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Jia C, Zhang M, Wu X, Zhang X, Lv Z, Zhao K, Zhang J, Su Y, Zhu F. HERV-W Env Induces Neuron Pyroptosis via the NLRP3-CASP1-GSDMD Pathway in Recent-Onset Schizophrenia. Int J Mol Sci 2025; 26:520. [PMID: 39859234 PMCID: PMC11765033 DOI: 10.3390/ijms26020520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/01/2025] [Accepted: 01/05/2025] [Indexed: 01/30/2025] Open
Abstract
HERVs (Human endogenous retroviruses) are remnants of ancient exogenous retroviruses that have integrated into the human genome, particularly in germ-line cells. Among these, the envelope protein gene HERV-W env (Human endogenous retroviruses W family envelope protein), located on chromosome 7 and primarily expressed in the human placenta, has been closely linked to various neuropsychiatric disorders, including schizophrenia, as well as autoimmune diseases and cancer. Recent studies have highlighted the abnormal expression of cytokines as a key factor in the pathophysiology of schizophrenia. Notably, elevated serum levels of IL-1β (interleukin 1 beta) in schizophrenia, a cytokine associated with inflammation, are a characteristic feature of pyroptosis-a form of pro-inflammatory programmed cell death. Although previous research has observed significant upregulation of pyroptosis-related genes such as CASP1 (Caspase-1), NLRP3 (NLR family pyrin domain containing 3), and IL1B (interleukin 1 beta) in the serum of schizophrenia patients, and extensive neuron pyroptosis has been documented in various neuropsychiatric disorders, including Alzheimer's disease, epilepsy, and multiple sclerosis, the occurrence of neuron pyroptosis in schizophrenia remains uncertain. Furthermore, the mechanisms underlying pyroptosis in schizophrenia and its potential connection with HERV-W env have yet to be fully elucidated. In this study, we found that the expression levels of pyroptosis-related genes, specifically CASP1, GSDMD (Gasdermin D), and IL1B, were significantly elevated in patients with schizophrenia compared to healthy controls. Furthermore, our analysis revealed a strong positive correlation between HERV-W env expression and the levels of CASP1/GSDMD/IL1B in these patients. Experimental evidence further demonstrated that HERV-W env promoted the activation of Caspase-1 and the cleavage of Gasdermin D, leading to increased release of LDH (lactate dehydrogenase) and IL-1β. Importantly, inhibitors targeting NLRP3, CASP1, and GSDMD significantly reduced the releases of LDH and IL-1β induced by HERV-W env, whereas BID (BH3 interacting domain death agonist) inhibitors did not have a notable effect. This suggests that HERV-W env induces CASP1-GSDMD-dependent pyroptosis through the NLRP3-CASP1-GSDMD signaling pathway. As pyroptosis is increasingly recognized for its connection to neurodegenerative diseases, this study provides insights into the molecular mechanisms of neuronal pyroptosis mediated by the NLRP3 inflammasome in the context of HERV-W env. Additionally, it explores the potential facilitation of HERV-W env in the development of schizophrenia via pyroptosis, proposing that certain pyroptosis indicators could serve as potential biomarkers for schizophrenia. Based on our existing research results and the findings of previous researchers, we infer that HERV-W env acts as a bridge in the onset and progression of schizophrenia. Furthermore, HERV-W env may serve as a potential target for the clinical treatment of schizophrenia, suggesting that monoclonal antibody therapy targeting HERV-W env could represent a novel approach to managing this disease.
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Affiliation(s)
- Chen Jia
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Mengqi Zhang
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Xiulin Wu
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Xu Zhang
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Zhao Lv
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Kexin Zhao
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Jiahang Zhang
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Yaru Su
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Fan Zhu
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
- Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University, Wuhan 430071, China
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Aourangzaib M, Chandra M, Maham R, Naz A, Malathi H, Qadeer S, Mateen RM, Parveen R. Solving the twin paradox-forensic strategies to identify the identical twins. Forensic Sci Int 2024; 363:112205. [PMID: 39213915 DOI: 10.1016/j.forsciint.2024.112205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/16/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024]
Abstract
Identical twins are also called monozygotic twins which originate from the same zygote that possesses the same genetic make-up. To discriminate between identical monozygotic twins, short tandem repeats has not been found effective, therefore, various techniques, including next-generation sequencing (NGS), are applied. Monozygotic twins can be identified through germ line genomes, through speech using deep learning networks, and through epigenetic analysis. Fingerprint analysis has also been used to distinguish between identical twins, as human beings have unique fingerprints. Two distinct levels of fingerprint are used to distinguish between monozygotic twins based upon the differences in the minutiae points. Examination of the methylation pattern of the genome has an enormous potential to differentiate between identical twins, as the methylation of DNA occurs uniquely to each individual. This article offers an insight into the latest methods and techniques used for the differentiation between the identical twins.
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Affiliation(s)
- Muhammad Aourangzaib
- Department of Life Sciences, School of Sciences, University of Management and Technology (UMT), Lahore, Punjab, Pakistan
| | - Muktesh Chandra
- Marwadi University Research Centre, Department of Bioinformatics, Faculty of Engineering and Technology, Marwadi University, Rajkot, Gujrat 360003, India
| | - Rabiya Maham
- Department of Life Sciences, School of Sciences, University of Management and Technology (UMT), Lahore, Punjab, Pakistan
| | - Alisha Naz
- Department of Life Sciences, School of Sciences, University of Management and Technology (UMT), Lahore, Punjab, Pakistan
| | - H Malathi
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Saima Qadeer
- Department of Zoology, Division of Science and Technology, University of Education, Lahore, Pakistan
| | - Rana Muhammad Mateen
- Department of Life Sciences, School of Sciences, University of Management and Technology (UMT), Lahore, Punjab, Pakistan.
| | - Rukhsana Parveen
- Cenre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
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Hime GR, Stonehouse SLA, Pang TY. Alternative models for transgenerational epigenetic inheritance: Molecular psychiatry beyond mice and man. World J Psychiatry 2021; 11:711-735. [PMID: 34733638 PMCID: PMC8546770 DOI: 10.5498/wjp.v11.i10.711] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 07/19/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Mental illness remains the greatest chronic health burden globally with few in-roads having been made despite significant advances in genomic knowledge in recent decades. The field of psychiatry is constantly challenged to bring new approaches and tools to address and treat the needs of vulnerable individuals and subpopulations, and that has to be supported by a continuous growth in knowledge. The majority of neuropsychiatric symptoms reflect complex gene-environment interactions, with epigenetics bridging the gap between genetic susceptibility and environmental stressors that trigger disease onset and drive the advancement of symptoms. It has more recently been demonstrated in preclinical models that epigenetics underpins the transgenerational inheritance of stress-related behavioural phenotypes in both paternal and maternal lineages, providing further supporting evidence for heritability in humans. However, unbiased prospective studies of this nature are practically impossible to conduct in humans so preclinical models remain our best option for researching the molecular pathophysiologies underlying many neuropsychiatric conditions. While rodents will remain the dominant model system for preclinical studies (especially for addressing complex behavioural phenotypes), there is scope to expand current research of the molecular and epigenetic pathologies by using invertebrate models. Here, we will discuss the utility and advantages of two alternative model organisms-Caenorhabditis elegans and Drosophila melanogaster-and summarise the compelling insights of the epigenetic regulation of transgenerational inheritance that are potentially relevant to human psychiatry.
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Affiliation(s)
- Gary R Hime
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, VIC, Australia
| | - Sophie LA Stonehouse
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville 3052, VIC, Australia
| | - Terence Y Pang
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, VIC, Australia
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville 3052, VIC, Australia
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Giménez-Orenga K, Oltra E. Human Endogenous Retrovirus as Therapeutic Targets in Neurologic Disease. Pharmaceuticals (Basel) 2021; 14:495. [PMID: 34073730 PMCID: PMC8225122 DOI: 10.3390/ph14060495] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/15/2021] [Accepted: 05/17/2021] [Indexed: 01/16/2023] Open
Abstract
Human endogenous retroviruses (HERVs) are ancient retroviral DNA sequences established into germline. They contain regulatory elements and encoded proteins few of which may provide benefits to hosts when co-opted as cellular genes. Their tight regulation is mainly achieved by epigenetic mechanisms, which can be altered by environmental factors, e.g., viral infections, leading to HERV activation. The aberrant expression of HERVs associates with neurological diseases, such as multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS), inflammatory processes and neurodegeneration. This review summarizes the recent advances on the epigenetic mechanisms controlling HERV expression and the pathogenic effects triggered by HERV de-repression. This article ends by describing new, promising therapies, targeting HERV elements, one of which, temelimab, has completed phase II trials with encouraging results in treating MS. The information gathered here may turn helpful in the design of new strategies to unveil epigenetic failures behind HERV-triggered diseases, opening new possibilities for druggable targets and/or for extending the use of temelimab to treat other associated diseases.
