Transposon Insertion Polymorphisms in Predispositions to Hematopoietic Neoplasia

描述（由申请人提供）：我们的基因组主要由重复的“垃圾DNA”组成，这些DNA来自于通过RNA中间体插入的序列。我们的研究小组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LD中，与癌症基因组广泛关联研究（GWAS）发现的性状相关snp相关。其他人的实验和我们基因组中移动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。这一提议的首要假设是，常见的移动DNA插入的一个子集易导致常见的癌症发展。我们测试这一假设的三部分方法将包括：(i)通过定位与GWAS有关的疾病风险区域附近的rip，确定在肿瘤中具有潜在作用的rip；（ii）通过分析临床样本中的区域连锁和RIP基因型输入，确定哪些RIP可能合理地解释癌症风险；（iii）研究转座子多态性对转录物表达水平和结构的影响。造血恶性肿瘤将在这些研究中得到特别优先考虑，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.