COMPUTATIONAL ANALYSIS OF HUMAN 'AT-RISK' DNA MOTIFS

人类“高危”DNA 基序的计算分析

• 批准号: 6133321
• 负责人: JUDITH E. STENGER
• 金额: $ 10.46万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6133321
• 关键词: environmental health; environmental toxicology; gene environment interaction; gene expression; gene rearrangement; genetic susceptibility; human genetic material tag; molecular biology information system; nucleic acid repetitive sequence; nucleic acid sequence; environmental health; environmental toxicology; gene environment interaction; gene expression; gene rearrangement; genetic susceptibility; human genetic material tag; molecular biology information system; nucleic acid repetitive sequence; nucleic acid sequence

DESCRIPTION (Taken from the Candidate's Abstract) At-Risk DNA Motifs (ARMS), which include repetitive elements such as Alu sequences, homonucleotide runs and triplet repeats, are potentially unstable segments of the human genome. ARMS are a factor in genetic susceptibility to disease, requiring particular combinations of genetic backgrounds and environmental triggers to express a disease phenotype. While some of the mechanisms are understood, it is not clear under what circumstances repetitive DNA elements mediate pathological mutagenesis. Although a high burden of these sequences is generally tolerated in humans, they can have an enormous impact on health by contributing to diseases that have devastating effects on afflicted individuals. For example, Alus have been linked to numerous diseases including Fanconi anemia, alphazerothalassemia, leukemia, hypertension, neurofibromatosis, breast, and colon cancers. Trinucleotide repeat expansions have been linked with Kennedy's Disease, Huntington's Disease, myotonic muscular dystrophy, and Friedreich ataxia. The long term objective of this proposal is to gain insight into the genetic factors that mitigate gene rearrangement in hopes of predicting when the presence of a repetitive element truly constitutes a threat to the health of an individual. The hypothesis is that the characterization of ARMS according to all possible attributes (i.e. size of repeats, separation distances between repeats, orientation, sequence similarity between repeats, nucleotide base constitution and proximity and/or containment of mutagenic and/or toxicological agent targets, DNA processive or other enzymatic target sites) can reveal largely excluded situations that can be viewed as unstable. It is also postulated that a multidimensional database of repetitive sequences characterized according to the aforementioned attributes can be used to predict repetitive elements that are most prone to mutation, ARMS, while increasing our understanding of the interactions between these genetic elements and their environment. The approach is to use a combination of computational biology and molecular genomic analysis to locate and analyze ARMS. The specific aims of this proposal are to: 1) characterize available data according to the conceivable relevant attributes of size, distance, orientation, degree of homology, base constitution and containment of known target sequences. 2) To test the hypothesis by computationally identifying loci that have already known to contain ARMS linked to a mutation resulting in disease, and then to identify specific genes that may be at-risk for mutation and experimentally testing them using molecular biological approaches. 3) To set up an interactive on-line database and program server so that the scientific community can use the information and apply it to drive experimental research.

描述（取自候选人的摘要） 高危DNA图案（臂），其中包括重复的元素，例如Alu 序列，同核苷酸运行和三重重复重复，可能是不稳定的 人类基因组的片段。 手臂是遗传易感性的因素 疾病，需要特殊的遗传背景和 环境触发表达疾病表型。 虽然有些 理解机制，在什么情况下尚不清楚重复 DNA元素介导病理诱变。 虽然很大的负担 这些序列通常在人类中耐受性，它们可以具有巨大的 对对健康产生造成毁灭性影响的疾病的影响 受苦的人。 例如，Alus已与许多 包括法科诺尼贫血，字母催眠药，白血病，包括疾病 高血压，神经纤维瘤病，乳腺癌和结肠癌。 三核苷酸 重复扩张与肯尼迪氏病，亨廷顿的 疾病，肌肉发育不全和弗里德里希共济失调。 长期 该提议的目的是了解遗传因素 减轻基因重排，以期预测何时存在 重复元素真正构成了个人健康的威胁。 假设是武器根据所有可能的表征 属性（即重复尺寸，重复之间的分离距离， 方向，重复序列之间的序列相似性，核苷酸碱基构造 以及诱变和/或毒理学剂的接近和/或遏制 靶标，DNA处理或其他酶促靶位点）可以在很大程度上揭示 排除的情况可以看作是不稳定的。 还假设 重复序列的多维数据库表征 根据上述属性可用于预测重复 最容易突变，武器的元素，同时增加我们的 了解这些遗传元素及其之间的相互作用 环境。 方法是结合计算生物学 和分子基因组分析以定位和分析臂。 具体目标 该建议的内容是：1）根据可用数据来表征 可以想象的大小，距离，方向，程度的相关属性 同源性，基础构成和已知目标序列的遏制。 2）到 通过计算识别已经识别的基因座来检验假设 已知包含与导致疾病的突变相关的臂，然后 确定可能处于突变和实验的可能处于危险的基因 使用分子生物学方法对其进行测试。 3）设置 交互式在线数据库和程序服务器，因此科学 社区可以使用该信息并将其应用于推动实验研究。