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Affiliation(s)
- Karen Giménez-Orenga
- Escuela de Doctorado, Universidad Católica de Valencia San Vicente Mártir, 46001 Valencia, Spain;
| | - Elisa Oltra
- School of Medicine and Health Sciences, Universidad Católica de Valencia San Vicente Mártir, 46001 Valencia, Spain
- Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, 46001 Valencia, Spain
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Gröger V, Emmer A, Staege MS, Cynis H. Endogenous Retroviruses in Nervous System Disorders. Pharmaceuticals (Basel) 2021; 14:ph14010070. [PMID: 33467098 PMCID: PMC7829834 DOI: 10.3390/ph14010070] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/11/2021] [Accepted: 01/13/2021] [Indexed: 02/06/2023] Open
Abstract
Human endogenous retroviruses (HERV) have been implicated in the pathogenesis of several nervous system disorders including multiple sclerosis and amyotrophic lateral sclerosis. The toxicity of HERV-derived RNAs and proteins for neuronal cells has been demonstrated. The involvement of HERV in the pathogenesis of currently incurable diseases might offer new treatment strategies based on the inhibition of HERV activities by small molecules or therapeutic antibodies.
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Affiliation(s)
- Victoria Gröger
- Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, 06120 Halle (Saale), Germany;
| | - Alexander Emmer
- Department of Neurology, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany;
| | - Martin S. Staege
- Department of Surgical and Conservative Pediatrics and Adolescent Medicine, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany
- Correspondence: (M.S.S.); (H.C.); Tel.: +49-345-557-7280 (M.S.S.); +49-345-13142835 (H.C.)
| | - Holger Cynis
- Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, 06120 Halle (Saale), Germany;
- Correspondence: (M.S.S.); (H.C.); Tel.: +49-345-557-7280 (M.S.S.); +49-345-13142835 (H.C.)
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Imamura A, Morimoto Y, Ono S, Kurotaki N, Kanegae S, Yamamoto N, Kinoshita H, Tsujita T, Okazaki Y, Ozawa H. Genetic and environmental factors of schizophrenia and autism spectrum disorder: insights from twin studies. J Neural Transm (Vienna) 2020; 127:1501-1515. [PMID: 32285255 PMCID: PMC7578126 DOI: 10.1007/s00702-020-02188-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/05/2020] [Indexed: 02/06/2023]
Abstract
Twin studies of psychiatric disorders such as schizophrenia and autism spectrum disorder have employed epidemiological approaches that determine heritability by comparing the concordance rate between monozygotic twins (MZs) and dizygotic twins. The basis for these studies is that MZs share 100% of their genetic information. Recently, biological studies based on molecular methods are now being increasingly applied to examine the differences between MZs discordance for psychiatric disorders to unravel their possible causes. Although recent advances in next-generation sequencing have increased the accuracy of this line of research, there has been greater emphasis placed on epigenetic changes versus DNA sequence changes as the probable cause of discordant psychiatric disorders in MZs. Since the epigenetic status differs in each tissue type, in addition to the DNA from the peripheral blood, studies using DNA from nerve cells induced from postmortem brains or induced pluripotent stem cells are being carried out. Although it was originally thought that epigenetic changes occurred as a result of environmental factors, and thus were not transmittable, it is now known that such changes might possibly be transmitted between generations. Therefore, the potential possible effects of intestinal flora inside the body are currently being investigated as a cause of discordance in MZs. As a result, twin studies of psychiatric disorders are greatly contributing to the elucidation of genetic and environmental factors in the etiology of psychiatric conditions.
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Affiliation(s)
- Akira Imamura
- Child and Adolescent Psychiatry Community Partnership Unit, Nagasaki University Hospital, Nagasaki, Japan.
| | - Yoshiro Morimoto
- Unit of Translation Medicine, Department of Neuropsychiatry, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shinji Ono
- Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Naohiro Kurotaki
- Department of Clinical Psychiatry, Graduate School of Medicine, Kagawa University, Kita-gun, Japan
| | - Shinji Kanegae
- Child and Adolescent Psychiatry Community Partnership Unit, Nagasaki University Hospital, Nagasaki, Japan
| | - Naoki Yamamoto
- Child and Adolescent Psychiatry Community Partnership Unit, Nagasaki University Hospital, Nagasaki, Japan
- Unit of Translation Medicine, Department of Neuropsychiatry, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hirohisa Kinoshita
- Unit of Translation Medicine, Department of Neuropsychiatry, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | | | - Yuji Okazaki
- Koseikai Michinoo Hospital, Nagasaki, Japan
- Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan
| | - Hiroki Ozawa
- Child and Adolescent Psychiatry Community Partnership Unit, Nagasaki University Hospital, Nagasaki, Japan
- Unit of Translation Medicine, Department of Neuropsychiatry, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Singh SM, Castellani CA, Hill KA. Postzygotic Somatic Mutations in the Human Brain Expand the Threshold-Liability Model of Schizophrenia. Front Psychiatry 2020; 11:587162. [PMID: 33192734 PMCID: PMC7642466 DOI: 10.3389/fpsyt.2020.587162] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 09/22/2020] [Indexed: 12/11/2022] Open
Abstract
The search for what causes schizophrenia has been onerous. This research has included extensive assessment of a variety of genetic and environmental factors using ever emerging high-resolution technologies and traditional understanding of the biology of the brain. These efforts have identified a large number of schizophrenia-associated genes, some of which are altered by mutational and epi-mutational mechanisms in a threshold liability model of schizophrenia development. The results, however, have limited predictability and the actual cause of the disease remains unknown. This current state asks for conceptualizing the problem differently in light of novel insights into the nature of mutations, the biology of the brain and the fine precision and resolution of emerging technologies. There is mounting evidence that mutations acquired during postzygotic development are more common than germline mutations. Also, the postzygotic somatic mutations including epimutations (PZMs), which often lead to somatic mosaicism, are relatively common in the mammalian brain in comparison to most other tissues and PZMs are more common in patients with neurodevelopmental mental disorders, including schizophrenia. Further, previously inaccessible, detection of PZMs is becoming feasible with the advent of novel technologies that include single-cell genomics and epigenomics and the use of exquisite experimental designs including use of monozygotic twins discordant for the disease. These developments allow us to propose a working hypothesis and expand the threshold liability model of schizophrenia that already encompasses familial genetic, epigenetic and environmental factors to include somatic de novo PZMs. Further, we offer a test for this expanded model using currently available genome sequences and methylome data on monozygotic twins discordant for schizophrenia (MZD) and their parents. The results of this analysis argue that PZMs play a significant role in the development of schizophrenia and explain extensive heterogeneity seen across patients. It also offers the potential to convincingly link PZMs to both nervous system health and disease, an area that has remained challenging to study and relatively under explored.
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Affiliation(s)
- Shiva M. Singh
- Molecular Genetics Unit, Department of Biology, The University of Western Ontario, London, ON, Canada
| | | | - Kathleen A. Hill
- Molecular Genetics Unit, Department of Biology, The University of Western Ontario, London, ON, Canada
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Grandi N, Tramontano E. Type W Human Endogenous Retrovirus (HERV-W) Integrations and Their Mobilization by L1 Machinery: Contribution to the Human Transcriptome and Impact on the Host Physiopathology. Viruses 2017; 9:v9070162. [PMID: 28653997 PMCID: PMC5537654 DOI: 10.3390/v9070162] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 06/08/2017] [Accepted: 06/20/2017] [Indexed: 01/07/2023] Open
Abstract
Human Endogenous Retroviruses (HERVs) are ancient infection relics constituting ~8% of our DNA. While HERVs’ genomic characterization is still ongoing, impressive amounts of data have been obtained regarding their general expression across tissues. Among HERVs, one of the most studied is the W group, which is the sole HERV group specifically mobilized by the long interspersed element-1 (LINE-1) machinery, providing a source of novel insertions by retrotransposition of HERV-W processed pseudogenes, and comprising a member encoding a functional envelope protein coopted for human placentation. The HERV-W group has been intensively investigated for its putative role in several diseases, such as cancer, inflammation, and autoimmunity. Despite major interest in the link between HERV-W expression and human pathogenesis, no conclusive correlation has been demonstrated so far. In general, (i) the absence of a proper identification of the specific HERV-W sequences expressed in a given condition; and (ii) the lack of studies attempting to connect the various observations in the same experimental conditions are the major problems preventing the definitive assessment of the HERV-W impact on human physiopathology. In this review, we summarize the current knowledge on the HERV-W group presence within the human genome and its expression in physiological tissues as well as in the main pathological contexts.
