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- All Subjects: Cancer
- All Subjects: Phylogenetics
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 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
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 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
Description
The 2017-2018 Influenza season was marked by the death of 80,000 Americans: the highest flu-related death toll in a decade. Further, the yearly economic toll to the US healthcare system and society is on the order of tens of billions of dollars. It is vital that we gain a better understanding of the dynamics of influenza transmission in order to prevent its spread. Viral DNA sequences examined using bioinformatics methods offer a rich framework with which to monitor the evolution and spread of influenza for public health surveillance. To better understand the influenza epidemic during the severe 2017-2018 season, we established a passive surveillance system at Arizona State University’s Tempe Campus Health Services beginning in January 2018. From this system, nasopharyngeal samples screening positive for influenza were collected. Using these samples, molecular DNA sequences will be generated using a combined multiplex RT-PCR and NGS approach. Phylogenetic analysis will be used to infer the severity and temporal course of the 2017-2018 influenza outbreak on campus as well as the 2018-2019 flu season. Through this surveillance system, we will gain knowledge of the dynamics of influenza spread in a university setting and will use this information to inform public health strategies.
ContributorsMendoza, Lydia Marie (Author) / Scotch, Matthew (Thesis director) / Hogue, Brenda (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
Phylogenetic analyses that were conducted in the past didn't have the ability or functionality to inform and implement useful public health decisions while using clustering. Models can be constructed to conduct any further analyses for the result of meaningful data to be used in the future of public health informatics. A phylogenetic tree is considered one of the best ways for researchers to visualize and analyze the evolutionary history of a certain virus. The focus of this study was to research HIV phylodynamic and phylogenetic methods. This involved identifying the fast growing HIV transmission clusters and rates for certain risk groups in the US. In order to achieve these results an HIV database was required to retrieve real-time data for implementation, alignment software for multiple sequence alignment, Bayesian analysis software for the development and manipulation of models, and graphical tools for visualizing the output from the models created. This study began by conducting a literature review on HIV phylogeographies and phylodynamics. Sequence data was then obtained from a sequence database to be run in a multiple alignment software. The sequence that was obtained was unaligned which is why the alignment was required. Once the alignment was performed, the same file was loaded into a Bayesian analysis software for model creation of a phylogenetic tree. When the model was created, the tree was edited in a tree visualization software for the user to easily interpret. From this study the output of the tree resulted the way it did, due to a distant homology or the mixing of certain parameters. For a further continuation of this study, it would be interesting to use the same aligned sequence and use different model parameter selections for the initial creation of the model to see how the output changes. This is because one small change for the model parameter could greatly affect the output of the phylogenetic tree.
ContributorsNandan, Meghana (Author) / Scotch, Matthew (Thesis director) / Liu, Li (Committee member) / Biomedical Informatics Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05