Mouse Models of Functional Insertion Polymorphisms

描述（由申请人提供）：我们的基因组主要由来自移动元件插入的重复“垃圾DNA”组成。我们的团队已经开发出方法来鉴定这些未被研究的序列的多态性插入，证明它们是我们基因组结构变异的主要来源，并发现它们经常发生在与GWAS鉴定的性状相关snp的连锁不平衡中。其他人的实验和基因组中移动dna的非随机分布的特征表明，它们具有显著的影响基因功能的潜力。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移动dna -具有表型后果。我们的具体目标是在等位基因转基因小鼠模型中分离和表征两个多态Alu插入的影响。第一个被研究的插入多态性是血管紧张素转换酶（ACE）基因位点上的一个内含子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，并通过降解缓激素参与血管稳态；Alu是一种研究充分的ACE酶水平降低的标记物，被认为是有功能的，尽管还没有直接测试。我们建议研究的第二个多态性是在富含at的相互作用结构域蛋白5B （ARID5B）位点上的168bp内含子Alu插入。我们最近将这种多态Alu与发生最常见的儿童癌症，前体b细胞急性淋巴细胞白血病（ALL）的风险联系起来。拟议的研究将是第一个分离和测量体内常见的、自然发生的TE插入多态性的影响，并建立模型来研究这些影响的机制。更广泛地说，这项工作将为GWAS后续小鼠建模提供研究设计，并开始为研究其他Alu插入的功能提供易感基因YAC资源。

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.