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Affiliation(s)
- Nicole Grandi
- Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato SS554, 09042 Monserrato, Cagliari, Italy.
| | - Enzo Tramontano
- Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato SS554, 09042 Monserrato, Cagliari, Italy.
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), 09042 Monserrato, Cagliari, Italy.
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Ellul P, Groc L, Leboyer M. [Implication of human endogenous retroviruses in schizophrenia and bipolar disorder]. Med Sci (Paris) 2017; 33:404-409. [PMID: 28497736 DOI: 10.1051/medsci/20173304010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Schizophrenia and bipolar disorder are neuropsychiatric disorders of unknown origin. It seems that these two disorders share some common etiopathogenic mechanisms including genetic, environmental and inflammatory ones. Reactivation of the human endogenous retrovirus type W (HERV-W) can be a shared element in the pathophysiology of schizophrenia and bipolar disorder, linked to immuno-genetic and environment risk factors. We will present studies that have highlighted the presence of HERV-W in schizophrenic and bipolar disorder patients. We will then describe a two-hit model which could explain the common pathophysiological mechanism of affective and non-affective psychosis. Identification of immuno-inflammatory mediated subgroup of schizophrenia and bipolar disorder associated to HERV-W reactivation might open the way for the development of diagnostic biomarker and more targeted treatments. These new tools pave the way towards personalized psychiatry for a better care of patients.
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Affiliation(s)
- Pierre Ellul
- Pôle psychiatrie des hôpitaux universitaires Henri Mondor, AP-HP, université Paris-Est, DHU PePSY, hôpital Albert Chenevier, 40, rue de Mesly, 94000 Créteil, France - Inserm U955, équipe 15, psychiatrie translationnelle, 94000 Créteil, France - Fondation FondaMental, 94000 Créteil, France
| | - Laurent Groc
- Institut interdisciplinaire de neuroscience, CNRS UMR 5297, Université de Bordeaux, 33076 Bordeaux, France - Fondation FondaMental, 94000 Créteil, France
| | - Marion Leboyer
- Pôle psychiatrie des hôpitaux universitaires Henri Mondor, AP-HP, université Paris-Est, DHU PePSY, hôpital Albert Chenevier, 40, rue de Mesly, 94000 Créteil, France - Inserm U955, équipe 15, psychiatrie translationnelle, 94000 Créteil, France - Fondation FondaMental, 94000 Créteil, France
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Grandi N, Cadeddu M, Blomberg J, Tramontano E. Contribution of type W human endogenous retroviruses to the human genome: characterization of HERV-W proviral insertions and processed pseudogenes. Retrovirology 2016; 13:67. [PMID: 27613107 PMCID: PMC5016936 DOI: 10.1186/s12977-016-0301-x] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 08/23/2016] [Indexed: 12/21/2022] Open
Abstract
Background Human endogenous retroviruses (HERVs) are ancient sequences integrated in the germ line cells and vertically transmitted through the offspring constituting about 8 % of our genome. In time, HERVs accumulated mutations that compromised their coding capacity. A prominent exception is HERV-W locus 7q21.2, producing a functional Env protein (Syncytin-1) coopted for placental syncytiotrophoblast formation. While expression of HERV-W sequences has been investigated for their correlation to disease, an exhaustive description of the group composition and characteristics is still not available and current HERV-W group information derive from studies published a few years ago that, of course, used the rough assemblies of the human genome available at that time. This hampers the comparison and correlation with current human genome assemblies. Results In the present work we identified and described in detail the distribution and genetic composition of 213 HERV-W elements. The bioinformatics analysis led to the characterization of several previously unreported features and provided a phylogenetic classification of two main subgroups with different age and structural characteristics. New facts on HERV-W genomic context of insertion and co-localization with sequences putatively involved in disease development are also reported. Conclusions The present work is a detailed overview of the HERV-W contribution to the human genome and provides a robust genetic background useful to clarify HERV-W role in pathologies with poorly understood etiology, representing, to our knowledge, the most complete and exhaustive HERV-W dataset up to date. Electronic supplementary material The online version of this article (doi:10.1186/s12977-016-0301-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Nicole Grandi
- Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato SS554, 09042, Monserrato, Cagliari, Italy
| | - Marta Cadeddu
- Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato SS554, 09042, Monserrato, Cagliari, Italy
| | - Jonas Blomberg
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Enzo Tramontano
- Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato SS554, 09042, Monserrato, Cagliari, Italy. .,Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.
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Slokar G, Hasler G. Human Endogenous Retroviruses as Pathogenic Factors in the Development of Schizophrenia. Front Psychiatry 2015; 6:183. [PMID: 26793126 PMCID: PMC4707225 DOI: 10.3389/fpsyt.2015.00183] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 12/15/2015] [Indexed: 11/13/2022] Open
Abstract
Schizophrenia is a complex disorder, characterized by the interplay between genetic and environmental factors. Human endogenous retroviruses (HERVs), genetic elements that originated from infections by exogenous retroviruses millions of years ago, comprise ~8% of the human genome. Here, we provide a comprehensive review of accumulating evidence, detailing HERV aberrancies associated with schizophrenia. Studies examining the genome, transcriptome, and proteome of individuals with schizophrenia provide data that support the association of these viral elements with the disorder. Molecular differences can be found within the central nervous system and peripheral tissues. However, additional studies are needed to substantiate the reported link and to address several discrepancies among previous investigations. We further discuss potentially relevant pathogenic mechanisms to the development of schizophrenia.
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Affiliation(s)
- Gorjan Slokar
- Psychiatric University Hospital, University of Bern , Bern , Switzerland
| | - Gregor Hasler
- Psychiatric University Hospital, University of Bern , Bern , Switzerland
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12
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13
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Feigenson KA, Kusnecov AW, Silverstein SM. Inflammation and the two-hit hypothesis of schizophrenia. Neurosci Biobehav Rev 2014; 38:72-93. [PMID: 24247023 PMCID: PMC3896922 DOI: 10.1016/j.neubiorev.2013.11.006] [Citation(s) in RCA: 198] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 10/26/2013] [Accepted: 11/07/2013] [Indexed: 12/12/2022]
Abstract
The high societal and individual cost of schizophrenia necessitates finding better, more effective treatment, diagnosis, and prevention strategies. One of the obstacles in this endeavor is the diverse set of etiologies that comprises schizophrenia. A substantial body of evidence has grown over the last few decades to suggest that schizophrenia is a heterogeneous syndrome with overlapping symptoms and etiologies. At the same time, an increasing number of clinical, epidemiological, and experimental studies have shown links between schizophrenia and inflammatory conditions. In this review, we analyze the literature on inflammation and schizophrenia, with a particular focus on comorbidity, biomarkers, and environmental insults. We then identify several mechanisms by which inflammation could influence the development of schizophrenia via the two-hit hypothesis. Lastly, we note the relevance of these findings to clinical applications in the diagnosis, prevention, and treatment of schizophrenia.
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Affiliation(s)
- Keith A Feigenson
- Robert Wood Johnson Medical School at Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA.
| | - Alex W Kusnecov
- Department of Psychology, Behavioral and Systems Neuroscience Program and Joint Graduate Program in Toxicology, Rutgers University, 52 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.
| | - Steven M Silverstein
- Robert Wood Johnson Medical School at Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA; University Behavioral Health Care at Rutgers, The State University of New Jersey, 671 Hoes Lane, Piscataway, NJ 08855, USA.
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14
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Darby MM, Sabunciyan S. Repetitive Elements and Epigenetic Marks in Behavior and Psychiatric Disease. ADVANCES IN GENETICS 2014; 86:185-252. [DOI: 10.1016/b978-0-12-800222-3.00009-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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15
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Kiran Kumar HB, Castellani C, Maiti S, O'Reilly R, Singh SM. Search for missing schizophrenia genes will require a new developmental neurogenomic perspective. J Genet 2013; 92:335-40. [PMID: 23970094 DOI: 10.1007/s12041-013-0262-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Even the most powerful experimental designs in search of genetic causes of schizophrenia have not met the desired goal. It is imperative to review the reasons for such an outcome and to formulate novel strategies for the future direction of this research in the new era of individual genomes. Here, we will review aspects of neurodevelopmental hypothesis of schizophrenia in the light of novel genomic and epigenomic insights. Specifically, we will argue for the involvement of de novo mutations and epigenetic modifications during neurodevelopment that may result in schizophrenia. Our conclusion is that the successful elucidation of hereditary mechanisms in neuropsychiatric disorders must begin with attention to discrete endophenotypes; consideration of ontogeny, forethought of genome structure including temporal and spatial patterns of (epi) mutations and the use of judicious techniques that go beyond association studies.
