Laboratorium Wirusologii, Instytut Immunologii i Terapii Doświadczalnej PAN we Wrocławiu, Wrocław, Poland. kjzwolinska@iitd.pan.wroc.pl
Retroviruses-derived elements in the human genome constitute 90% of non-coding mobile sequences. Reverse transcriptase (RT) plays an essential role in their transposition as do long terminal repeats (LTRs), which contain promotors, enhancers, and regulatory sequences. Some retroelements (pseudogens and retrogenes, e.g. SINE) are non-autonomic and do not possess their own RT. These elements are dependent on autonomic elements (retroposons, e.g. LINE, retrotransposons, exo- and endogenous retroviruses). The genome of retroviruses is composed of gag, pol, and env genes flanked by long terminal repeats. Endogenous retroviruses are probably the remnants of ancient germ cell infection by exogenous retroviruses and are transmissible to the next generation in a Mendelian way. Most of them are defective (because of mutation accumulation), but some are still active and their expression is regulated by different factors (UV radiation, inflammatory cytokines, steroid hormones, and exogenous virus products). Retroelements as well as their gene products exert influence on the organism's functions. They influence the plasticity and evolution of genomes, are a source of promotors and regulatory sequences, but they also supply additional signals of transcription initiation, mRNA splicing, and STOP codons. One of the positive aspects of human endogenous retroviruses (HERVs) is the participation of their products in normal syncytiotrophoblast formation. They also block exogenous retrovirus replication by receptor interference or antisense mRNA. Their presence is considered to be connected with a number of autoimmunological diseases (multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus), cancer, or even psychiatric disorders (schizophrenia). There are also other problems connected with the potential role of ERVs in genomic therapy (with retroviruses vectors) and transplantology (xenotransplantation).
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Laboratorium Wirusologii, Instytut Immunologii i Terapii Doświadczalnej PAN im. L. Hirszfelda we Wrocławiu, Poland.
HIV infection causes progressive immune system deficiency, the development of AIDS and eventual death. Genetic factors play a very important role in the susceptibility to HIV infection and disease progression. Estimation of their effects is realized by comparing different patients groups. Four group of HIV-infected patients are taken into account: RP - rapid progressors, SP - slow progressors, LTNP - long term non-progressors and EU - exposed but uninfected. Genetic factors influencing the course of disease can be divided in groups, for example genes coding proteins connected with viral entry into cells (chemokine receptors, chemokines, lectins receptors), proteins engaged in the innate response to viral infections (cytokines, MBL, cyclophilin A, TRIM-5 alpha, APOBEC3G), human leukocyte antigens (HLAs) and killer cell immunoglobulin-like receptors (KIRs). It is suggested that some sequences of human endogenous retroviruses (HERV) and microRNA (miRNA) can also interact with the course of HIV infection. Knowledge of the roles of genetic determinants in HIV infection is very important and useful for their cognitive significance as well as in the prognosis of AIDS progression and the selection of specific therapies for individual patients. It is also a basis for the development of new antiviral drugs and vaccines.
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Mol Cells. 2012 May 4;:
22562360
Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan, 609-735, Korea, khs307@pusan.ac.kr.
Human endogenous retroviruses (HERVs) mediate structural variation and genomic instability based on their multiple copy number, inherent ability to mobilize via reverse transcriptase, and high sequence similarity. Moreover, they undergo multiple amplification and retrotransposition events, resulting in the widespread distribution of complete or partial retroviral sequences throughout the primate genome. As such, HERV elements have played important biological roles in genome evolution, and their long terminal repeat (LTR) elements contain numerous regulatory sequences, including effective promoters, enhancers, polyadenylation signals, and transcription factorbinding sites. Lastly, HERV elements are capable of influencing the expression of neighboring genes, a process that also contributed to primate evolution.
Department of Zoology, University of Oxford, Oxford OX1 3PS, United Kingdom.
Endogenous retroviruses (ERVs) differ from typical retroviruses in being inherited through the host germline and therefore are a unique combination of pathogen and selfish genetic element. Some ERV lineages proliferate by infecting germline cells, as do typical retroviruses, whereas others lack the env gene required for virions to enter cells and thus behave like retrotransposons. We wished to know what factors determined the relative abundance of different ERV lineages, so we analyzed ERV loci recovered from 38 mammal genomes by in silico screening. By modeling the relationship between proliferation and replication mechanism in detail within one group, the intracisternal A-type particles (IAPs), and performing simple correlations across all ERV lineages, we show that when ERVs lose the env gene their proliferation within that genome is boosted by a factor of ∼30. We also show that ERV abundance follows the Pareto principle or 20/80 rule, with ∼20% of lineages containing 80% of the loci. This rule is observed in many biological systems, including infectious disease epidemics, where commonly ∼20% of the infected individuals are responsible for 80% of onward infection. We thus borrow simple epidemiological and ecological models and show that retrotransposition and loss of env is the trait that leads endogenous retroviruses to becoming genomic superspreaders that take over a significant proportion of their host's genome.
