccessArticle

Transposable Elements Shape the Genome Diversity and the Evolution of Noctuidae Species

by Chunhui Zhang, Lei Wang, Liang Dou, Bisong Yue, Jinchuan Xing and Jing Li

Genes 2023, 14(6), 1244; https://doi.org/10.3390/genes14061244 - 10 Jun 2023

Cited by 1 | Viewed by 1200

Abstract

Noctuidae is known to have high species diversity, although the genomic diversity of Noctuidae species has yet to be studied extensively. Investigation of transposable elements (TEs) in this family can improve our understanding of the genomic diversity of Noctuidae. In this study, we [...] Read more.

Noctuidae is known to have high species diversity, although the genomic diversity of Noctuidae species has yet to be studied extensively. Investigation of transposable elements (TEs) in this family can improve our understanding of the genomic diversity of Noctuidae. In this study, we annotated and characterized genome-wide TEs in ten noctuid species belonging to seven genera. With multiple annotation pipelines, we constructed a consensus sequence library containing 1038–2826 TE consensus. The genome content of TEs showed high variation in the ten Noctuidae genomes, ranging from 11.3% to 45.0%. The relatedness analysis indicated that the TE content, especially the content of LINEs and DNA transposons, is positively correlated with the genome size (r = 0.86, p-value = 0.001). We identified SINE/B2 as a lineage-specific subfamily in Trichoplusia ni, a species-specific expansion of the LTR/Gypsy subfamily in Spodoptera exigua, and a recent expansion of SINE/5S subfamily in Busseola fusca. We further revealed that of the four TE classes, only LINEs showed phylogenetic signals with high confidence. We also examined how the expansion of TEs contributed to the evolution of noctuid genomes. Moreover, we identified 56 horizontal transfer TE (HTT) events among the ten noctuid species and at least three HTT events between the nine Noctuidae species and 11 non-noctuid arthropods. One of the HTT events of a Gypsy transposon might have caused the recent expansion of the Gypsy subfamily in the S. exigua genome. By determining the TE content, dynamics, and HTT events in the Noctuidae genomes, our study emphasized that TE activities and HTT events substantially impacted the Noctuidae genome evolution. Full article

(This article belongs to the Special Issue Mobile-Element-Related Genetic Variation)

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Review

Jump to: Research, Other

21 pages, 1107 KiB

Open AccessReview

Human Endogenous Retrovirus-K (HML-2)-Related Genetic Variation: Human Genome Diversity and Disease

by Wonseok Shin, Seyoung Mun and Kyudong Han

Genes 2023, 14(12), 2150; https://doi.org/10.3390/genes14122150 - 28 Nov 2023

Cited by 3 | Viewed by 1109

Abstract

Human endogenous retroviruses (HERVs) comprise a significant portion of the human genome, making up roughly 8%, a notable comparison to the 2–3% represented by coding sequences. Numerous studies have underscored the critical role and importance of HERVs, highlighting their diverse and extensive influence [...] Read more.

Human endogenous retroviruses (HERVs) comprise a significant portion of the human genome, making up roughly 8%, a notable comparison to the 2–3% represented by coding sequences. Numerous studies have underscored the critical role and importance of HERVs, highlighting their diverse and extensive influence on the evolution of the human genome and establishing their complex correlation with various diseases. Among HERVs, the HERV-K (HML-2) subfamily has recently attracted significant attention, integrating into the human genome after the divergence between humans and chimpanzees. Its insertion in the human genome has received considerable attention due to its structural and functional characteristics and the time of insertion. Originating from ancient exogenous retroviruses, these elements succeeded in infecting germ cells, enabling vertical transmission and existing as proviruses within the genome. Remarkably, these sequences have retained the capacity to form complete viral sequences, exhibiting activity in transcription and translation. The HERV-K (HML-2) subfamily is the subject of active debate about its potential positive or negative effects on human genome evolution and various pathologies. This review summarizes the variation, regulation, and diseases in human genome evolution arising from the influence of HERV-K (HML-2). Full article

(This article belongs to the Special Issue Mobile-Element-Related Genetic Variation)

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12 pages, 607 KiB

Open AccessReview

Emerging Opportunities to Study Mobile Element Insertions and Their Source Elements in an Expanding Universe of Sequenced Human Genomes

by Scott E. Devine

Genes 2023, 14(10), 1923; https://doi.org/10.3390/genes14101923 - 10 Oct 2023

Cited by 1 | Viewed by 1610

Abstract

Three mobile element classes, namely Alu, LINE-1 (L1), and SVA elements, remain actively mobile in human genomes and continue to produce new mobile element insertions (MEIs). Historically, MEIs have been discovered and studied using several methods, including: (1) Southern blots, (2) PCR [...] Read more.

Three mobile element classes, namely Alu, LINE-1 (L1), and SVA elements, remain actively mobile in human genomes and continue to produce new mobile element insertions (MEIs). Historically, MEIs have been discovered and studied using several methods, including: (1) Southern blots, (2) PCR (including PCR display), and (3) the detection of MEI copies from young subfamilies. We are now entering a new phase of MEI discovery where these methods are being replaced by whole genome sequencing and bioinformatics analysis to discover novel MEIs. We expect that the universe of sequenced human genomes will continue to expand rapidly over the next several years, both with short-read and long-read technologies. These resources will provide unprecedented opportunities to discover MEIs and study their impact on human traits and diseases. They also will allow the MEI community to discover and study the source elements that produce these new MEIs, which will facilitate our ability to study source element regulation in various tissue contexts and disease states. This, in turn, will allow us to better understand MEI mutagenesis in humans and the impact of this mutagenesis on human biology. Full article

(This article belongs to the Special Issue Mobile-Element-Related Genetic Variation)

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Other

Jump to: Research, Review

7 pages, 961 KiB

Open AccessBrief Report

Localization of Insertion Sequences in Plasmids for L-Cysteine Production in E. coli

by Kevin Heieck and Thomas Brück

Genes 2023, 14(7), 1317; https://doi.org/10.3390/genes14071317 - 22 Jun 2023

Cited by 1 | Viewed by 1026

Abstract

Insertion sequence elements (ISE) are often found to be responsible for the collapse of production in synthetically engineered Escherichia coli. By the transposition of ISE into the open reading frame of the synthetic pathway, E. coli cells gain selection advantage over cells [...] Read more.

Insertion sequence elements (ISE) are often found to be responsible for the collapse of production in synthetically engineered Escherichia coli. By the transposition of ISE into the open reading frame of the synthetic pathway, E. coli cells gain selection advantage over cells expressing the metabolic burdensome production genes. Here, we present the exact entry sites of insertion sequence (IS) families 3 and 5 within plasmids for l-cysteine production in evolved E. coli populations. Furthermore, we identified an uncommon occurrence of an 8-bp direct repeat of IS5 which is atypical for this particular family, potentially indicating a new IS5 target site. Full article

(This article belongs to the Special Issue Mobile-Element-Related Genetic Variation)

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