Structural Constraints on RNA Virus Evolution

Abstract

The recently discovered hepatitis G virus (HGV) or GB virus C (GBV-C) is widely distributed in human populations, and homologues such as HGV/GBV-CCPZ and GBV-A are found in a variety of different primate species. Both epidemiological and phylogenetic analyses support the hypothesis that GB viruses coevolved with their primate hosts, although their degree of sequence similarity appears incompatible with the high rate of sequence change of HGV/GBV-C over short observation periods. Comparison of complete coding sequences (8,500 bases) of different genotypes of HGV/GBV-C showed an excess of invariant synonymous sites (at 23% of all codons) compared with the frequency expected by chance (10%). To investigate the hypothesis that RNA secondary-structure formation through internal base pairing limited sequence variability at these sites, an algorithm was developed to detect covariant sites among HGV/GBV-C sequences of different genotypes. At least 35 covariant sites that were spatially associated with potential stem-loop structures were detected, whose positions correlated with positions in the genome that showed reductions in synonymous variability. Although the functional roles of the predicted secondary structures remain unclear, the restriction of sequence change imposed by secondary-structure formation provides a mechanism for differences in net rate of accumulation of nucleotide substitutions at different sites. However, the resulting disparity between short- and long-term rates of sequence change of HGV/GBV-C violates the assumptions of the “molecular clock.” This places a major restriction on the use of nucleotide or amino acid sequence comparisons to calculate times of divergence of other viruses evolving under the same structural constraints as GB viruses.

Human Bocaviruses Are Highly Diverse, Dispersed, Recombination Prone, and Prevalent in Enteric Infections

“…The totality of HBoV1 sequences collected worldwide by multiple groups show very low protein and nucleotide sequence diversity ( Table 2 and Figure 4A) [35,36]. In contrast, this single study found substantial diversity among HBoV2 and HBoV3, a fourth species (HBoV4), and extensive viral recombination (Figures 3, 4B, and 4C).…”

“…Recombination analyses. Similarity values based on Jukes-Cantor corrected nucleotide distances between full-length sequences were calculated using the program SequenceDist in the Simmonic2005 v1.6 Sequence Editor Package [35]. To assess similarity across the genomes, sequence scans were performed using a fragment length of 300 bases and an increment of 9 bases between fragments.…”

Parallel molecular evolution and adaptation in viruses

“…Various approaches have been developed to test for selection on non-coding regions [51] and to predict the secondary structure of RNA molecules [52,53], but to date their use has been limited in evolutionary analyses of viruses. Further development of these methods could improve our understanding of the role that RNA structures play in virus evolution [54].…”

Viruses as Quasispecies: Biological Implications

“…4. Multiple constraints for variability have been evidenced in viral genomes (Simmonds and Smith 1999;Simmonds et al 2004). Therefore, many variants with one or few mutations that may confer biologically relevant, adaptive traits may not be represented in a mutant spectrum (under a set of environmental conditions) due to fitness costs.…”