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.
The purpose of the proposed studies is to test the hypothesis that inherited retrotransposon insertion polymorphisms (RIPs) predispose carriers to neoplasias. We will discover potentially relevant RIPs, ascertain which candidates associate with disease risk as appreciated by genome-wide association studies (GWAS), and determine the biologic basis of such effects by gene expression studies.
|Zampella, John G; RodiÄ‡, Nemanja; Yang, Wan Rou et al. (2016) A map of mobile DNA insertions in the NCI-60 human cancer cell panel. Mob DNA 7:20|
|Achanta, Pragathi; Steranka, Jared P; Tang, Zuojian et al. (2016) Somatic retrotransposition is infrequent in glioblastomas. Mob DNA 7:22|
|Sharma, Reema; RodiÄ‡, Nemanja; Burns, Kathleen H et al. (2016) Immunodetection of Human LINE-1 Expression in Cultured Cells and Human Tissues. Methods Mol Biol 1400:261-80|
|Taylor, Martin S; LaCava, John; Dai, Lixin et al. (2016) Characterization of L1-Ribonucleoprotein Particles. Methods Mol Biol 1400:311-38|
|Doucet-O'Hare, Tara T; RodiÄ‡, Nemanja; Sharma, Reema et al. (2015) LINE-1 expression and retrotransposition in Barrett's esophagus and esophageal carcinoma. Proc Natl Acad Sci U S A 112:E4894-900|
|RodiÄ‡, Nemanja; Steranka, Jared P; Makohon-Moore, Alvin et al. (2015) Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma. Nat Med 21:1060-4|
|RodiÄ‡, Nemanja; Sharma, Reema; Sharma, Rajni et al. (2014) Long interspersed element-1 protein expression is a hallmark of many human cancers. Am J Pathol 184:1280-6|
|Halper-Stromberg, Eitan; Steranka, Jared; Burns, Kathleen H et al. (2014) Visualization and probability-based scoring of structural variants within repetitive sequences. Bioinformatics 30:1514-21|
|RodiÄ‡, Nemanja; Zampella, John G; Cornish, Toby C et al. (2013) Translocation junctions in TCF3-PBX1 acute lymphoblastic leukemia/lymphoma cluster near transposable elements. Mob DNA 4:22|
|Gnanakkan, Veena P; Jaffe, Andrew E; Dai, Lixin et al. (2013) TE-array--a high throughput tool to study transposon transcription. BMC Genomics 14:869|
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