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Affiliation(s)
- H B Kiran Kumar
- Molecular Genetics Unit, Department of Biology and Psychiatry, University of Western Ontario, London, Ontario, Canada N6A 5B7
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16
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Leboyer M, Tamouza R, Charron D, Faucard R, Perron H. Human endogenous retrovirus type W (HERV-W) in schizophrenia: a new avenue of research at the gene-environment interface. World J Biol Psychiatry 2013; 14:80-90. [PMID: 21936762 DOI: 10.3109/15622975.2010.601760] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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.
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Affiliation(s)
- Marion Leboyer
- AP-HP, Henri Mondor-Albert Chenevier Hospitals, Department of Psychiatry, Creteil, France
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17
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Garcia-Montojo M, Dominguez-Mozo M, Arias-Leal A, Garcia-Martinez Á, De las Heras V, Casanova I, Faucard R, Gehin N, Madeira A, Arroyo R, Curtin F, Alvarez-Lafuente R, Perron H. The DNA copy number of human endogenous retrovirus-W (MSRV-type) is increased in multiple sclerosis patients and is influenced by gender and disease severity. PLoS One 2013; 8:e53623. [PMID: 23308264 PMCID: PMC3538585 DOI: 10.1371/journal.pone.0053623] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 11/30/2012] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Multiple sclerosis is an autoimmune disease more prevalent in women than in men. Multiple Sclerosis Associated Retrovirus element (MSRV) is a member of type-W endogenous retrovirus family (HERV-W), known to be associated to MS. Most HERVs are unable to replicate but MSRV expression associated with reverse-transcriptase activity in MS would explain reported DNA copy number increase in MS patients. A potential link between HERV-W copies on chromosome X and gender differential prevalence has been suggested. The present study addresses MSRV-type DNA load in relation with the gender differences and clinical status in MS and healthy controls. RESULTS 178 MS patients (62.9% women) and 124 controls (56.5% women) were included. MSRV env load (copies/pg of DNA) was analyzed by real time qPCR with specific primers and probe for its env gene, in DNA from peripheral blood mononuclear cells (PBMCs). MSRV load was more elevated in MS patients than in controls (p = 4.15e-7). MS women presented higher MSRV load than control women (p = 0.009) and MS men also had higher load than control men (p = 2.77e-6). Besides, women had higher levels than men, both among patients (p = 0.007) and controls (p = 1.24e-6). Concordantly, EDSS and MSSS scores were higher among female patients with an elevated MSRV load (p = 0.03 and p = 0.04, respectively). CONCLUSIONS MSRV increases its copy number in PBMC of MS patients and particularly in women with high clinical scores. This may explain causes underlying the higher prevalence of MS in women. The association with the clinical severity calls for further investigations on MSRV load in PBMCs as a biomarker for MS.
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Affiliation(s)
- Marta Garcia-Montojo
- Multiple Sclerosis Unit, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.
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18
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Perron H, Hamdani N, Faucard R, Lajnef M, Jamain S, Daban-Huard C, Sarrazin S, LeGuen E, Houenou J, Delavest M, Moins-Teiserenc H, Bengoufa D, Yolken R, Madeira A, Garcia-Montojo M, Gehin N, Burgelin I, Ollagnier G, Bernard C, Dumaine A, Henrion A, Gombert A, Le Dudal K, Charron D, Krishnamoorthy R, Tamouza R, Leboyer M, Leboyer M. Molecular characteristics of Human Endogenous Retrovirus type-W in schizophrenia and bipolar disorder. Transl Psychiatry 2012; 2:e201. [PMID: 23212585 PMCID: PMC3565190 DOI: 10.1038/tp.2012.125] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type 'W' family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10-4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders.
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Affiliation(s)
- H Perron
- Geneuro, Plan-Les-Ouates, Geneva, Switzerland.
| | - N Hamdani
- Inserm U955, Psychiatrie Génétique, Créteil, France,AP-HP, Hôpital Henri Mondor-Albert Chenevier, Pôle de Psychiatrie, Créteil, France,Fondation Fondamental, Créteil, France,Université Paris Est Créteil, Faculté de Médecine, Créteil, France
| | - R Faucard
- Geneuro-Innovation, Pre-Clinical R&D Department, Lyon, France
| | - M Lajnef
- Inserm U955, Psychiatrie Génétique, Créteil, France,AP-HP, Hôpital Henri Mondor-Albert Chenevier, Pôle de Psychiatrie, Créteil, France,Fondation Fondamental, Créteil, France
| | - S Jamain
- Inserm U955, Psychiatrie Génétique, Créteil, France,Fondation Fondamental, Créteil, France
| | - C Daban-Huard
- Inserm U955, Psychiatrie Génétique, Créteil, France,AP-HP, Hôpital Henri Mondor-Albert Chenevier, Pôle de Psychiatrie, Créteil, France,Fondation Fondamental, Créteil, France
| | - S Sarrazin
- Inserm U955, Psychiatrie Génétique, Créteil, France,AP-HP, Hôpital Henri Mondor-Albert Chenevier, Pôle de Psychiatrie, Créteil, France,Fondation Fondamental, Créteil, France,CEA Saclay, Neurospin, Gif-Sur-Yvette, France
| | - E LeGuen
- Inserm U955, Psychiatrie Génétique, Créteil, France,AP-HP, Hôpital Henri Mondor-Albert Chenevier, Pôle de Psychiatrie, Créteil, France,Fondation Fondamental, Créteil, France
| | - J Houenou
- Inserm U955, Psychiatrie Génétique, Créteil, France,AP-HP, Hôpital Henri Mondor-Albert Chenevier, Pôle de Psychiatrie, Créteil, France,Fondation Fondamental, Créteil, France,CEA Saclay, Neurospin, Gif-Sur-Yvette, France
| | - M Delavest
- Fondation Fondamental, Créteil, France,AP-HP, Université Paris Diderot, Service de Psychiatrie, Hôpital Lariboisiere Fernand Widal, Paris, France
| | - H Moins-Teiserenc
- Jean Dausset Department and INSERM UMRS 940, Hôpital Saint Louis, Paris, France
| | - D Bengoufa
- Jean Dausset Department and INSERM UMRS 940, Hôpital Saint Louis, Paris, France
| | - R Yolken
- Stanley Laboratory of Developmental Neurovirology, Johns Hopkins University Medical Center, Baltimore, MD, USA
| | - A Madeira
- Geneuro-Innovation, Pre-Clinical R&D Department, Lyon, France
| | | | - N Gehin
- Geneuro-Innovation, Pre-Clinical R&D Department, Lyon, France
| | - I Burgelin
- Geneuro-Innovation, Pre-Clinical R&D Department, Lyon, France
| | - G Ollagnier
- Geneuro-Innovation, Pre-Clinical R&D Department, Lyon, France
| | - C Bernard
- Geneuro, Plan-Les-Ouates, Geneva, Switzerland
| | - A Dumaine
- Inserm U955, Psychiatrie Génétique, Créteil, France,Fondation Fondamental, Créteil, France
| | - A Henrion
- Inserm U955, Psychiatrie Génétique, Créteil, France,Fondation Fondamental, Créteil, France
| | - A Gombert
- Inserm U955, Psychiatrie Génétique, Créteil, France,Fondation Fondamental, Créteil, France
| | - K Le Dudal
- Plateforme de Ressources Biologiques AP-HP, Créteil, France,Stanley Research Program, Sheppard Pratt, Baltimore, MD, USA,INSERM-CIC 006, Créteil, France
| | - D Charron
- Jean Dausset Department and INSERM UMRS 940, Hôpital Saint Louis, Paris, France
| | | | - R Tamouza
- Jean Dausset Department and INSERM UMRS 940, Hôpital Saint Louis, Paris, France
| | - M Leboyer
- Inserm U955, Psychiatrie Génétique, Créteil, France,AP-HP, Hôpital Henri Mondor-Albert Chenevier, Pôle de Psychiatrie, Créteil, France,Fondation Fondamental, Créteil, France,Université Paris Est Créteil, Faculté de Médecine, Créteil, France,AP-HP, Hôpital Henri Mondor-Albert Chenevier, Pôle de Psychiatrie, 40, rue de Mesly, 94010 Créteil, France. E-mail:
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19
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Perron H, Lang A. The human endogenous retrovirus link between genes and environment in multiple sclerosis and in multifactorial diseases associating neuroinflammation. Clin Rev Allergy Immunol 2010; 39:51-61. [PMID: 19697163 DOI: 10.1007/s12016-009-8170-x] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Endogenous retroviruses represent about 8% of the human genome and belong to the superfamily of transposable and retrotransposable genetic elements. Altogether, these mobile genetic elements and their numerous inactivated "junk" sequences represent nearly one half of the human DNA. Nonetheless, a significant part of this "non-conventional" genome has retained potential activity. Epigenetic control is notably involved in silencing most of these genetic elements but certain environmental factors such as viruses are known to dysregulate their expression in susceptible cells. More particularly, embryonal cells with limited gene methylation are most susceptible to uncontrolled activation of these mobile genetic elements by, e.g., viral infections. In particular, certain viruses transactivate promoters from endogenous retroviral family type W (HERV-W). HERV-W RNA was first isolated in circulating viral particles (Multiple Sclerosis-associated RetroViral element, MSRV) that have been associated with the evolution and prognosis of multiple sclerosis. HERV-W elements encode a powerful immunopathogenic envelope protein (ENV) that activates a pro-inflammatory and autoimmune cascade through interaction with Toll-like receptor 4 on immune cells. This ENV protein has repeatedly been detected in MS brain lesions and may be involved in other diseases. Epigenetic factors controlling HERV-W ENV protein expression then reveal critical. This review addresses the gene-environment epigenetic interface of such HERV-W elements and its potential involvement in disease.
