Diverse endogenous retroviruses generate structural variation between human genomes via LTR recombination

ABSTRACTHuman endogenous retroviruses (HERVs) occupy a substantial fraction of the genome and impact cellular function with both beneficial and deleterious consequences. The vast majority of HERV sequences descend from ancient retroviral families no longer capable of infection or genomic propagation. In fact, most are no longer represented by full-length proviruses but by solitary long terminal repeats (solo LTRs) that arose via non-allelic recombination events between the two LTRs of a proviral insertion. Because LTR-LTR recombination events may occur long after proviral insertion but are challenging to detect in resequencing data, we hypothesize that this mechanism produces an underappreciated amount of genomic variation in the human population. To test this idea, we develop a computational pipeline specifically designed to capture such dimorphic HERV alleles from short-read genome sequencing data. When applied to 279 individuals sequenced as part of the Simons Genome Diversity Project, the pipeline retrieves most of the dimorphic variants previously reported for the HERV-K(HML2) subfamily as well as dozens of additional candidates, including members of the HERV-H and HERV-W families. We experimentally validate several of these candidates, including the first reported instance of an unfixed HERV-W provirus. These data indicate that human proviral content exhibit more extensive interindividual variation than previously recognized. These findings have important implications for our understanding of the contribution of HERVs to human physiology and disease.

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Human Endogenous Retrovirus HERV-K14 Families: Status, Variants, Evolution, and Mobilization of Other Cellular Sequences

Journal of Virology ◽

10.1128/jvi.79.5.2941-2949.2005 ◽

2005 ◽

Vol 79 (5) ◽

pp. 2941-2949 ◽

Cited By ~ 20

Author(s):

Aline Flockerzi ◽

Stefan Burkhardt ◽

Werner Schempp ◽

Eckart Meese ◽

Jens Mayer

Keyword(s):

Human Genome ◽

Germ Line ◽

Endogenous Retrovirus ◽

Endogenous Retroviruses ◽

Human Endogenous Retrovirus ◽

Long Terminal Repeats ◽

Essential Information ◽

Human Endogenous Retroviruses ◽

Consensus Sequences

ABSTRACT The human genome harbors many distinct families of human endogenous retroviruses (HERVs) that stem from exogenous retroviruses that infected the germ line millions of years ago. Many HERV families remain to be investigated. We report in the present study the detailed characterization of the HERV-K14I and HERV-K14CI families as they are represented in the human genome. Most of the 68 HERV-K14I and 23 HERV-K14CI proviruses are severely mutated, frequently displaying uniform deletions of retroviral genes and long terminal repeats (LTRs). Both HERV families entered the germ line ∼39 million years ago, as evidenced by homologous sequences in hominoids and Old World primates and calculation of evolutionary ages based on a molecular clock. Proviruses of both families were formed during a brief period. A majority of HERV-K14CI proviruses on the Y chromosome mimic a higher evolutionary age, showing that LTR-LTR divergence data can indicate false ages. Fully translatable consensus sequences encoding major retroviral proteins were generated. Most HERV-K14I loci lack an env gene and are structurally reminiscent of LTR retrotransposons. A minority of HERV-K14I variants display an env gene. HERV-K14I proviruses are associated with three distinct LTR families, while HERV-K14CI is associated with a single LTR family. Hybrid proviruses consisting of HERV-K14I and HERV-W sequences that appear to have produced provirus progeny in the genome were detected. Several HERV-K14I proviruses harbor TRPC6 mRNA portions, exemplifying mobilization of cellular transcripts by HERVs. Our analysis contributes essential information on two more HERV families and on the biology of HERV sequences in general.

