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Description
Genomic structural variation (SV) is defined as gross alterations in the genome broadly classified as insertions/duplications, deletions inversions and translocations. DNA sequencing ushered structural variant discovery beyond laboratory detection techniques to high resolution informatics approaches. Bioinformatics tools for computational discovery of SVs however are still missing variants in the complex

Genomic structural variation (SV) is defined as gross alterations in the genome broadly classified as insertions/duplications, deletions inversions and translocations. DNA sequencing ushered structural variant discovery beyond laboratory detection techniques to high resolution informatics approaches. Bioinformatics tools for computational discovery of SVs however are still missing variants in the complex cancer genome. This study aimed to define genomic context leading to tool failure and design novel algorithm addressing this context. Methods: The study tested the widely held but unproven hypothesis that tools fail to detect variants which lie in repeat regions. Publicly available 1000-Genomes dataset with experimentally validated variants was tested with SVDetect-tool for presence of true positives (TP) SVs versus false negative (FN) SVs, expecting that FNs would be overrepresented in repeat regions. Further, the novel algorithm designed to informatically capture the biological etiology of translocations (non-allelic homologous recombination and 3&ndashD; placement of chromosomes in cells –context) was tested using simulated dataset. Translocations were created in known translocation hotspots and the novel&ndashalgorithm; tool compared with SVDetect and BreakDancer. Results: 53% of false negative (FN) deletions were within repeat structure compared to 81% true positive (TP) deletions. Similarly, 33% FN insertions versus 42% TP, 26% FN duplication versus 57% TP and 54% FN novel sequences versus 62% TP were within repeats. Repeat structure was not driving the tool's inability to detect variants and could not be used as context. The novel algorithm with a redefined context, when tested against SVDetect and BreakDancer was able to detect 10/10 simulated translocations with 30X coverage dataset and 100% allele frequency, while SVDetect captured 4/10 and BreakDancer detected 6/10. For 15X coverage dataset with 100% allele frequency, novel algorithm was able to detect all ten translocations albeit with fewer reads supporting the same. BreakDancer detected 4/10 and SVDetect detected 2/10 Conclusion: This study showed that presence of repetitive elements in general within a structural variant did not influence the tool's ability to capture it. This context-based algorithm proved better than current tools even with half the genome coverage than accepted protocol and provides an important first step for novel translocation discovery in cancer genome.
ContributorsShetty, Sheetal (Author) / Dinu, Valentin (Thesis advisor) / Bussey, Kimberly (Committee member) / Scotch, Matthew (Committee member) / Wallstrom, Garrick (Committee member) / Arizona State University (Publisher)
Created2014
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Description
The processes of a human somatic cell are very complex with various genetic mechanisms governing its fate. Such cells undergo various genetic mutations, which translate to the genetic aberrations that we see in cancer. There are more than 100 types of cancer, each having many more subtypes with aberrations being

The processes of a human somatic cell are very complex with various genetic mechanisms governing its fate. Such cells undergo various genetic mutations, which translate to the genetic aberrations that we see in cancer. There are more than 100 types of cancer, each having many more subtypes with aberrations being unique to each. In the past two decades, the widespread application of high-throughput genomic technologies, such as micro-arrays and next-generation sequencing, has led to the revelation of many such aberrations. Known types and subtypes can be readily identified using gene-expression profiling and more importantly, high-throughput genomic datasets have helped identify novel sub-types with distinct signatures. Recent studies showing usage of gene-expression profiling in clinical decision making in breast cancer patients underscore the utility of high-throughput datasets. Beyond prognosis, understanding the underlying cellular processes is essential for effective cancer treatment. Various high-throughput techniques are now available to look at a particular aspect of a genetic mechanism in cancer tissue. To look at these mechanisms individually is akin to looking at a broken watch; taking apart each of its parts, looking at them individually and finally making a list of all the faulty ones. Integrative approaches are needed to transform one-dimensional cancer signatures into multi-dimensional interaction and regulatory networks, consequently bettering our understanding of cellular processes in cancer. Here, I attempt to (i) address ways to effectively identify high quality variants when multiple assays on the same sample samples are available through two novel tools, snpSniffer and NGSPE; (ii) glean new biological insight into multiple myeloma through two novel integrative analysis approaches making use of disparate high-throughput datasets. While these methods focus on multiple myeloma datasets, the informatics approaches are applicable to all cancer datasets and will thus help advance cancer genomics.
ContributorsYellapantula, Venkata (Author) / Dinu, Valentin (Thesis advisor) / Scotch, Matthew (Committee member) / Wallstrom, Garrick (Committee member) / Keats, Jonathan (Committee member) / Arizona State University (Publisher)
Created2014
ContributorsMendoza, Daniel (Author) / Grando, Adela (Thesis director) / Scotch, Matthew (Committee member) / Barrett, The Honors College (Contributor) / College of Health Solutions (Contributor) / School of Life Sciences (Contributor)
Created2023-05
ContributorsMendoza, Daniel (Author) / Grando, Adela (Thesis director) / Scotch, Matthew (Committee member) / Barrett, The Honors College (Contributor) / College of Health Solutions (Contributor) / School of Life Sciences (Contributor)
Created2023-05
ContributorsMendoza, Daniel (Author) / Grando, Adela (Thesis director) / Scotch, Matthew (Committee member) / Barrett, The Honors College (Contributor) / College of Health Solutions (Contributor) / School of Life Sciences (Contributor)
Created2023-05
ContributorsMendoza, Daniel (Author) / Grando, Adela (Thesis director) / Scotch, Matthew (Committee member) / Barrett, The Honors College (Contributor) / College of Health Solutions (Contributor) / School of Life Sciences (Contributor)
Created2023-05
ContributorsMendoza, Daniel (Author) / Grando, Adela (Thesis director) / Scotch, Matthew (Committee member) / Barrett, The Honors College (Contributor) / College of Health Solutions (Contributor) / School of Life Sciences (Contributor)
Created2023-05
ContributorsMendoza, Daniel (Author) / Grando, Adela (Thesis director) / Scotch, Matthew (Committee member) / Barrett, The Honors College (Contributor) / College of Health Solutions (Contributor) / School of Life Sciences (Contributor)
Created2023-05
ContributorsMendoza, Daniel (Author) / Grando, Adela (Thesis director) / Scotch, Matthew (Committee member) / Barrett, The Honors College (Contributor) / College of Health Solutions (Contributor) / School of Life Sciences (Contributor)
Created2023-05
ContributorsMendoza, Daniel (Author) / Grando, Adela (Thesis director) / Scotch, Matthew (Committee member) / Barrett, The Honors College (Contributor) / College of Health Solutions (Contributor) / School of Life Sciences (Contributor)
Created2023-05