Transposon Insertion Polymorphisms in Predispositions to Hematopoietic Neoplasia

描述(申请人提供)：我们的基因组主要由重复的‘垃圾DNA’组成，这些重复的‘垃圾DNA’是通过RNA中间体插入序列而来的。我们的团队已经开发出方法来识别这些未被研究的序列的多态插入，证明它们是我们基因组结构变化的主要来源，并发现它们经常出现在LD中，并且癌症基因组广泛关联研究(GWAS)发现了与特征相关的SNPs。其他人的实验和对移动DNA在我们基因组中的非随机分布的表征表明，它们具有显著的影响基因功能的潜力。这一建议的主要假设是，常见的移动DNA插入的子集容易导致常见癌症的发生。我们检验这一假设的三部分方法将包括：(I)(2)通过定位GWAS所涉及的疾病风险区域附近的RIPs，确定在肿瘤形成中具有潜在作用的RIPs；通过分析临床样本中的区域连锁和RIP基因，确定哪些RIP基因可以合理地解释癌症风险；以及(Iii)研究转座子多态对转录表达水平和结构的影响。血液系统恶性肿瘤将在这些研究中得到特别重视，来自白血病、淋巴瘤和相关疾病患者的临床样本将用于定向RIP发现工作和评估基因表达效应的机制。

DESCRIPTION (provided by applicant): Our genomes are mostly made up of repetitive 'junk DNA' derived from insertions of sequences through RNA intermediates. 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 LD with trait associated SNPs identified by cancer genome wide association study (GWAS). Experiments by others and characterizations of the non-random distribution of mobile DNAs in our genome indicate they have significant potential to effect gene function. The overarching hypothesis of this proposal is that a subset of common mobile DNA insertions predispose to common cancer development. Our three part approach to test this hypothesis will include: (i.) identification of RIPs with potential roles in neoplasia by locating those in the vicnity of regions implicated in disease risk by GWAS; (ii.) determining which of these RIPs may reasonably account for cancer risk by analyses of area linkage and RIP genotype imputing in clinical samples; and (iii.) investigating effects of transposon polymorphisms on transcript expression levels and structure. Hematopoietic malignancies will receive special priority in these studies, and clinical samples from patients with leukemias, lymphomas, and related disordered will be used for a directed RIP discovery effort and for evaluating mechanisms of gene expression effects.