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ClipSV: improving structural variation detection by read extension, spliced alignment and tree-based decision rules

NAR Genomics and Bioinformatics ◽

10.1093/nargab/lqab003 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Peng Xu ◽

Yu chen ◽

Min Gao ◽

Zechen Chong

Keyword(s):

Complex Traits ◽

Structural Variation ◽

Decision Rules ◽

Genomic Variation ◽

Read Length ◽

Sequencing Data ◽

Sequence Alignments ◽

Spliced Alignment ◽

Genomic Studies ◽

Low Sensitivity

Abstract Structural variation (SV), which consists of genomic variation from 50 to millions of base pairs, confers considerable impacts on human diseases, complex traits and evolution. Accurately detecting SV is a fundamental step to characterize the features of individual genomes. Currently, several methods have been proposed to detect SVs using the next-generation sequencing (NGS) platform. However, due to the short length of sequencing reads and the complexity of SV content, the SV-detecting tools are still limited by low sensitivity, especially for insertion detection. In this study, we developed a novel tool, ClipSV, to improve SV discovery. ClipSV utilizes a read extension and spliced alignment approach to overcoming the limitation of read length. By reconstructing long sequences from SV-associated short reads, ClipSV discovers deletions and short insertions from the long sequence alignments. To comprehensively characterize insertions, ClipSV implements tree-based decision rules that can efficiently utilize SV-containing reads. Based on the evaluations of both simulated and real sequencing data, ClipSV exhibited an overall better performance compared to currently popular tools, especially for insertion detection. As NGS platform represents the mainstream sequencing capacity for routine genomic applications, we anticipate ClipSV will serve as an important tool for SV characterization in future genomic studies.

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Schizophrenia risk from locus-specific human endogenous retroviruses

10.1101/798017 ◽

2019 ◽

Author(s):

Rodrigo R.R. Duarte ◽

Matthew L. Bendall ◽

Miguel de Mulder ◽

Christopher E. Ormsby ◽

Greta A. Beckerle ◽

...

Keyword(s):

Association Studies ◽

Endogenous Retroviruses ◽

Substantial Contribution ◽

Genome Wide Association Studies ◽

Sequencing Data ◽

Human Endogenous Retroviruses ◽

Risk Variants ◽

Repetitive Nature ◽

Common Genetic Variants ◽

Dorsolateral Prefrontal

AbstractSchizophrenia genome-wide association studies highlight the substantial contribution of risk attributed to the non-coding genome where human endogenous retroviruses (HERVs) are encoded. These ancient viral elements have previously been overlooked in genetic and transcriptomic studies due to their poor annotation and repetitive nature. Using a new, comprehensive HERV annotation, we found that the fraction of the genome where HERVs are located (the ‘retrogenome’) is enriched for schizophrenia risk variants, and that there are 148 disparate HERVs involved in susceptibility. Analysis of RNA-sequencing data from the dorsolateral prefrontal cortex of 259 schizophrenia cases and 279 controls from the CommonMind Consortium showed that HERVs are actively expressed in the brain (n = 3,979), regulated in cis by common genetic variants (n = 1,759), and differentially expressed in patients (n = 81). Convergent analyses implicate LTR25_6q21 and ERVLE_8q24.3h as HERVs of etiological relevance to schizophrenia, which are co-regulated with genes involved in neuronal and mitochondrial function, respectively. Our findings provide a strong rationale for exploring the retrogenome and the expression of these locus-specific HERVs as novel risk factors for schizophrenia and potential diagnostic biomarkers and treatment targets.

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TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2110758118 ◽

2021 ◽

Vol 118 (34) ◽

pp. e2110758118

Author(s):

Maike Bensberg ◽

Olof Rundquist ◽

Aida Selimović ◽

Cathrine Lagerwall ◽

Mikael Benson ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Lymphoblastic Leukemia ◽

