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Freie Universität Berlin

1. Trimpert, Jakob. The role of DNA polymerase fidelity on genetic variation and pathogenicity of Marek’s disease virus.

Degree: 2020, Freie Universität Berlin

Gallid herpesvirus 2, also known as Marek’s disease virus, is the causative agent of Marek’s disease in chickens that can cause up to 100 % mortality in unvaccinated hosts. Vaccination against MDV is one of the most successful vaccination campaigns in the history of veterinary medicine, reducing disease incidence by more than 99%. Despite this success, MDV is still prevalent in chicken flocks worldwide and has shown a remarkable increase in virulence over the past decades. A major reason for the persistence of MDV could be the fact that vaccination against MD is not inducing sterilizing immunity but is permissive for (reduced) viral replication and shedding. It is argued that the imperfection of vaccination drives viral evolution towards higher virulence by selecting for viral phenotypes that maintain lytic replication and thereby the ability to be shed and transmitted in the presence of vaccine-induced immune response. The phenotypes selected in this way could ultimately benefit from vaccination, as vaccinated chickens which survive the infection shed the most replication competent viruses for a prolonged time, and thus contribute to the spread and evolution of particularly virulent virus strains. As a result, the development of MDV vaccines is caught in a vicious circle – vaccination drives selection of rapidly replicating escape mutants, which requires development of new vaccines based on viral strains that can replicate in the vaccinated host. This scenario has indeed been observed with vaccines of the first and second generation. In the light of these possibilities, the increase in virulence observed during the last decades is undoubtedly alarming. In the context of selection for higher virulence, genetic variation of MDV in vaccinated hosts could provide a selective advantage similar to what is known for some RNA viruses, which have evolved error-prone genome replication and form highly diverse quasispecies. As large DNA virus, MDV is believed to be genetically relatively stable, employing a proofreading DNA polymerase for genome replication. There is, however, evidence for remarkable genetic variation among several large DNA viruses, including herpes viruses such as HCMV and HSV-1. The objectives of this study were 1) to develop a NGS sequencing strategy for this highly cell associated virus 2) to determine, if genetic variation in MDV is a function of the fidelity of its DNA polymerase and 3) to examine replicative fitness and pathogenicity of proofreading-deficient viruses in vivo. Following the development of a tiling array for highly specific capture of viral sequences from infected chicken cell extracts, we were able to sequence whole viral genomes from a variety of samples ranging from infected chicken embryonic cells to dust collected from chicken farms. Next, we constructed MDV mutants with point mutations, in the exonuclease and finger domain of Pol (UL30), that could enhance or reduce replication fidelity. The observed level of residual… Advisors/Committee Members: male (gender), Osterrieder, Nikolaus (firstReferee), Hafez, Hafez Mohamed (furtherReferee), McMahon, Dino Peter (furtherReferee).

Subjects/Keywords: Quasispecies; Herpes; Marek's Disease; Evolution; DNA virus; Fidelity; 500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie::576 Genetik und Evolution; 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit

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APA (6th Edition):

Trimpert, J. (2020). The role of DNA polymerase fidelity on genetic variation and pathogenicity of Marek’s disease virus. (Thesis). Freie Universität Berlin. Retrieved from http://dx.doi.org/10.17169/refubium-26085

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Trimpert, Jakob. “The role of DNA polymerase fidelity on genetic variation and pathogenicity of Marek’s disease virus.” 2020. Thesis, Freie Universität Berlin. Accessed January 24, 2020. http://dx.doi.org/10.17169/refubium-26085.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Trimpert, Jakob. “The role of DNA polymerase fidelity on genetic variation and pathogenicity of Marek’s disease virus.” 2020. Web. 24 Jan 2020.

Vancouver:

Trimpert J. The role of DNA polymerase fidelity on genetic variation and pathogenicity of Marek’s disease virus. [Internet] [Thesis]. Freie Universität Berlin; 2020. [cited 2020 Jan 24]. Available from: http://dx.doi.org/10.17169/refubium-26085.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Trimpert J. The role of DNA polymerase fidelity on genetic variation and pathogenicity of Marek’s disease virus. [Thesis]. Freie Universität Berlin; 2020. Available from: http://dx.doi.org/10.17169/refubium-26085

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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