A computational framework to assess genome-wide distribution of polymorphic human endogenous retrovirus-K in human populations

Li, Weiling; Lin, Lin; Malhotra, Raunaq; Yang, Lei; Acharya, Raj; Poss, Mary

doi:10.1101/444034

Cited by 7 publications

(10 citation statements)

References 55 publications

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“…Hence, some bioinformatics tools have been developed to discover insertional polymorphic transposable elements, including one that is specifically designed for HERVs [ 62 ]. In this way, it is possible to detect insertional polymorphic HERVs and to study their frequency in different human populations [ 63 , 64 , 65 , 66 , 67 , 68 ]. However, it is still difficult to study insertional polymorphisms within the same individual by using whole-genome sequences data.…”

Section: Examples Of High-throughput Applications In Herv Researchmentioning

confidence: 99%

“…Hence, the recent insertional activity of the HML-2 group is of particular interest for the presence of polymorphic proviruses [ 38 , 47 ]. In total, there are 36 HML-2 proviruses in the human population that are not included in the human reference genome [ 39 , 63 , 64 , 65 , 84 , 85 ]. Furthermore, also some of the proviruses present in the human genome assemblies hg19 and hg38 are known to be unfixed among the population [ 39 , 47 , 64 ].…”

Section: New Insights On Herv Contribution To Human Pathophysiologmentioning

confidence: 99%

“…In total, there are 36 HML-2 proviruses in the human population that are not included in the human reference genome [ 39 , 63 , 64 , 65 , 84 , 85 ]. Furthermore, also some of the proviruses present in the human genome assemblies hg19 and hg38 are known to be unfixed among the population [ 39 , 47 , 64 ]. The analysis of data from the 1000 Genomes Project has revealed differences in the frequency of HML-2 insertions among the five super-populations: African, East Asian, Admixed American, European, and South Asian.…”

Section: New Insights On Herv Contribution To Human Pathophysiologmentioning

confidence: 99%

“…The analysis of data from the 1000 Genomes Project has revealed differences in the frequency of HML-2 insertions among the five super-populations: African, East Asian, Admixed American, European, and South Asian. Not all the HML-2 insertions occur in the different populations with the same frequency [ 63 , 64 ], and the state of presence or absence of the totality of the proviruses is sufficient to distinguish the five super-populations [ 63 , 64 ]. Many of the unfixed insertions are rare, and the East Asian population is the one with the lowest prevalence of HML-2 insertional polymorphisms [ 63 , 64 ].…”

Section: New Insights On Herv Contribution To Human Pathophysiologmentioning

confidence: 99%

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High-Throughput Sequencing is a Crucial Tool to Investigate the Contribution of Human Endogenous Retroviruses (HERVs) to Human Biology and Development

Pisano

Grandi

Tramontano

2020

Viruses

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Human Endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that represent a large fraction of our genome. Their transcriptional activity is finely regulated in early developmental stages and their expression is modulated in different cell types and tissues. Such activity has an impact on human physiology and pathology that is only partially understood up to date. Novel high-throughput sequencing tools have recently allowed for a great advancement in elucidating the various HERV expression patterns in different tissues as well as the mechanisms controlling their transcription, and overall, have helped in gaining better insights in an all-inclusive understanding of the impact of HERVs in biology of the host.

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Section: Examples Of High-throughput Applications In Herv Researchmentioning

confidence: 99%

Section: New Insights On Herv Contribution To Human Pathophysiologmentioning

confidence: 99%

Section: New Insights On Herv Contribution To Human Pathophysiologmentioning

confidence: 99%

Section: New Insights On Herv Contribution To Human Pathophysiologmentioning

confidence: 99%

See 2 more Smart Citations

High-Throughput Sequencing is a Crucial Tool to Investigate the Contribution of Human Endogenous Retroviruses (HERVs) to Human Biology and Development

Pisano

Grandi

Tramontano

2020

Viruses

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“…Although replication competent HERV-K molecular clones have been created in the laboratory (14)(15)(16), none of the sequences found in the human genome appear to produce a replicating, full-length integration-competent virus, despite the fact that some have complete open reading frames and two Long Terminal Repeats (LTRs) (14). Furthermore, many of these viruses are polymorphic in the human population, and new copies are still being discovered, so it remains possible that some of them are still capable of active retro-transposition (17,18). In addition to the proviral copies, more than 900 solo HERV-K LTRs, which have arisen from recombination events, are also present (14).…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Rev interacts with HERV-K RcREs present in the human genome and promotes export of unspliced HERV-K proviral RNA