Survival Rates ◽

Endogenous Retroviruses ◽

Sequencing Data ◽

Human Endogenous Retroviruses ◽

Cell Acute Lymphoblastic Leukemia ◽

Normal Human ◽

T Cell Malignancies

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy resulting from overproduction of immature T-cells in the thymus and is typified by widespread alterations in DNA methylation. As survival rates for relapsed T-ALL remain dismal (10 to 25%), development of targeted therapies to prevent relapse is key to improving prognosis. Whereas mutations in the DNA demethylating enzyme TET2 are frequent in adult T-cell malignancies, TET2 mutations in T-ALL are rare. Here, we analyzed RNA-sequencing data of 321 primary T-ALLs, 20 T-ALL cell lines, and 25 normal human tissues, revealing that TET2 is transcriptionally repressed or silenced in 71% and 17% of T-ALL, respectively. Furthermore, we show that TET2 silencing is often associated with hypermethylation of the TET2 promoter in primary T-ALL. Importantly, treatment with the DNA demethylating agent, 5-azacytidine (5-aza), was significantly more toxic to TET2-silenced T-ALL cells and resulted in stable re-expression of the TET2 gene. Additionally, 5-aza led to up-regulation of methylated genes and human endogenous retroviruses (HERVs), which was further enhanced by the addition of physiological levels of vitamin C, a potent enhancer of TET activity. Together, our results clearly identify 5-aza as a potential targeted therapy for TET2-silenced T-ALL.

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Rate of Recombinational Deletion among Human Endogenous Retroviruses

Journal of Virology ◽

10.1128/jvi.02216-06 ◽

2007 ◽

Vol 81 (17) ◽

pp. 9437-9442 ◽

Cited By ~ 74

Author(s):

Robert Belshaw ◽

Jason Watson ◽

Aris Katzourakis ◽

Alexis Howe ◽

John Woolven-Allen ◽

...

Keyword(s):

Homologous Recombination ◽

Full Length ◽

Endogenous Retroviruses ◽

Single Mutation ◽

Long Terminal Repeats ◽

Recombination Rates ◽

Human Endogenous Retroviruses ◽

Deletion Rate ◽

Terminal Repeats ◽

The Relationship

ABSTRACT The fate of most human endogenous retroviruses (HERVs) has been to undergo recombinational deletion. This process involves homologous recombination between the flanking long terminal repeats (LTRs) of a full-length element, leaving a relic structure in the genome termed a solo LTR. We examined loci in one family, HERV-K(HML2), and found that the deletion rate decreased markedly with age: the rate among recently integrated loci was almost 200-fold higher than that among loci whose insertion predated the divergence of humans and chimpanzees (8 × 10−5 and 4 × 10−7 recombinational deletion events per locus per generation, respectively). One hypothesis for this finding is that increasing mutational divergence between the flanking LTRs reduces the probability of homologous recombination and thus the rate of solo LTR formation. Consistent with this idea, we were able to replicate the observed rates by a simulation in which the probability of recombinational deletion was reduced 10-fold by a single mutation and 100-fold by any additional mutations. We also discuss the evidence for other factors that may influence the relationship between locus age and the rate of deletion, for example, host recombination rates and selection, and highlight the consequences of recombinational deletion for dating recent HERV integrations.

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Human Endogenous Retroviruses in Glioblastoma Multiforme

Microorganisms ◽

10.3390/microorganisms9040764 ◽

2021 ◽

Vol 9 (4) ◽

pp. 764

Author(s):

Zihao Yuan ◽

Yuntao Yang ◽

Ningyan Zhang ◽

Claudio Soto ◽

Xiaoqian Jiang ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Repetitive Elements ◽