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Affiliation(s)
- Hervé Perron
- GeNeuro, 18, Chemin des Aulx, 1228, Plan-Les Ouates, Geneva, Switzerland.
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20
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Haque FN, Gottesman II, Wong AHC. Not really identical: epigenetic differences in monozygotic twins and implications for twin studies in psychiatry. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2009; 151C:136-41. [PMID: 19378334 DOI: 10.1002/ajmg.c.30206] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Classical twin studies in the field of psychiatry generally fall into one of two categories: (1) those designed to identify environmental risk factors causing discordance in monozygotic (MZ) twins and (2) those geared towards identifying genetic risk factors. However, neither environment nor differences in DNA sequence can fully account for phenotypic discordance among MZ twins. The field of epigenetics--DNA modifications that can affect gene expression--offers new models to understand discordance in MZ twins. In the past, MZ twins were regarded as genetically-identical controls for differing environmental conditions. In contrast, the evolving current concept is that epigenetic differences between MZ twins may modulate differences in diverse phenotype, from disease to personality. In this article, we review some twin studies, and discuss the dynamic interactions between stochastic, environmental, and epigenetic variables that influence neurobiological phenotypes.
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Singh SM, O'Reilly R. (Epi)genomics and neurodevelopment in schizophrenia: monozygotic twins discordant for schizophrenia augment the search for disease-related (epi)genomic alterations. Genome 2009; 52:8-19. [PMID: 19132067 DOI: 10.1139/g08-095] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Unlike stunning breakthroughs in the identification of genes for Mendelian disorders during the last three decades, gene identification in most complex disorders has been full of twists and turns and little progress. Doing more of the same will not guarantee success. The lessons learned argue for a need to reconsider genetic models that are appropriate for the disorder in question along with an interdisciplinary, systematic approach using genomic methods that have now become possible. We will use schizophrenia as an example to review the genetic progress to date that has been disappointing. We will argue that the causation of this complex disease may involve heterogeneous genomic changes of major effect. We will provide three approaches, retroviral transpositions, methylation, and copy number variations, to test this hypothesis. We will present arguments to suggest that such experiments will be most effective if undertaken on monozygotic twins. It will include our experience with associated experiments on the monozygotic twins discordant for schizophrenia. The results support that (epi)genomic changes of major effect, rather than accumulation of mutations of small effect, underlie the causation of this complex disease. More important, this experimental strategy will be an effective strategy for studies on other complex (behavioural) disorders as well.
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Affiliation(s)
- Shiva M Singh
- Molecular Genetics Laboratories, Department of Biology, and Division of Medical Genetics, The University of Western Ontario, London, ON N6A5B7, Canada.
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22
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Singh SM, Castellani CA, O'Reilly RL. Copy number variation showers in schizophrenia: an emerging hypothesis. Mol Psychiatry 2009; 14:356-8. [PMID: 19139749 DOI: 10.1038/mp.2008.149] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Genetic discoveries on Schizophrenia remain challenging. Traditional approaches have provided clues, but no genes. Novel theories that must account for extensive heterogeneity, including high discordance of monozygotic (MZD) twins, are needed. To this end, the extensive repeats of the human genome may provide the predisposition for DNA replication errors operational at every cell cycle during meiosis and mitosis. These errors will shower the genome with replication errors including copy number variations. Depending on the timing and the genes involved, this will contribute to the mutational load and disease. The evidence for such a mechanism in schizophrenia is emerging.
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Affiliation(s)
- S M Singh
- University of Western Ontario, London, ON, Canada.
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23
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Abstract
For millions of years, retroviral infections have challenged vertebrates, occasionally leading to germline integration and inheritance as ERVs, genetic parasites whose remnants today constitute some 7% to 8% of the human genome. Although they have had significant evolutionary side effects, it is useful to view ERVs as fossil representatives of retroviruses extant at the time of their insertion into the germline and not as direct players in the evolutionary process itself. Expression of particular ERVs is associated with several positive physiological functions as well as certain diseases, although their roles in human disease as etiological agents, possible contributing factors, or disease markers-well demonstrated in animal models-remain to be established. Here we discuss ERV contributions to host genome structure and function, including their ability to mediate recombination, and physiological effects on the host transcriptome resulting from their integration, expression, and other events.
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Affiliation(s)
- Patric Jern
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
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24
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Perron H, Mekaoui L, Bernard C, Veas F, Stefas I, Leboyer M. Endogenous retrovirus type W GAG and envelope protein antigenemia in serum of schizophrenic patients. Biol Psychiatry 2008; 64:1019-23. [PMID: 18760403 DOI: 10.1016/j.biopsych.2008.06.028] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2008] [Revised: 06/23/2008] [Accepted: 06/29/2008] [Indexed: 02/06/2023]
Abstract
BACKGROUND Recent and independent molecular studies have shown an association between human endogenous retroviruses type "W" family (HERV-W) and schizophrenia, mostly by polymerase chain reaction studies, but none has yet addressed specific antigen detection in living patients. METHODS Forty-nine schizophrenic patients and an equivalent number of healthy control subjects were included in the present exploratory study. The HERV-W GAG and envelope (ENV) proteins were quantified in the serum with a dedicated immunoassay set-up with specific monoclonal antibodies to either antigen. RESULTS In schizophrenic patients, positive antigenemia for ENV was found in 23 of 49 (47%) and for GAG in 24 of 49 (49%). Only 1 of 30 (3%) for ENV and 2 of 49 (4%) for GAG were positive in blood donors (p < .01 for ENV; p < .001 for GAG). Interestingly, bioclinical data analyses revealed significant correlation between GAG or ENV antigenemia (a protein causing dysimmune inflammatory effects) and C-reactive protein (CRP) levels (a systemic inflammation biomarker). CONCLUSIONS Frequently elevated CRP has previously been described in schizophrenic patients and has been shown to match with an evolution toward cognitive deficit and neuronal loss. Elsewhere viruses such as influenza, long-associated with risk for schizophrenia through perinatal infections, have been shown to activate HERV-W elements in human cells. We therefore discuss a relationship between environment factors long-associated with early risk, genetic factors represented by this endogenous family, the production of its pro-inflammatory ENV protein and known "inflammation-mediated" neurotoxicity, as a possible hypothesis for a pathogenic cascade in association with HERV-W. Our present results thus confirm that HERV-W studies have opened a novel avenue of research in schizophrenia.
