TITLE:
Bayesian Coalescent Analysis of the Intra-Host Evolution of Hepatitis C Virus: Memory Genomes and Clinical Implications
AUTHORS:
Ricardo Recarey, Juan Cristina
KEYWORDS:
Hepatitis C Virus, Evolution, Bayesian, Coalescent Analysis, Quasispecies
JOURNAL NAME:
Natural Science,
Vol.6 No.9,
May
12,
2014
ABSTRACT:
Genetic variability plays a
key role in the biology and medical treatment of RNA viruses. As an RNA virus, Hepatitis
C virus (HCV) replicate as complex distributions of closely related genomes
termed viral quasispecies. The behavior of the evolving HCV quasispecies
population is influenced by the ensemble of mutants that compose the viral
population. One such influence is the presence of minority subpopulations,
termed memory genomes, in the mutant spectra. Biologically relevant mutants
have been previously observed to be present as memory genomes in RNA viral
populations. For that reason, an in-depth analysis of HCV quasispecies
populations is crucial for our understanding viral evolution, drug resistance
and therapy outcome. Recently developed next-generation sequencing (NGS)
platforms make it possible to investigate viral quasispecies at much greater
detail. In order to gain insight into these matters, we have performed a
Bayesian coalescent analysis of hypervariable region 1 (HVR1) sequences of a
HCV quasispecies population circulating in a chronic patient, recently obtained
by ultra-deep sequencing. The results of these studies revealed a mean rate of
evolution of HCV HVR1 of the intra-host quasispecies population of 4.80 × 10-2 amino acid substitutions/site/year. A sharp and rapid diversification of the
HCV quasispecies isolated from the patient in three different sub-populations
was observed. The most abundant sequence in the quasispecies population was not
found to be the center of a tight and complex network around this sequence,
suggesting that the quasispecies population as a whole efficiently explore a
wide sequence space. Co-evolution of relevant amino acid sites had been identified
in the HVR1. This speaks of the possible roll of these residues in HVR1 to
allow the virus to shift between combinations of residues to escape the immune
system while retaining its structure and functions. The results of these
studies highlight the importance of minority genomes in HCV population history
and evolution, the mutant clouds as reservoirs of phenotypic and genetic variants
for virus adaptability, as well as the roll of the mutant spectra to overcome
selective constraints.