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

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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.


Putative reorganization of conserved structures within the HCV genome over time.The local RNA structure for codons 357–370 were modeled using example sequences from L1a. (A) L1a dominant sequence motif from sample 1. (B) L1a dominant sequence motif from sample 8. Whereas the mutations observed led to an overall decrease in the minimum free energy of the structure, it is the cumulative contribution of mutations across the length of the amplicon that determine overall stability. The predicted ΔG for the full length amplicon was -93.94 and -100.4 for the dominant sequence motifs from sample 1 and 8, respectively. Synonymous mutations at codons 363, 366 and 367 are shown in red.
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pone.0167089.g007: Putative reorganization of conserved structures within the HCV genome over time.The local RNA structure for codons 357–370 were modeled using example sequences from L1a. (A) L1a dominant sequence motif from sample 1. (B) L1a dominant sequence motif from sample 8. Whereas the mutations observed led to an overall decrease in the minimum free energy of the structure, it is the cumulative contribution of mutations across the length of the amplicon that determine overall stability. The predicted ΔG for the full length amplicon was -93.94 and -100.4 for the dominant sequence motifs from sample 1 and 8, respectively. Synonymous mutations at codons 363, 366 and 367 are shown in red.

Mentions: Discrete RNA structures have been suggested to participate in innate immune evasion and contribute to overall viral fitness [18–20]. Similar secondary structures were predicted within our sequence set. SL1412 as described by Pirakitikulr and colleagues (2016), spans codons 357–371 of the amplicon (Fig 7) [18]. This region is implicated in significant synonymous-synonymous interactions, specifically codons 166 and 167 (Fig 3).


Synonymous Co-Variation across the E1/E2 Gene Junction of Hepatitis C Virus Defines Virion Fitness
Putative reorganization of conserved structures within the HCV genome over time.The local RNA structure for codons 357–370 were modeled using example sequences from L1a. (A) L1a dominant sequence motif from sample 1. (B) L1a dominant sequence motif from sample 8. Whereas the mutations observed led to an overall decrease in the minimum free energy of the structure, it is the cumulative contribution of mutations across the length of the amplicon that determine overall stability. The predicted ΔG for the full length amplicon was -93.94 and -100.4 for the dominant sequence motifs from sample 1 and 8, respectively. Synonymous mutations at codons 363, 366 and 367 are shown in red.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0167089.g007: Putative reorganization of conserved structures within the HCV genome over time.The local RNA structure for codons 357–370 were modeled using example sequences from L1a. (A) L1a dominant sequence motif from sample 1. (B) L1a dominant sequence motif from sample 8. Whereas the mutations observed led to an overall decrease in the minimum free energy of the structure, it is the cumulative contribution of mutations across the length of the amplicon that determine overall stability. The predicted ΔG for the full length amplicon was -93.94 and -100.4 for the dominant sequence motifs from sample 1 and 8, respectively. Synonymous mutations at codons 363, 366 and 367 are shown in red.
Mentions: Discrete RNA structures have been suggested to participate in innate immune evasion and contribute to overall viral fitness [18–20]. Similar secondary structures were predicted within our sequence set. SL1412 as described by Pirakitikulr and colleagues (2016), spans codons 357–371 of the amplicon (Fig 7) [18]. This region is implicated in significant synonymous-synonymous interactions, specifically codons 166 and 167 (Fig 3).

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.