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25
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Quantitative expression of the HERV-W env gene in human tissues. Arch Virol 2008; 153:1587-91. [DOI: 10.1007/s00705-008-0159-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2007] [Accepted: 06/10/2008] [Indexed: 10/21/2022]
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Kakiuchi C, Ishiwata M, Nanko S, Ozaki N, Iwata N, Umekage T, Tochigi M, Kohda K, Sasaki T, Imamura A, Okazaki Y, Kato T. Up-regulation of ADM and SEPX1 in the lymphoblastoid cells of patients in monozygotic twins discordant for schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2008; 147B:557-64. [PMID: 18081029 DOI: 10.1002/ajmg.b.30643] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The contribution of genetic factors to schizophrenia is well established and recent studies have indicated several strong candidate genes. However, the pathophysiology of schizophrenia has not been totally elucidated yet. To date, studies of monozygotic twins discordant for schizophrenia have provided insight into the pathophysiology of this illness; this type of study can exclude inter-individual variability and confounding factors such as effects of drugs. In this study we used DNA microarray analysis to examine the mRNA expression patterns in the lymphoblastoid (LB) cells derived from two pairs of monozygotic twins discordant for schizophrenia. From five independent replicates for each pair of twins, we selected five genes, which included adrenomedullin (ADM) and selenoprotein X1 (SEPX1), as significantly changed in both twins with schizophrenia. Interestingly, ADM was previously reported to be up-regulated in both the LB cells and plasma of schizophrenic patients, and SEPX1 was included in the list of genes up-regulated in the peripheral blood cells of schizophrenia patients by microarray analysis. Then, we performed a genetic association study of schizophrenia in the Japanese population and examined the copy number variations, but observed no association. These findings suggest the possible role of ADM and SEPX1 as biomarkers of schizophrenia. The results also support the usefulness of gene expression analysis in LB cells of monozygotic twins discordant for an illness.
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Affiliation(s)
- Chihiro Kakiuchi
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan
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Voisset C, Weiss RA, Griffiths DJ. Human RNA "rumor" viruses: the search for novel human retroviruses in chronic disease. Microbiol Mol Biol Rev 2008; 72:157-96, table of contents. [PMID: 18322038 PMCID: PMC2268285 DOI: 10.1128/mmbr.00033-07] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Retroviruses are an important group of pathogens that cause a variety of diseases in humans and animals. Four human retroviruses are currently known, including human immunodeficiency virus type 1, which causes AIDS, and human T-lymphotropic virus type 1, which causes cancer and inflammatory disease. For many years, there have been sporadic reports of additional human retroviral infections, particularly in cancer and other chronic diseases. Unfortunately, many of these putative viruses remain unproven and controversial, and some retrovirologists have dismissed them as merely "human rumor viruses." Work in this field was last reviewed in depth in 1984, and since then, the molecular techniques available for identifying and characterizing retroviruses have improved enormously in sensitivity. The advent of PCR in particular has dramatically enhanced our ability to detect novel viral sequences in human tissues. However, DNA amplification techniques have also increased the potential for false-positive detection due to contamination. In addition, the presence of many families of human endogenous retroviruses (HERVs) within our DNA can obstruct attempts to identify and validate novel human retroviruses. Here, we aim to bring together the data on "novel" retroviral infections in humans by critically examining the evidence for those putative viruses that have been linked with disease and the likelihood that they represent genuine human infections. We provide a background to the field and a discussion of potential confounding factors along with some technical guidelines. In addition, some of the difficulties associated with obtaining formal proof of causation for common or ubiquitous agents such as HERVs are discussed.
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Affiliation(s)
- Cécile Voisset
- CNRS-UMR8161, Institut de Biologie de Lille et Institut Pasteur de Lille, Lille, France
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Schumacher A, Petronis A. Epigenetics of Complex Diseases: From General Theory to Laboratory Experiments. Curr Top Microbiol Immunol 2006; 310:81-115. [PMID: 16909908 DOI: 10.1007/3-540-31181-5_6] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Despite significant effort, understanding the causes and mechanisms of complex non-Mendelian diseases remains a key challenge. Although numerous molecular genetic linkage and association studies have been conducted in order to explain the heritable predisposition to complex diseases, the resulting data are quite often inconsistent and even controversial. In a similar way, identification of environmental factors causal to a disease is difficult. In this article, a new interpretation of the paradigm of "genes plus environment" is presented in which the emphasis is shifted to epigenetic misregulation as a major etiopathogenic factor. Epigenetic mechanisms are consistent with various non-Mendelian irregularities of complex diseases, such as the existence of clinically indistinguishable sporadic and familial cases, sexual dimorphism, relatively late age of onset and peaks of susceptibility to some diseases, discordance of monozygotic twins and major fluctuations on the course of disease severity. It is also suggested that a substantial portion of phenotypic variance that traditionally has been attributed to environmental effects may result from stochastic epigenetic events in the cell. It is argued that epigenetic strategies, when applied in parallel with the traditional genetic ones, may significantly advance the discovery of etiopathogenic mechanisms of complex diseases. The second part of this chapter is dedicated to a review of laboratory methods for DNA methylation analysis, which may be useful in the study of complex diseases. In this context, epigenetic microarray technologies are emphasized, as it is evident that such technologies will significantly advance epigenetic analyses in complex diseases.
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Affiliation(s)
- A Schumacher
- The Krembil Family Epigenetics Laboratory, Centre for Addiction and Mental Health, ON, Toronto, Canada
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Hu L, Hornung D, Kurek R, Ostman H, Helen O, Blomberg J, Bergqvist A. Expression of human endogenous gammaretroviral sequences in endometriosis and ovarian cancer. AIDS Res Hum Retroviruses 2006; 22:551-7. [PMID: 16796530 DOI: 10.1089/aid.2006.22.551] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Endogenous retroviruses (ERVs) probably originate from ancient germ cell infections by exogenous retroviruses. A high expression of retroviruses in reproductive tissue increases the risk of viral transmission to germ line cells. We therefore investigated the expression of human ERVs (HERVs) in normal endometrium, endometriosis, normal ovaries, and ovarian cancer. Four real-time PCRs (QPCRs) for HERV-E, HERV-I/T, HERV-H, and HERV-W, respectively, and an expression control gene were used. HERV-E RNA expression was significantly higher in endometriotic tissue (average, SD) than in normal endometrium (average, SD), both measured as ratios versus control gene expression and as. HERV-E and HERV-W RNA were higher in normal ovarian tissue than in ovarian cancer. This illustrates that HERV expression is not automatically higher in malignant tissues. The other HERV PCRs did not show expression patterns as distinctive as HERVE and HERV-W in the two kinds of reproductive tissue. A small number of candidate HERV-E loci from which the transcription took place were identified by sequencing of amplimers. The role of HERV-E and HERV-W in endometriosis merits further investigation.
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Affiliation(s)
- Lijuan Hu
- Section of Virology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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Andersson AC, Yun Z, Sperber GO, Larsson E, Blomberg J. ERV3 and related sequences in humans: structure and RNA expression. J Virol 2005; 79:9270-84. [PMID: 15994821 PMCID: PMC1168766 DOI: 10.1128/jvi.79.14.9270-9284.2005] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The ERV3 locus at chromosome 7q11 is a much studied human endogenous retroviral (HERV) sequence, owing to an env open reading frame (ORF) and placental RNA and protein expression. An analysis of the human genome demonstrated that ERV3 is one of a group of 41 highly related elements (ERV3-like HERVs) which use proline, isoleucine, or arginine tRNA in their primer binding sites. In addition to elements closely related to ERV3, the group included the previously known retinoic acid-inducible element, RRHERVI, also referred to as HERV15, but was separate from the related HERV-E elements. The ERV3-like elements are defective. The only element with an ORF among gag, pro, pol, and env genes was the env ORF of the original ERV3 locus. A search in dbEST revealed ERV3 RNA expression in placenta, skin, carcinoid tumor, and adrenal glands. Expression was also studied with newly developed real-time quantitative PCRs (QPCR) of ERV3 and HERV-E(4-1) env sequences. Results from a novel histone 3.3 RNA QPCR result served as the expression control. QPCR results for ERV3 were compatible with previously published results, with a stronger expression in adrenal gland and placenta than in 15 other human tissues. The expression of the envelope (env) of ERV3 at chromosome 7q11 was also studied by using stringent in situ hybridization. Expression was found in corpus luteum, testis, adrenal gland, Hassal's bodies in thymus, brown fat, pituitary gland, and epithelium of the lung. We conclude that ERV3 env is most strongly expressed in adrenal and sebaceous glands as well as in placenta.
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Kato T, Iwamoto K, Kakiuchi C, Kuratomi G, Okazaki Y. Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders. Mol Psychiatry 2005; 10:622-30. [PMID: 15838537 DOI: 10.1038/sj.mp.4001662] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Classical twin research focused on differentiating genetic factors from environmental factors by comparing the concordance rate between monozygotic (MZ) and dizygotic twins. On the other hand, recent twin research tries to identify genetic or epigenetic differences between MZ twins discordant for mental disorders. There are a number of reports of MZ twins discordant for genetic disorders caused by genetic or epigenetic differences of known pathogenic genes. In the case of mental disorder research, for which the causative gene has not been established yet, we are trying to identify the 'pathogenic gene' by comprehensive analysis of genetic or epigenetic difference between discordant MZ twins. To date, no compelling evidence suggesting such difference between MZ twins has been reported. However, if the genetic or epigenetic difference responsible for the discordant phenotype is found, it will have impact on the biology of mental disorder, in which few conclusive molecular genetic evidences have been obtained.
