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Synonymous Co-Variation across the E1/E2 Gene Junction of Hepatitis C Virus Defines Virion Fitness

View Article: PubMed Central - PubMed

ABSTRACT

Hepatitis C virus is a positive-sense single-stranded RNA virus. The gene junction partitioning the viral glycoproteins E1 and E2 displays concurrent sequence evolution with the 3′-end of E1 highly conserved and the 5′-end of E2 highly heterogeneous. This gene junction is also believed to contain structured RNA elements, with a growing body of evidence suggesting that such structures can act as an additional level of viral replication and transcriptional control. We have previously used ultradeep pyrosequencing to analyze an amplicon library spanning the E1/E2 gene junction from a treatment naïve patient where samples were collected over 10 years of chronic HCV infection. During this timeframe maintenance of an in-frame insertion, recombination and humoral immune targeting of discrete virus sub-populations was reported. In the current study, we present evidence of epistatic evolution across the E1/E2 gene junction and observe the development of co-varying networks of codons set against a background of a complex virome with periodic shifts in population dominance. Overtime, the number of codons actively mutating decreases for all virus groupings. We identify strong synonymous co-variation between codon sites in a group of sequences harbouring a 3 bp in-frame insertion and propose that synonymous mutation acts to stabilize the RNA structural backbone.

No MeSH data available.


Effective number of codons utilized by each HCV (sub-)lineage overtime.Values less than the threshold of 40 (dashed line) are considered as biased utilization of the available redundancy within the genetic code.
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pone.0167089.g002: Effective number of codons utilized by each HCV (sub-)lineage overtime.Values less than the threshold of 40 (dashed line) are considered as biased utilization of the available redundancy within the genetic code.

Mentions: It was apparent that the accommodation of the in-frame insertion into the HVR1 of L1b sequences negatively impacted on the mutational flexibility of the HVR1. L1b sequences accounted for 96.5% of all sample 7 isolates, yet at that time only four HVR1 codons were actively mutating (and only three thereafter) (Fig 1). This was further evidenced when codon usage frequencies were assessed. Evidence of codon usage bias was present in the data for each of L1a, L1b and L2 (Fig 2). L1b sequence ENC values were consistently lower over the 10 sampling points (minimum ENC 32.4).


Synonymous Co-Variation across the E1/E2 Gene Junction of Hepatitis C Virus Defines Virion Fitness
Effective number of codons utilized by each HCV (sub-)lineage overtime.Values less than the threshold of 40 (dashed line) are considered as biased utilization of the available redundancy within the genetic code.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120871&req=5

pone.0167089.g002: Effective number of codons utilized by each HCV (sub-)lineage overtime.Values less than the threshold of 40 (dashed line) are considered as biased utilization of the available redundancy within the genetic code.
Mentions: It was apparent that the accommodation of the in-frame insertion into the HVR1 of L1b sequences negatively impacted on the mutational flexibility of the HVR1. L1b sequences accounted for 96.5% of all sample 7 isolates, yet at that time only four HVR1 codons were actively mutating (and only three thereafter) (Fig 1). This was further evidenced when codon usage frequencies were assessed. Evidence of codon usage bias was present in the data for each of L1a, L1b and L2 (Fig 2). L1b sequence ENC values were consistently lower over the 10 sampling points (minimum ENC 32.4).

View Article: PubMed Central - PubMed

ABSTRACT

Hepatitis C virus is a positive-sense single-stranded RNA virus. The gene junction partitioning the viral glycoproteins E1 and E2 displays concurrent sequence evolution with the 3′-end of E1 highly conserved and the 5′-end of E2 highly heterogeneous. This gene junction is also believed to contain structured RNA elements, with a growing body of evidence suggesting that such structures can act as an additional level of viral replication and transcriptional control. We have previously used ultradeep pyrosequencing to analyze an amplicon library spanning the E1/E2 gene junction from a treatment naïve patient where samples were collected over 10 years of chronic HCV infection. During this timeframe maintenance of an in-frame insertion, recombination and humoral immune targeting of discrete virus sub-populations was reported. In the current study, we present evidence of epistatic evolution across the E1/E2 gene junction and observe the development of co-varying networks of codons set against a background of a complex virome with periodic shifts in population dominance. Overtime, the number of codons actively mutating decreases for all virus groupings. We identify strong synonymous co-variation between codon sites in a group of sequences harbouring a 3 bp in-frame insertion and propose that synonymous mutation acts to stabilize the RNA structural backbone.

No MeSH data available.