| LDR | | 00000nam u2200205 4500 |
| 001 | | 000000434227 |
| 005 | | 20200226142910 |
| 008 | | 200131s2019 ||||||||||||||||| ||eng d |
| 020 | |
▼a 9781088316474 |
| 035 | |
▼a (MiAaPQ)AAI13881359 |
| 040 | |
▼a MiAaPQ
▼c MiAaPQ
▼d 247004 |
| 082 | 0 |
▼a 576.6 |
| 100 | 1 |
▼a Graepel, Kevin Whittle. |
| 245 | 10 |
▼a Tracing Adaptive Pathways in a Proofreading-Deficient Coronavirus. |
| 260 | |
▼a [S.l.]:
▼b Vanderbilt University.,
▼c 2019. |
| 260 | 1 |
▼a Ann Arbor:
▼b ProQuest Dissertations & Theses,
▼c 2019. |
| 300 | |
▼a 300 p. |
| 500 | |
▼a Source: Dissertations Abstracts International, Volume: 81-04, Section: B. |
| 500 | |
▼a Advisor: Denison, Mark R. |
| 502 | 1 |
▼a Thesis (Ph.D.)--Vanderbilt University, 2019. |
| 506 | |
▼a This item must not be sold to any third party vendors. |
| 520 | |
▼a 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. |
| 590 | |
▼a School code: 0242. |
| 650 | 4 |
▼a Virology. |
| 690 | |
▼a 0720 |
| 710 | 20 |
▼a Vanderbilt University.
▼b Microbiology and Immunology. |
| 773 | 0 |
▼t Dissertations Abstracts International
▼g 81-04B. |
| 773 | |
▼t Dissertation Abstract International |
| 790 | |
▼a 0242 |
| 791 | |
▼a Ph.D. |
| 792 | |
▼a 2019 |
| 793 | |
▼a English |
| 856 | 40 |
▼u http://www.riss.kr/pdu/ddodLink.do?id=T15491183
▼n KERIS
▼z 이 자료의 원문은 한국교육학술정보원에서 제공합니다. |
| 980 | |
▼a 202002
▼f 2020 |
| 990 | |
▼a ***1816162 |
| 991 | |
▼a E-BOOK |