Genome Med. 2012 Feb 24;4 (2):12
22364178
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Broadway Research Building, Room 412, 733 N, Broadway, Baltimore, MD 21205, USA. kazazian@jhmi.edu.
ABSTRACT: Perhaps as much as two-thirds of the mammalian genome is composed of mobile genetic elements ('jumping genes'), a fraction of which is still active or can be reactivated. By their sheer number and mobility, retrotransposons, DNA transposons and endogenous retroviruses have shaped our genotype and phenotype both on an evolutionary scale and on an individual level. Notably, at least the non-long terminal repeat retrotransposons are still able to cause disease by insertional mutagenesis, recombination, providing enzymatic activities for other mobile DNA, and perhaps by transcriptional overactivation and epigenetic effects. Currently, there are nearly 100 examples of known retroelement insertions that cause disease. In this review, we highlight those genome-scale technologies that have expanded our knowledge of the diseases that these mobile elements can elicit, and we discuss the potential impact of these findings for medicine. It is now likely that at least some types of cancer and neurological disorders arise as a result of retrotransposon mutagenesis.
J Biosci. 2012 Mar ;37 (1):19-24
22357199
Colleges of Life Science, and Teafood Science and Technology, Anhui Agricultural University, Hefei 230030, China.
Flanking regulatory long terminal repeats (LTRs) in Human endogenous retrovirus (HERV) is a kind of typical DNA repeat that is widespread in the human genome. Currently, many algorithms have been developed to detect the latent periodicity of a wide range of DNA repeats. However, no such attempt was made for HERV LTRs. The present study focused on the investigation of the possible sequence periodic patterns in the HERV LTRs and their regulatory mechanisms. We calculated the sequence periods of 5', 3' and combined LTRs in HERVs with our devised matrix simulation algorithm. It is interesting that 5' and 3' LTRs have the same period of 7, and combined LTRs have a period of 9. These results indicated that HERV LTRs have predominant periodic patterns. Based on the obtained sequence periodicity, we constructed periodic consensus sequences of 5', 3' and combined LTRs. As to 5' and 3' LTRs with the same period - 7, we manually scanned the nucleotide bases in the corresponding positions of their periodic consensus sequences, and found some positions have the nucleotide base unchanged, such as the 1st, 5th and 7th positions. These conservative nucleotide base positions represent critical binding sites of regulatory LTRs, and may be indicative of conserved regulatory mechanisms in LRT-participating regulatory networks.
Front Biosci. 2012 ;17 :1345-61
22201808
Tulane University, Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane Cancer Center, SL-66 1430 Tulane Ave., New Orleans, LA 70112.
Mobile elements account for almost half of the mass of the human genome. Only the retroelements from the non-LTR (long terminal repeat) retrotransposon family, which include the LINE-1 (L1) and its non-autonomous partners, are currently active and contributing to new insertions. Although these elements seem to share the same basic amplification mechanism, the activity and success of the different types of retroelements varies. For example, Alu-induced mutagenesis is responsible for the majority of the documented instances of human disease induced by insertion of retroelements. Using copy number in mammals as an indicator, some SINEs have been vastly more successful than other retroelements, such as the retropseudogenes and even L1, likely due to differences in post-insertion selection and ability to overcome cellular controls. SINE and LINE integration can be differentially influenced by cellular factors, indicating some differences between in their amplification mechanisms. We focus on the known aspects of this group of retroelements and highlight their similarities and differences that may significantly influence their biological impact.
Department of Animal and Plant Sciences, Sheffield University, UK.
There is growing evidence that the env genes of two or more human endogenous retroviruses (HERVs) of the W family are contributing to the inflammatory processes, and thus to the pathogenesis, of multiple sclerosis (MS). Increasing understanding of the human endogenous retroviral locus, ERVWE1, and the putative multiple sclerosis associated retrovirus, or MSRV, and in particular of the HERV-W env sequences associated with these, offers the potential of new lines of pharmacological research that might assist diagnosis, prognosis and therapy of multiple sclerosis.
Retrovirology. 2011 ;8 :90
22067224
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA.
