| dc.identifier.uri | http://hdl.handle.net/11401/77618 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | Codon pair bias, the preferential pairing of certain codons over others, has been observed in all species analyzed ranging from bacteria to mammals. Previous research has shown that artificial coupling of underrepresented codon pairs (codon pair deoptimization) in viral genomes (such as poliovirus and influenza virus) reduces gene function and leads to virus death or attenuation. Although the reason for this phenomenon is unclear, increasing underrepresented codon pairs in an RNA viral coding region consequently increases the frequency of CpG and UpA dinucleotides. These dinucleotides are suppressed in a variety of species and may be responsible for attenuation by codon pair deoptimization. The current study aims to determine the effects of CpG and UpA dinucleotide frequencies on viral attenuation by codon pair deoptimization. In order to do so, four versions of poliovirus that address each characteristic (either individually or in combination with another) were designed and synthesized. Thorough analysis of these viruses indicates that increasing CpG or UpA dinucleotides, or decreasing the codon pair bias alone, affects poliovirus at different stages of infection. Specifically, while codon pair bias alone affects RNA replication or a stage upstream of replication during infection, increasing CpG dinucleotides reduces gene expression and increasing UpA dinucleotides shortens mRNA half-life. All three characteristics affect viral infectivity to varying extents. Interestingly, there does not seem to be a direct correlation between the rate of replication or protein synthesis and peak viral titer. Although additional aspects of codon pair bias remain unclarified, the current work provides a novel route for strategic adjustment of genetic patterns during genome design depending on the objective of synthesis. These results can act as a foundation for the design of genes with altered expression, of attenuated vaccine candidates or even of gene therapy vectors with increased stability. | |
| dcterms.available | 2017-09-20T16:53:02Z | |
| dcterms.contributor | Krug, Laurie | en_US |
| dcterms.contributor | Wimmer, Eckard | en_US |
| dcterms.contributor | Reich, Nancy | en_US |
| dcterms.contributor | Karzai, Wali | en_US |
| dcterms.contributor | Grubman, Marvin. | en_US |
| dcterms.creator | Arabov, Malka | |
| dcterms.dateAccepted | 2017-09-20T16:53:02Z | |
| dcterms.dateSubmitted | 2017-09-20T16:53:02Z | |
| dcterms.description | Department of Genetics. | en_US |
| dcterms.extent | 99 pg. | en_US |
| dcterms.format | Monograph | |
| dcterms.format | Application/PDF | en_US |
| dcterms.identifier | http://hdl.handle.net/11401/77618 | |
| dcterms.issued | 2014-12-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:53:02Z (GMT). No. of bitstreams: 1
Arabov_grad.sunysb_0771E_11874.pdf: 7604537 bytes, checksum: 681bfd90a85578d347c23c64abe6b74f (MD5)
Previous issue date: 1 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Virology | |
| dcterms.subject | codon bias, codon pair bias, dinucleotides, poliovirus | |
| dcterms.title | The effects of CpG and UpA dinucleotides on the attenuation of poliovirus by codon pair deoptimization | |
| dcterms.type | Dissertation | |