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Affiliation(s)
- T Kato
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.
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Abstract
The plethora of genomic information gathered by the sequencing of the human and mouse genomes has paved the way for a new era of genetics. While in the past we focused mainly on the small percentage of DNA that codes for proteins, we can now concentrate on the remainder, i.e. the noncoding sequences that interrupt and separate genes. This portion of the genome is made up, in most part, of repetitive DNA sequences including DNA transposons, long terminal repeat (LTR) retrotransposons, LINEs (long interspersed nuclear elements) and SINEs (short interspersed nuclear elements). Some of these elements are transcriptionally active and can transpose or retrotranspose around the genome, resulting in insertional mutagenesis that can cause disease. In these cases, insertions have occurred in the coding sequence. However, recent evidence suggests that the main effect of these elements is their ability to influence transcription of neighbouring genes. The elements themselves contain promoters that can initiate transcription of flanking genomic DNA. Furthermore, they are susceptible to epigenetic silencing, which is often stochastic and incomplete, resulting in complex patterns of transcription. This review discusses some diseases in both human and mouse that are caused by these repetitive elements.
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Affiliation(s)
- R Druker
- School of Molecular and Microbial Biosciences, University of Sydney, New South Wales, Australia
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Abstract
The retroviral capacity for integration into the host genome can give rise to endogenous retroviruses (ERVs): retroviral sequences that are transmitted vertically as part of the host germ line, within which they may continue to replicate and evolve. ERVs represent both a unique archive of ancient viral sequence information and a dynamic component of host genomes. As such they hold great potential as informative markers for studies of both virus evolution and host genome evolution. Numerous novel ERVs have been described in recent years, particularly as genome sequencing projects have advanced. This review discusses the evolution of ERV lineages, considering the processes by which ERV distribution and diversity is generated. The diversity of ERVs isolated so far is summarised in terms of both their distribution across host taxa, and their relationships to recognised retroviral genera. Finally the relevance of ERVs to studies of genome evolution, host disease and viral ecology is considered, and recent findings discussed.
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Affiliation(s)
- Robert Gifford
- Department of Biological Sciences, Imperial College, Silwood Park, Buckhurst Road, Ascot Berkshire, SL5 7PY, UK
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Affiliation(s)
- Håkan Karlsson
- Department of Neuroscience, Division of neurodegenerative Disorders, Karolinska Institutet, Stockholm, Sweden.
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Abstract
Human monozygotic (MZ) twins estimated to occur once in 250 live births, result from an errant decision by embryonic cell(s) to develop as separate embryos. They are considered genetically identical and any phenotypic discordance between them has been used to implicate the role of environment. More recent literature, however, has questioned these assumptions but the frequency and the nature of any genetic discordance between MZ twins remains poorly understood. We will review published cases of phenotypic and genetic discordance between monozygotic twins to argue that not all discordance between such twins is due to differences in environment. The causes of reduced concordance between MZ twins remains poorly understood. They represent among the challenging aspects of the genetics of complex multi-factorial traits and diseases. A number of questions regarding the published results on MZ twins merit a re-assessment in the light of modern molecular insight of the human genome. Such an assessment is needed in directing future studies on MZ twins. In particular, we will deal with the origin, development, genetic and epigenetic factors that may have implications in discordance of the MZ twin pairs.
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Affiliation(s)
- S M Singh
- Molecular Genetics Unit, Department of Biology and Division of Medical Genetics, The University of Western Ontario, London, Ontario, Canada.
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Jern P, Lindeskog M, Karlsson D, Blomberg J. Full-length HERV-H elements with env SU open reading frames in the human genome. AIDS Res Hum Retroviruses 2002; 18:671-6. [PMID: 12079564 DOI: 10.1089/088922202760019383] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Human endogenous retroviruses (HERVs) are estimated to represent at least 1% of the human genome. An HERV-H env SU sequence (HERV-H19) was used to screen the high-throughput (htgs) and nonredundant (nr) databases for other HERV-H SU open reading frames (ORFs) and thus possible functional proteins. Using PCR with primers derived from HERV-H19 SU, we also obtained several new sequences with ORFs from a human DNA sample. In a phylogenetic analysis, ORF-containing sequences clustered with HERV-H sequences from chromosomes 1 and 2. SU ORF- and non-SU ORF-containing elements had about the same difference between 5' and 3' long terminal repeats (LTRs) (about 4%), indicating a similar time of integration. SU ORF sequences had a moderately high number of synonymous-versus-nonsynonymous mutations, which indicates a selection for maintenance of the HERV-H SU ORFs.
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Affiliation(s)
- Patric Jern
- Section of Virology, Department of Medical Science, Uppsala University, SE-751 85 Uppsala, Sweden.
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Andersson AC, Venables PJW, Tönjes RR, Scherer J, Eriksson L, Larsson E. Developmental expression of HERV-R (ERV3) and HERV-K in human tissue. Virology 2002; 297:220-5. [PMID: 12083821 DOI: 10.1006/viro.2002.1428] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The human endogenous retroviruses (HERVs), ERV3 (HERV-R) and HERV-K, are both known to be transcriptionally active in human placenta. In the case of ERV3 there is also indirect evidence for its participation in cellular differentiation. In this study we examined the expression of ERV3 (HERV-R) and HERV-K in human normal fetal tissues by in situ hybridization. The highest level of ERV3 env expression was detected in primitive adrenal cortex. Elevated levels of expression were also found in the following developing tissues: kidneys (tubules), tongue, heart, liver, and central nervous system. Tissue-specific expression was found for HERV-K rec (former cORF) but not for pol/int transcripts. The highest rec expression was found in placenta and levels slightly higher than sense control were found in the rest of the tissues examined. Pol/Int was not possible to quantitate. It appears that ERV3 is expressed in an organ-specific way during embryogenesis and might suggest a possible role in the development and differentiation of human tissues.
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Yi JM, Lee WH, Kim HM, Kim HS. Identification of new endogenous retroviral sequences belonging to the HERV-W family in human cancer cells. Intervirology 2002; 44:333-8. [PMID: 11805438 DOI: 10.1159/000050067] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
A human endogenous retroviral family (HERV-W) has recently been identified on chromosome 7 that contains a single complete open reading frame putatively encoding an envelope protein. We have identified fifteen HERV-W families on human genomic DNA using a monochromosomal panel in our previous study. In order to identify additional families, we examined genomic DNA derived from cancer cell lines (A549, AZ521, OVCAR3, RT4) using the PCR approach. Five env fragments of a HERV-W family were newly identified and analyzed. They showed a high degree of nucleotide sequence similarity (93-97%) to that of the other HERV-W families. Translation of the env fragments showed no frameshift and termination codon by deletion/insertion or point mutation in clones A549-2, AZ521-3, and OVCAR-3. The ratio of synonymous to nonsynonymous substitutions indicated that negative selective pressure is acting on A549-2, AZ521-3, and OVCAR-3 sequences. These env gene sequences could be associated with an active provirus in human cancer cells (A549, AZ521, OVCAR3).
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Affiliation(s)
- J M Yi
- Division of Biological Sciences, College of Natural Sciences, Pusan National University, Pusan, Korea
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39
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Deb-Rinker P, O'Reilly RL, Torrey EF, Singh SM. Molecular characterization of a 2.7-kb, 12q13-specific, retroviral-related sequence isolated by RDA from monozygotic twin pairs discordant for schizophrenia. Genome 2002; 45:381-90. [PMID: 11962635 DOI: 10.1139/g01-152] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
This report deals with the molecular characterization of a representational difference analysis (RDA)-derived sequence (SZRV-2, GenBank accession No. AF135486; Genome Database accession Nos. 7692183 and 7501402) from three monozygotic twin pairs discordant for schizophrenia (MZD). The results suggest that it is a primate-specific, heavily methylated, and placentally expressed (-7-kb mRNA) endogenous retroviral-related (ERV) sequence of the human genome. We have mapped this sequence to 12q13 using two SZRV-2 positive BAC clones (4K11 (Genome Survey Sequence Database No. 1752076; GenBank accession No. AZ301773) and 501H16) by fluorescence in situ hybridization. End sequencing of the 4K11 BAC clone has allowed identification of nearby genes from the human genome database at NCBI that may be of interest in schizophrenia research. These include viral-related sequences (potential hot spots for insertions), developmental, channel, and signal transduction genes, as well as genes affecting expression of certain receptors in neurons. Furthermore, when used as a probe on Southern blots, SZRV-2 detected no difference between schizophrenia patients from southwestern Ontario and their matched controls. However, it identified aberrant methylation in one of the eight patients and none of the 21 unaffected controls. Although additional experiments will be required to establish the significance, if any, of SZRV-2 methylation in the complex etiology of schizophrenia, molecular results included offer a novel insight into the role of retroviral-related sequences in the origin, organization, and regulation of the human genome.
