The Significance of Polymorphic Endogenous Retroviruses to Human Mental Health

多态性内源性逆转录病毒对人类心理健康的意义

• 批准号: 7906702
• 负责人: Julia Vera Halo
• 金额: $ 4.14万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906702
• 关键词: Affect; Age; Betaretrovirus; Brain Diseases; Cells; Cloning; Code; DNA; Diagnosis; Disease; Endogenous Retroviruses; Evolution; Genes; Genetic; Genetic Polymorphism; Genomics; Germ Cells; Goals; HERVs; Hominidae; Human; Incidence; Individual; Inherited; Knowledge; Link; Mental Health; Mental disorders; Methods; Modeling; Mutation; National Institute of Mental Health; Open Reading Frames; Patients; Population; Prevention strategy; Proviruses; Retroviridae; Sampling; Schizophrenia; Screening procedure; Site; Techniques; Transcript; United States; Viral; Virus; base; brain tissue; cost; disease diagnosis; genetic association; genetic linkage; genetic linkage analysis; human DNA; novel; particle

DESCRIPTION (provided by applicant): Human endogenous retroviruses (HERVs) result from the integration of retroviral DMA into germ cells. The HERV-K(HML-2) proviruses represent the most recently integrated HERV group. Although most are defective, HML-2 proviruses with intact open reading frames in some or all genes exist. HML-2 have been under purifying selection, suggesting reinfection, and their insertion rate appears constant during hominid evolution. HML-2 expression has been associated with brain disorders, particularly schizophrenia, by the presence of viral particles, genomic RNA, or transcripts. The consequences of HERV expression in human brain tissue are poorly understood. We hypothesize the existence of an replication competent HML-2 provirus whose expression has negative genetic effects on nearby cells. Although infectious viruses could potentially be generated from multiple loci in trans, an intact provirus could alone produce infectious virus, the most likely candidates for which are very recent insertions. We propose to identify novel HML-2 polymorphic insertions in humans using a combination of blotting, PCR, cloning, and sequencing. The incidence of each newly identified HML-2 provirus and disease will be analyzed in a high-throughput PCR screening of human DNA samples. Finally, we will look for HML-2 insertions in DNA extracted from schizophrenia-associated brain tissue against age-matched controls using blotting and PCR techniques. New, clonal HML-2 insertions detected in such an analysis would provide strong evidence of an expressed, replication competent HML-2 provirus. Close proximity of a new integration to a host coding region will be considered as preliminary evidence for a model of transcriptional alteration, and would provide the basis for further studies. An inherited HML-2 provirus with a significant incidence in patients with schizophrenia would be an important discovery. This knowledge would affect not only the diagnosis of the disease, but strategies for prevention and treatment could be adjusted appropriately as an alternative to current methods. Schizophrenia currently affects about one percent of the United States population and costs the public nearly $100 billion each year (National Institutes of Mental Health). Recently integrated proviruses may be genetically linked to this mental disorder through the expression of inherited endogenous loci, the most likely of which belong to the HERV-K(HML-2) group of retroviruses. The goal of this proposal is to clarify the relationship between HML-2 expression and schizophrenia by either establishing a genetic linkage of an inherited provirus with the disorder, or demonstrating the presence of novel proviruses in brain tissue from the patients diagnosed with schizophrenia versus age-matched controls.

描述（由申请人提供）： 人内源性逆转录病毒 (HERV) 由逆转录病毒 DMA 整合到生殖细胞中产生。 HERV-K(HML-2) 原病毒代表最近整合的 HERV 组。尽管大多数都有缺陷，但在部分或全部基因中具有完整开放阅读框的 HML-2 原病毒仍然存在。 HML-2 一直处于纯化选择之下，表明发生了再感染，并且它们的插入率在原始人类进化过程中似乎是恒定的。 HML-2 表达因病毒颗粒、基因组 RNA 或转录本的存在而与脑部疾病（尤其是精神分裂症）相关。人们对 HERV 在人类脑组织中表达的后果知之甚少。我们假设存在具有复制能力的 HML-2 原病毒，其表达对附近细胞具有负面遗传影响。尽管传染性病毒可能由多个基因座反式产生，但完整的原病毒可以单独产生传染性病毒，最有可能的候选者是最近插入的病毒。我们建议结合印迹、PCR、克隆和测序来鉴定人类体内新的 HML-2 多态性插入。每种新发现的 HML-2 原病毒和疾病的发病率将通过人类 DNA 样本的高通量 PCR 筛查进行分析。最后，我们将使用印迹和 PCR 技术，与年龄匹配的对照相比，从精神分裂症相关脑组织中提取的 DNA 中寻找 HML-2 插入。在此类分析中检测到的新克隆 HML-2 插入将为表达的、具有复制能力的 HML-2 原病毒提供强有力的证据。新整合与宿主编码区的紧密接近将被视为转录改变模型的初步证据，并将为进一步研究提供基础。在精神分裂症患者中发病率显着的遗传性 HML-2 原病毒将是一个重要的发现。这些知识不仅会影响疾病的诊断，而且可以适当调整预防和治疗策略，作为当前方法的替代方案。目前，精神分裂症影响着大约 1% 的美国人口，每年给公众造成近 1000 亿美元的损失（美国国家心理健康研究所）。最近整合的原病毒可能通过遗传性内源基因座的表达与这种精神障碍存在遗传联系，其中最有可能属于逆转录病毒的 HERV-K(HML-2) 组。该提案的目的是通过建立遗传性原病毒与精神分裂症之间的遗传联系，或证明精神分裂症患者与年龄组患者的脑组织中存在新型原病毒，从而阐明 HML-2 表达与精神分裂症之间的关系。匹配的控件。