Mouse Models of Functional Insertion Polymorphisms

功能插入多态性的小鼠模型

• 批准号: 8423827
• 负责人: KATHLEEN H BURNS
• 金额: $ 28.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-02 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423827
• 关键词: ARID Domain; Acute Lymphocytic Leukemia; Affect; Aldosterone; Alleles; Angiotensins; B-Cell Acute Lymphoblastic Leukemia; B-Cell Development; B-Lymphocytes; Binding; Biomedical Research; Blood Pressure; Blood Vessels; Bradykinin; Chromatin Structure; Chromosomes, Artificial, Yeast; Clinical; Cloning; DNA Transposable Elements; Development; Diagnosis; Disease; Early Diagnosis; Elements; Enzyme Gene; Enzymes; Feasibility Studies; Functional RNA; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genotype; Goals; Haplotypes; Homeostasis; Human; Human Genetics; Inherited; Introns; Junk DNA; Knowledge; Laboratories; Link; Linkage Disequilibrium; Malignant Childhood Neoplasm; Marrow; Measures; Methods; Modeling; Molecular Biology; Mus; Nucleotides; Other Genetics; Pathogenesis; Patients; Peptidyl-Dipeptidase A; Phase; Phenotype; Physiological; Positioning Attribute; Prevention; Proteins; Renin; Research Design; Research Personnel; Resources; Risk; Role; Serum; Signal Transduction; Source; Study models; System; Testing; Transcript; Transgenes; Transgenic Mice; Variant; Work; base; blood pressure regulation; clinical assay development; disorder risk; enzyme activity; experience; follow-up; gene function; genetic variant; genome wide association study; human disease; in vivo; innovation; mRNA Expression; mouse model; prototype; public health relevance; research study; synthetic biology; trait; transcription factor; transposon/insertion element; yeast genetics

DESCRIPTION (provided by applicant): Our genomes are mostly made up of repetitive 'junk DNA' derived from insertions of mobile elements. Our group has developed methods to identify polymorphic insertions of these understudied sequences, demonstrated they are major sources of structural variation our genome, and found they occur frequently in linkage disequilibrium with trait associated SNPs identified by GWAS. Experiments by others and characterizations of the non-random distribution of mobile DNAs in genomes indicate they have significant potential to effect gene function. Our overarching hypothesis is that a subset of Alu insertions - the most prevalent and polymorphic mobile DNAs in humans - has phenotypic consequence. Our specific objectives are to isolate and characterize the effects of two polymorphic Alu insertions in allelogenic transgenic mouse models. The first insertion polymorphism to be studied is an intronic Alu 287bp in the angiotensin converting enzyme (ACE) gene locus. ACE encodes a key component of the renin-angiotensin-aldosterone blood pressure control system and is also involved in vascular homeostasis through degradation of bradykinin; the Alu is a well-studied marker of reduced ACE enzyme levels and presumed to be functional, although this has not been directly tested. The second polymorphism we propose to study is a 168bp intronic Alu insertion in the AT-rich interactive domain-containing protein 5B (ARID5B) locus. We recently associated this polymorphic Alu with risk for developing the most common childhood cancer, precursor B-cell acute lymphoblastic leukemia (ALL). The proposed studies will be the first to isolate and measure effects common, naturally-occurring TE insertion polymorphisms in vivo and to generate models to study mechanisms of these effects. More broadly, the work will provide a study design for mouse modeling in GWAS follow-up and begin work to make available an allelogenic YAC resource for studying functions of other Alu insertions.

描述（由申请人提供）：我们的基因组主要由源自移动元件插入的重复“垃圾DNA”组成。我们的小组开发了方法来识别这些待研究序列的多态性插入，证明它们是我们基因组结构变异的主要来源，并发现它们经常与 GWAS 识别的性状相关 SNP 发生连锁不平衡。其他人的实验以及基因组中移动 DNA 非随机分布的表征表明，它们具有影响基因功能的巨大潜力。我们的首要假设是 Alu 插入的一个子集——人类中最普遍和多态性的可移动 DNA——具有表型后果。我们的具体目标是分离和表征两个多态性 Alu 插入在异体转基因小鼠模型中的影响。第一个要研究的插入多态性是血管紧张素转换酶 (ACE) 基因座中的内含子 Alu 287bp。 ACE 编码肾素-血管紧张素-醛固酮血压控制系统的关键组成部分，并且还通过缓激肽的降解参与血管稳态； Alu 是经过充分研究的 ACE 酶水平降低的标志物，并且被认为具有功能，尽管尚未经过直接测试。我们建议研究的第二个多态性是在富含 AT 的相互作用域蛋白 5B (ARID5B) 基因座中插入 168bp 的内含子 Alu。我们最近将这种多态性 Alu 与罹患最常见的儿童癌症——前体 B 细胞急性淋巴细胞白血病 (ALL) 的风险联系起来。拟议的研究将首次分离和测量体内常见的、自然发生的 TE 插入多态性的影响，并生成模型来研究这些影响的机制。更广泛地说，这项工作将为 GWAS 随访中的小鼠建模提供研究设计，并开始为研究其他 Alu 插入的功能提供等位基因 YAC 资源。