BACKGROUND Integration of retroviral DNA into a germ cell may lead to a provirus that is transmitted vertically to that host's offspring as an endogenous retrovirus (ERV). In humans, ERVs (HERVs) comprise about 8% of the genome, the vast majority of which are truncated and/or highly mutated and no longer encode functional genes. The most recently active retroviruses that integrated into the human germ line are members of the Betaretrovirus-like HERV-K (HML-2) group, many of which contain intact open reading frames (ORFs) in some or all genes, sometimes encoding functional proteins that are expressed in various tissues. Interestingly, this expression is upregulated in many tumors ranging from breast and ovarian tissues to lymphomas and melanomas, as well as schizophrenia, rheumatoid arthritis, and other disorders. RESULTS No study to date has characterized all HML-2 elements in the genome, an essential step towards determining a possible functional role of HML-2 expression in disease. We present here the most comprehensive and accurate catalog of all full-length and partial HML-2 proviruses, as well as solo LTR elements, within the published human genome to date. Furthermore, we provide evidence for preferential maintenance of proviruses and solo LTR elements on gene-rich chromosomes of the human genome and in proximity to gene regions. CONCLUSIONS Our analysis has found and corrected several errors in the annotation of HML-2 elements in the human genome, including mislabeling of a newly identified group called HML-11. HML-elements have been implicated in a wide array of diseases, and characterization of these elements will play a fundamental role to understand the relationship between endogenous retrovirus expression and disease.
Viruses. 2011 Jun ;3 (6):901-5
21994760
Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, 49 Convent Drive MSC 4483, Bethesda, MD 20892, USA; E-Mail: lmeihong@mail.nih.gov.
Retroviruses integrate a reverse transcribed double stranded DNA copy of their viral genome into the chromosomal DNA of cells they infect. Occasionally, exogenous retroviruses infect germ cells and when this happens a profound shift in the virus host dynamic occurs. Retroviruses maintained as hereditable viral genetic material are referred to as endogenous retroviruses (ERVs). After millions of years of co-evolution with their hosts many human ERVs retain some degree of function and a few have even become symbionts. Thousands of copies of endogenous retrovirus long terminal repeats (LTRs) exist in the human genome. There are approximately 3000 to 4000 copies of the ERV-9 LTRs in the human genome and like other solo LTRs, ERV-9 LTRs can exhibit distinct promoter/enhancer activity in different cell lineages. It has been recently reported that a novel transcript of p63, a primordial member of the p53 family, is under the transcriptional control of an ERV-9 LTR [1]. The expression of different p63 transcript isoforms has been previously shown to have an important role in replenishing cutaneous epithelial stem cells and maintaining the fidelity of the female germ line [2]. In this recent report, a novel p63 transcript, designated GTAp63, is described as specifically expressed in healthy human testes and germ cell precursors of human testes but not in testicular cancer cells. The ability of ERV-9 regulatory regions to contribute to the maintenance of male germ line stability is yet another example of how ERVs have evolved to serve an important function in the physiology of their human hosts.
AP-HP, Henri Mondor-Albert Chenevier Hospitals, Department of Psychiatry , Creteil , France.
Abstract Objectives. Provide a synthetic review of recent studies evidencing an association between human endogenous retrovirus-W (HERV-W) and schizophrenia. Methods. Bibliography analysis and contextual synthesis. Results. Epidemiological studies suggest that the aetiology of schizophrenia is complex and involves a complex interplay of genetic and environmental factors such as infections. Eight percentof the human genome consists of human endogenous retroviruses (HERV), and this part of the genome was previously thought to be without importance, but new research has refuted this. HERVs share similarities with viruses and it is assumed that HERVs are present in the genome as a result of retroviruses infecting germ line cells many million years ago. A specific type of HERVs, called HERV-W, has through several recent studies been associated with schizophrenia. Elevated transcription of HERV-W elements has been documented, and antigens of HERV-W envelope and capsid proteins have been found in blood samples from patients. Viruses that have been implicated in pathology of schizophrenia, such as herpes and influenza, have been shown to activate HERV-W elements, and such activation has been associated with elevated biomarkers of systemic inflammation. New research indicates that HERV-W may be an important genetic factor interplaying with the environmental risk factor of infections and that, through this, HERV-W may be important for disease pathogenesis. Conclusions. A lifelong scenario of a detrimental interaction between infectious agents and HERV-W genes may decipher the actual development and course of schizophrenia. Further research is needed to find out if specific treatment strategies could reduce the expression of HERV-W and if this will be associated with remission.
Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
The long terminal repeat (LTR) sequences of endogenous retroviruses and retroelements contain promoter elements and are known to form chimeric transcripts with nearby cellular genes. Here we show that an LTR of the THE1D retroelement family has been domesticated as an alternative promoter of human IL2RB, the gene encoding the β subunit of the IL-2 receptor. The LTR promoter confers expression specifically in the placental trophoblast as opposed to its native transcription in the hematopoietic system. Rather than sequence-specific determinants, DNA methylation was found to regulate transcription initiation and splicing efficiency in a tissue-specific manner. Furthermore, we detected the cytoplasmic signaling domain of the IL-2Rβ protein in the placenta, suggesting that IL-2Rβ undergoes preferential proteolytic cleavage in this tissue. These findings implicate novel functions for this cytokine receptor subunit in the villous trophoblast and reveal an intriguing example of ancient LTR exaptation to drive tissue-specific gene expression.
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