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Affiliation(s)
- Paromita Deb-Rinker
- Department of Zoology and Division of Medical Genetics, The University of Western Ontario, London, Canada
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40
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41
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Torrey EF, Yolken RH. The schizophrenia-rheumatoid arthritis connection: infectious, immune, or both? Brain Behav Immun 2001; 15:401-10. [PMID: 11782106 DOI: 10.1006/brbi.2001.0649] [Citation(s) in RCA: 89] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Schizophrenia and rheumatoid arthritis share an impressive number of similarities. Both are chronic, relapsing diseases of unknown etiology. Both became prominent in the early 19th century and have prevalences of approximately 1% in North America and Europe. Both run in families, have pairwise concordance rates of approximately 30% among monozygotic twins, and are more common among individuals born in urban areas. For both diseases, studies have reported greater exposure to cats in childhood than in controls. Both diseases have been associated with similar class II HLA antigens. Both have also been suspected of having infectious etiology, with similar agents--retroviruses, herpesviruses including EBV, and Toxoplasma gondii--having been associated in some cases. Since there is also a well-documented inverse correlation between these two diseases, it is possible that they share a common infectious and/or immune etiology and that once a person gets one of the diseases then they are relatively immune to the other.
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Affiliation(s)
- E F Torrey
- Stanley Foundation and Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799, USA
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42
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Abstract
A new human endogenous retroviral family (HERV-W) has been described that is related to multiple sclerosis-associated retrovirus (MSRV) sequences that have been identified in particles recovered from monocyte cultures from patients with multiple sclerosis. Using the PCR approach with a human monochromosomal somatic cell hybrid DNA panel, 24 pol fragments of the HERV-W family from chromsomes 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 20, 21, X, and Y were identified and analyzed. They showed a high degree of nucleotide sequence similarity (89.3-91.3%) with that of the HERV-W. Translation of the pol fragments showed no frameshift and termination codon by deletion/insertion or point mutation in some clones: HWP4-1, HWP4-2 from chromosome 4, and HWPX-1 from chromosome X. Phylogenetic analysis of the HERV-W family indicates that the pol fragments have evolved independently among chromosomes or represent separate integration events during primate evolution.
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Affiliation(s)
- H S Kim
- Division of Biological Sciences, College of Natural Sciences, Pusan National University, Pusan 609-735, South Korea.
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Kim HS, Lee WH. Human endogenous retrovirus HERV-W family: chromosomal localization, identification, and phylogeny. AIDS Res Hum Retroviruses 2001; 17:643-8. [PMID: 11375061 DOI: 10.1089/088922201300119752] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
A new human endogenous retroviral family (HERV-W) has been described that is related to multiple sclerosis-associated retrovirus sequences that have been identified in particles recovered from monocyte cultures from patients with multiple sclerosis. Using the polymerase chain reaction approach with a human monochromosomal somatic cell hybrid DNA panel, 15 env fragments of the HERV-W family from chromosomes 1, 3, 4, 5, 6, 7, 12, 14, 17, 20, and X were identified and analyzed. These env fragments showed a high degree of nucleotide sequence similarity (91.6-99.6%) to that of HERV-W. Translation of the env fragments showed no frameshift and termination codons by deletion/insertion or point mutation in some clones (W-1-1, W-3-8, W-4-1, W-7-1, W-14-1, W-17-5, W-20-9, and W-X-3). Phylogenetic analysis of the HERV-W family indicates that the HERV-W env fragments divided into five groups through evolutionary divergence in the primate genome. In group IV, a clone (W-12-2) on chromosome 12 shared 100% sequence identity with a clone (W-17-5) on chromosome 17, suggesting either a retrotransposition or a chromosomal translocation in the last 2 to 5 million years.
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Affiliation(s)
- H S Kim
- Division of Biological Sciences, College of Natural Sciences, Pusan National University, Pusan 609-735, South Korea.
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Karlsson H, Bachmann S, Schröder J, McArthur J, Torrey EF, Yolken RH. Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia. Proc Natl Acad Sci U S A 2001; 98:4634-9. [PMID: 11296294 PMCID: PMC31886 DOI: 10.1073/pnas.061021998] [Citation(s) in RCA: 247] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Schizophrenia is a serious brain disease of uncertain etiology. A role for retroviruses in the etiopathogenesis of some cases of schizophrenia has been postulated on the basis of clinical and epidemiological observations. We found sequences homologous to retroviral pol genes in the cell-free cerebrospinal fluids (CSFs) of 10 of 35 (29%) individuals with recent-onset schizophrenia or schizoaffective disorder. Retroviral sequences also were identified in the CSFs of 1 of 20 individuals with chronic schizophrenia. However, retroviral sequences were not identified in any of the CSFs obtained from 22 individuals with noninflammatory neurological diseases or from 30 individuals without evidence of neurological or psychiatric diseases (chi(2) = 19.25, P < 0.001). The nucleotide sequences identified in the CSFs of the individuals with schizophrenia or schizoaffective disorder were related to those of the human endogenous retroviral (HERV)-W family of endogenous retroviruses and to other retroviruses in the murine leukemia virus genus. Transcription of RNA homologous to members of the HERV-W family of retroviruses also was found to be up-regulated differentially in the frontal cortex regions of brains obtained postmortem from individuals with schizophrenia, as compared with corresponding tissue from individuals without psychiatric diseases. The transcriptional activation of certain retroviral elements within the central nervous system may be associated with the development of schizophrenia in at least some individuals. The further characterization of retroviral elements within the central nervous system of individuals with schizophrenia might lead to improved methods for the diagnosis and management of this disorder.
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Affiliation(s)
- H Karlsson
- Stanley Division of Developmental Neurovirology, Department of Pediatrics, and Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
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Lawoko A, Johansson B, Rabinayaran D, Pipkorn R, Blomberg J. Increased immunoglobulin G, but not M, binding to endogenous retroviral antigens in HIV-1 infected persons. J Med Virol 2000; 62:435-44. [PMID: 11074471 DOI: 10.1002/1096-9071(200012)62:4<435::aid-jmv7>3.0.co;2-r] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The modes of interaction between products of human endogenous retroviral (HERV) sequences and the immune system are largely unknown. In HIV infected persons, an exogenous retrovirus adds further complexity to the situation. Therefore, 14 synthetic peptides with sequences derived from conserved regions of various endogenous retroviruses (ERVs) and from related exogenous retroviruses were used to search for IgG and IgM antibodies that bind to such antigens in 15 HIV-1 seropositive and 17 seronegative immunosuppressed patients. IgG binding to three peptides, namely, the C-terminal half of murine leukemia virus (MLV) capsid protein, the conserved portion of HERV-H transmembrane protein, and the Pol region of human mouse mammary tumor virus (MMTV)-like (HML3) sequence, was observed in both groups. Binding was, however, more frequent and more firm in HIV-1 positive samples (P<0.0001, Wilcoxon rank sum test). IgM binding to the same peptides showed no significant differentiation between the two groups of patients. Binding to both immunoglobulin isotypes was sometimes variable over time in both groups. No correlation of either IgG or IgM peptide binding with progression to AIDS in HIV-1 infected individuals was observed. Inhibition studies using analogous endogenous and exogenous retroviral peptides, including HIV-1, demonstrated specificity of the IgG antibodies for a narrow range of MLV- and MMTV-like retroviral antigens, and excluded cross-reactivity of antibodies to HIV-1 as a cause of these observations. Thus, unlike IgG, IgM binding to retroviral antigens was ubiquitous. It is suggested that anti-HERV IgM belong to a class of natural antibodies and might serve as primers in the mediation of humoral immune responses to more or less related exogenous retroviruses. Increased IgG binding in HIV-1 infected individuals could result from such priming, or reflect higher HERV antigen expression.
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Affiliation(s)
- A Lawoko
- Department of Medical Sciences, Section of Virology, Uppsala Academic Hospital, Uppsala, Sweden.
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