Dinamica evolutiva de virus RNA
Author
Ojosnegros Martos, SamuelAdvisor
Domingo Solans, EstebanEntity
UAM. Departamento de Biología Molecular; Centro de Biología Molecular Severo Ochoa (CBM)Date
2009-01-09Subjects
ARN-Tesis doctorales; Virus-Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular . Fecha de lectura: 09-01-2009Abstract
Quasispecies dynamics is involved in several aspects of RNA virus pathogenesis. It derives from
high error rates during RNA virus replication, large viral population sizes and short replicative
cycles. These features lead necessarily to highly polymorphic populations in which the time needed
to fix a specific mutation is longer than the time that it takes to generate new variants.
A clonal population of foot-and-mouth disease virus (FMDV) evolved towards dominance of
genomes with internal deletions, that were infectious by complementation in the absence of standard
virus. In this thesis, the genome composition of intermediate passages in the course of evolution of
the segmented version of FMDV has been analyzed. Multiple minority genomes harboring internal
deletions have been characterized. The results provide evidence of a transient state with genetic
instability. Increased thermal stability of the viral particles containing genomic RNA with internal
deletions, relative to the stability of the standard FMDV, has been associated with the selective
advantage of the segmented version relative to standard FMDV. No significant differences have
been noted in virus entry into cells, levels of intracellular RNA, viral protein synthesis or virus exit
from the cell.
The segmented form of FMDV induced anti-FMDV neutralizing antibodies, and protected
B57/BL6 mice against challenge with a lethal dose of the standard virus. Thus, the segmented
FMDV version constitutes a live-attenuated vaccine candidate.
In the present thesis, populations of FMDV subjected to lethal mutagenesis by base and nucleoside
analogues have been analyzed by PAQ (Partition Analysis of Quasispecies), and by standard
phylogenetic methods. The results have documented expansions and compressions of mutant spectrum
complexity, as well as the operation of negative selection in the course of mutagenesis. Extinction
can occur with modest increases of mutant spectrum complexity. The results suggest that
PAQ can be very useful to unveil changes in the internal composition of mutant spectra subjected
to mutagenesis or other perturbations.
The diversification of a clonal population of FMDV into two distinct subpopulations has been
characterized. Recombinant forms between components of the two subpopulations have been identified
by nucleotide sequence comparisons and phylogenetic analysis. The two subpopulations differed
in virulence (cell killing ability), replication rate, and interference exerted on other FMDV populations.
The results fit an ecological model in which the virus differentiated into ”colonizers” and
”competitors” for limited and patched resources, in this case the host cells.
The three main aspects of viral dynamics examined in the present thesis have characterized major
evolutionary transitions into new genotypic and phenotypic traits. Some transitions (towards
segmentation, differentiation into resource-coping strategies) have occurred in the course of unperturbed
evolution, while others (internal changes of mutant spectrum composition) were triggered
by enhanced mutagenesis.
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