Novel Microsatellite Detection, Microsatellite Based Biomarker Discovery In Lung Cancer And The Exome-Wide Effects Of A Dysfunctional DNA Repair Mechanism

Simple item page
dc.contributor.authorVelmurugan, Karthik Rajaen
dc.contributor.committeechairBevan, David R.en
dc.contributor.committeechairGarner, Harold Rayen
dc.contributor.committeememberLawrence, Christopher B.en
dc.contributor.committeememberMichalak, Pawelen
dc.contributor.departmentAnimal and Poultry Sciencesen
dc.date.accessioned2018-10-25T06:01:08Zen
dc.date.available2018-10-25T06:01:08Zen
dc.date.issued2017-05-02en
dc.description.abstractSince the dawn of the genomics era, the genetics of numerous human disorders has been understood which has led to improvements in targeted therapeutics. However, the focus of most research has been primarily on protein coding genes, which account for only 2% of the entire genome, leaving much of the remaining genome relatively unstudied. In particular, repetitive sequences, called microsatellites (MST), which are tandem repeats of 1 to 6 bases, are known to be mutational hotspots and have been linked to diseases, such as Huntington disease and Fragile X syndrome. This work represents a significant effort towards closing this knowledge gap. Specifically, we developed a next generation sequencing based enrichment method along with the supporting computational pipeline for detecting novel MST sequences in the human genome. Using this global MST enrichment protocol, we have identified 790 novel sequences. Analysis of these novel sequences has identified previously unknown functional elements, demonstrating its potential for aiding in the completion of the euchromatic DNA. We also developed a disease risk diagnostic using a novel target specific enrichment method that produces high resolution MST sequencing data that has the potential to validate, for the first time, the link between MST genotype variation and cancer. Combined with publicly available exome datasets of non-small cell lung cancer and 1000 genomes project, the target specific MST enrichment method uncovered a signature set of 21 MST loci that can differentiate between lung cancer and non-cancer control samples with a sensitivity ratio of 0.93. Finally, to understand the molecular causes of MST instability, we analyzed genomic variants and gene expression data for an autosomal recessive disorder, Fanconi anemia (FA). This first of its kind study quantified the heterogeneity of FA cells and demonstrated the possibility of utilizing the DNA crosslink repair dysfunctional FA cells as a suitable system to further study the causes of MST instability.en
dc.description.degreePh. D.en
dc.format.mediumETDen
dc.identifier.othervt_gsexam:9877en
dc.identifier.urihttp://hdl.handle.net/10919/85506en
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectMicrosatelliteen
dc.subjectNext-Generation Sequencingen
dc.subjectLung Canceren
dc.subjectFanconi Anemiaen
dc.subjectBiomarker Discoveryen
dc.subjectBioinformatics algorithmen
dc.titleNovel Microsatellite Detection, Microsatellite Based Biomarker Discovery In Lung Cancer And The Exome-Wide Effects Of A Dysfunctional DNA Repair Mechanismen
dc.typeDissertationen
thesis.degree.disciplineGenetics, Bioinformatics, and Computational Biologyen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Velmurugan_K_D_2017.pdf
Size:
4.19 MB
Format:
Adobe Portable Document Format
Download

Collections

Doctoral Dissertations