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Tracing Adaptive Pathways in a Proofreading-Deficient Coronavirus
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Tracing Adaptive Pathways in a Proofreading-Deficient Coronavirus. |
| 개인저자 | Graepel, Kevin Whittle. |
| 단체저자명 | Vanderbilt University. Microbiology and Immunology. |
| 발행사항 | [S.l.]: Vanderbilt University., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 300 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-04B. Dissertation Abstract International |
| ISBN | 9781088316474 |
| 학위논문주기 | Thesis (Ph.D.)--Vanderbilt University, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-04, Section: B.
Advisor: Denison, Mark R. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | Coronaviruses (CoVs) are a family of positive-sense RNA viruses that cause human illnesses ranging from the common cold to severe and lethal respiratory disease. Since 2002, two CoVs (SARS- and MERS-CoV) have emerged as zoonoses with pandemic potential, and closely-related viruses continue to circulate in animal populations. CoVs are distinguished from other RNA viruses by the complexity of their replication machinery, including the presence of a 3'-5' exoribonuclease (ExoN) within nonstructural protein 14 (nsp14-ExoN). The CoV-nsp14-ExoN is the first and, to date, only proofreading enzyme identified in an RNA virus and mediates high-fidelity replication. ExoN activity is critical for CoV biology, as proofreading-deficient CoVs with disrupted ExoN activity [ExoN(-)] are either nonviable or have significant defects in replication, RNA synthesis, fidelity, and in vivo virulence. Remarkably, despite these fitness costs, ExoN(-) CoVs do not revert the engineered mutations under diverse selective environments. In this dissertation, I use experimental evolution to examine the adaptive landscape of an ExoN(-) CoV, murine hepatitis virus (MHV). I show that the lack of reversion of MHV-ExoN(-) is driven by the limitations and opportunities of the adaptive landscape, which favors compensation over direct reversion. These results reveal a remarkable capacity for MHV to compensate for a disrupted ExoN, support the proposed link between CoV fidelity and fitness, illuminate complex functional and evolutionary relationships between CoV replicase proteins, and identify potential mechanisms for stabilization of attenuated ExoN(-) CoVs. New assays for measuring CoV fidelity and fitness are also discussed. |
| 일반주제명 | Virology. |
| 언어 | 영어 |
| 바로가기 | 
: 이 자료의 원문은 한국교육학술정보원에서 제공합니다. |