Gray¹,

Jackson²,

Jackson³

et al. 2019

Preprint

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BackgroundThe HERV-K (HML-2) viruses are the youngest of the human endogenous retroviruses. They are present as several almost complete proviral copies and numerous fragments in the human genome. Many HERV-K proviruses express a regulatory protein Rec, which binds to an element present in HERV-K mRNAs called the RcRE. This interaction is necessary for the nucleo-cytoplasmic export and expression of HERV-K mRNAs that retain introns and plays a role analogous to that of Rev and the RRE in HIV replication. There are over 900 HERV-K RcREs distributed throughout the human genome. Thus, it was of interest to determine if Rev could functionally interact with selected RcRE elements that map either to HERV-K proviruses or human gene regions. This interaction would have the potential to alter the expression of both HERV-K mRNAs and cellular mRNAs during HIV-1 infection. ResultsIn this study we employed a combination of RNAseq, bioinformatics and cell-based functional assays. Potential RcREs were identified through a number of bioinformatic approaches. They were then tested for their ability to promote export and translation of a reporter mRNA with a retained intron in conjunction with Rev or Rec. Some of the selected elements functioned well with either Rev, Rec or both, whereas some showed little or no function. Rev function on individual RcREs varied and was also dependent on the Rev sequence. We also performed RNAseq on total and cytoplasmic RNA isolated from SupT1 cells expressing HIV Rev, with or without Tat, or HERV-K Rec. Proviral mRNA from three HERV-K loci (4p16.1b, 22q11.23 and most significantly 3q12.3) accumulated in the cytoplasm in the presence of Rev or Tat and Rev, but not Rec. Consistent with this, the 3' RcRE from 3q12.3 functioned well with HIV-Rev in our reporter assay. In contrast, this RcRE showed little or no function with Rec. ConclusionsThe HIV Rev protein can functionally interact with many RcREs present in the human genome, depending on the RcRE sequence, as well as the Rev sequence. This leads to export of some of the HERV-K proviral mRNAs and also has the potential to change the expression of non-viral genes.

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Retroviral Elements in Pathophysiology and as Therapeutic Targets for Amyotrophic Lateral Sclerosis

Pandya

Pasternack

et al. 2022

Neurotherapeutics

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The study of the role of retroviruses in amyotrophic lateral sclerosis (ALS) dates back to the 1960s shortly after transposable elements themselves were first discovered. It was quickly realized that in wild mice both horizontal and vertical transmissions of retroviral elements were key to the development of an ALS-like syndrome leading to the postulate that endogenous retroviruses (ERVs) contribute significantly to the pathogenicity of this disease. Subsequent studies identified retroviral reverse transcriptase activity in brains of individuals with ALS from Guam. However, except for a single study from the former Soviet Union, ALS could not be transmitted to rhesus macaques. The discovery of an ALS-like syndrome in human immunodeficiency virus (HIV) and human T cell leukemia virus infected individuals led to renewed interest in the field and reverse transcriptase activity was found in the blood and cerebrospinal fluid of individuals with sporadic ALS. However, exogenous retroviruses could not be found in individuals with ALS which further reinforced the possibility of involvement of a human ERV (HERV). The first demonstration of the involvement of a HERV was the discovery of the activation of human endogenous retrovirus-K subtype HML-2 in the brains of individuals with ALS. The envelope protein of HML-2 is neurotoxic and transgenic animals expressing the envelope protein develop an ALS-like syndrome. Activation of HML-2 occurs in the context of generalized transposable element activation and is not specific for ALS. Individuals with HIV-associated ALS show a remarkable response to antiretroviral therapy; however, antiretroviral trials in ALS down-regulate HML-2 without ameliorating the disease. This highlights the need for specific drugs to be developed against HML-2 as a novel therapeutic target for ALS. Other approaches might include antisense oligonucleotides, shRNA targeted against the envelope gene or antibodies that can target the extracellular envelope protein. Future clinical trials in ALS should consider combination therapies to control these ERVs.

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A computational framework to assess genome-wide distribution of polymorphic human endogenous retrovirus-K in human populations

Abstract: 22 42 3 43

Cited by 7 publications

References 55 publications

High-Throughput Sequencing is a Crucial Tool to Investigate the Contribution of Human Endogenous Retroviruses (HERVs) to Human Biology and Development

High-Throughput Sequencing is a Crucial Tool to Investigate the Contribution of Human Endogenous Retroviruses (HERVs) to Human Biology and Development

HIV-1 Rev interacts with HERV-K RcREs present in the human genome and promotes export of unspliced HERV-K proviral RNA

Retroviral Elements in Pathophysiology and as Therapeutic Targets for Amyotrophic Lateral Sclerosis

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