Endogenous Retroviruses ◽

Differentially Expressed ◽

P Value ◽

Normal Brain ◽

Sequencing Data ◽

Significant Differential Expression ◽

Human Endogenous Retroviruses ◽

Brain Tissues

Glioblastoma multiforme (GBM) is the most aggressive and deadly brain tumor. It is primarily diagnosed in the elderly and has a 5-year survival rate of less than 6% even with the most aggressive therapies. The lack of biomarkers has made the development of immunotherapy for GBM challenging. Human endogenous retroviruses (HERVs) are a group of viruses with long terminal repeat (LTR) elements, which are believed to be relics from ancient viral infections. Recent studies have found that those repetitive elements play important roles in regulating various biological processes. The differentially expressed LTR elements from HERVs are potential biomarkers for immunotherapy to treat GBM. However, the understanding of the LTR element expression in GBM is greatly lacking. Methods: We obtained 1077.4 GB of sequencing data from public databases. These data were generated from 111 GBM tissue studies, 30 GBM cell lines studies, and 45 normal brain tissues studies. We analyzed repetitive elements that were differentially expressed in GBM and normal brain samples. Results: We found that 48 LTR elements were differentially expressed (p-value < 0.05) between GBM and normal brain tissues, of which 46 were HERV elements. Among these 46 elements, 34 significantly changed HERVs belong to the ERV1 superfamily. Furthermore, 43 out of the 46 differentially expressed HERV elements were upregulated. Conclusion: Our results indicate significant differential expression of many HERV LTR elements in GBM and normal brain tissues. Expression levels of these elements could be developed as biomarkers for GBM treatments.

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Extensive genome-wide duplications in the eastern oyster ( Crassostrea virginica )

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2020.0164 ◽

2021 ◽

Vol 376 (1825) ◽

Author(s):

Tejashree H. Modak ◽

Robert Literman ◽

Jonathan B. Puritz ◽

Kevin M. Johnson ◽

Erin M. Roberts ◽

...

Keyword(s):

Crassostrea Virginica ◽

Structural Variation ◽

Structural Changes ◽

Sequence Data ◽

Phenotypic Diversity ◽

Critical Role ◽

Eastern Oyster ◽

Genomic Variation ◽

Interindividual Variation ◽

Whole Genome Sequence

Genomic structural variation is an important source of genetic and phenotypic diversity, playing a critical role in evolution. The recent availability of a high-quality reference genome for the eastern oyster, Crassostrea virginica , and whole-genome sequence data of samples from across the species range in the USA, provides an opportunity to explore structural variation across the genome of this species. Our analysis shows significantly greater individual-level duplications of regions across the genome than that of most model vertebrate species. Duplications are widespread across all ten chromosomes with variation in frequency per chromosome. The eastern oyster shows a large interindividual variation in duplications as well as particular chromosomal regions with a higher density of duplications. A high percentage of duplications seen in C. virginica lie completely within genes and exons, suggesting the potential for impacts on gene function. These results support the hypothesis that structural changes may play a significant role in standing genetic variation in C. virginica , and potentially have a role in their adaptive and evolutionary success. Altogether, these results suggest that copy number variation plays an important role in the genomic variation of C. virginica . This article is part of the Theo Murphy meeting issue ‘Molluscan genomics: broad insights and future directions for a neglected phylum’.

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Unusually long target site duplications flanking some of the long terminal repeats of human endogenous retrovirus K in the human genome

Journal of General Virology ◽

10.1099/vir.0.19717-0 ◽

2004 ◽

Vol 85 (6) ◽

pp. 1485-1488 ◽

Cited By ~ 4

Author(s):

Ilgar Z. Mamedov ◽

Yuri B. Lebedev ◽

Eugene D. Sverdlov

Keyword(s):

Human Genome ◽

Endogenous Retrovirus ◽

Endogenous Retroviruses ◽

Human Endogenous Retrovirus ◽

Substantial Part ◽

Direct Repeats ◽

Long Terminal Repeats ◽

Solo Ltrs ◽

Insertion Mechanism ◽

Terminal Repeats

Human endogenous retroviruses (HERVs) make up a substantial part of the human genome. HERVs and solitary long terminal repeats (solo LTRs) are usually flanked by 4–6 nt short direct repeats through the well-known mechanism of their integration. A number of solo LTRs flanked by unusually long direct repeats were detected in the human genome. These unusual structures might be a product of an alternative virus insertion mechanism.

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