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FRESCo: finding regions of excess synonymous constraint in diverse viruses.

Sealfon RS, Lin MF, Jungreis I, Wolf MY, Kellis M, Sabeti PC - Genome Biol. (2015)

Bottom Line: Synonymous substitutions in these regions would be selectively disfavored and thus these regions are characterized by excess synonymous constraint.Codon choice can also modulate transcriptional efficiency, translational accuracy, and protein folding.We developed a phylogenetic codon model-based framework, FRESCo, designed to find regions of excess synonymous constraint in short, deep alignments, such as individual viral genes across many sequenced isolates.

View Article: PubMed Central - PubMed

ABSTRACT

Background: The increasing availability of sequence data for many viruses provides power to detect regions under unusual evolutionary constraint at a high resolution. One approach leverages the synonymous substitution rate as a signature to pinpoint genic regions encoding overlapping or embedded functional elements. Protein-coding regions in viral genomes often contain overlapping RNA structural elements, reading frames, regulatory elements, microRNAs, and packaging signals. Synonymous substitutions in these regions would be selectively disfavored and thus these regions are characterized by excess synonymous constraint. Codon choice can also modulate transcriptional efficiency, translational accuracy, and protein folding.

Results: We developed a phylogenetic codon model-based framework, FRESCo, designed to find regions of excess synonymous constraint in short, deep alignments, such as individual viral genes across many sequenced isolates. We demonstrated the high specificity of our approach on simulated data and applied our framework to the protein-coding regions of approximately 30 distinct species of viruses with diverse genome architectures.

Conclusions: FRESCo recovers known multifunctional regions in well-characterized viruses such as hepatitis B virus, poliovirus, and West Nile virus, often at a single-codon resolution, and predicts many novel functional elements overlapping viral genes, including in Lassa and Ebola viruses. In a number of viruses, the synonymously constrained regions that we identified also display conserved, stable predicted RNA structures, including putative novel elements in multiple viral species.

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Identifying putative novel overlapping elements in bluetongue virus. (A) FRESCo recovers a previously identified overlapping ORF in the VP6 gene as a pronounced region of excess synonymous constraint. (B) For each segment of the bluetongue virus genome, we show with red bars positions with SCEs at a 10-codon resolution. As in rotavirus, SCEs are concentrated near the 5’ and 3’ ends of genome segments. (C) A conserved ORF in NS3 corresponds to a strong signal of excess synonymous constraint. (D) The region also has a weak signal for a conserved RNA structure, suggesting an alternative possible function for the SCE.
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Fig5: Identifying putative novel overlapping elements in bluetongue virus. (A) FRESCo recovers a previously identified overlapping ORF in the VP6 gene as a pronounced region of excess synonymous constraint. (B) For each segment of the bluetongue virus genome, we show with red bars positions with SCEs at a 10-codon resolution. As in rotavirus, SCEs are concentrated near the 5’ and 3’ ends of genome segments. (C) A conserved ORF in NS3 corresponds to a strong signal of excess synonymous constraint. (D) The region also has a weak signal for a conserved RNA structure, suggesting an alternative possible function for the SCE.

Mentions: We recover several expected signals of synonymous constraint in the bluetongue virus genome. Firstly, we recover the known overlapping gene as a strong region of internal synonymous constraint in VP6 (Figure 5A). In all bluetongue virus segments, we also identify signals of excess synonymous constraint near the 5’ or 3’ termini of the segment (Figure 5B). This is a similar pattern to that observed in rotavirus and may influence packaging, genome replication, or translation as has been hypothesized in rotavirus, also a member of the reovirus family [36].Figure 5


FRESCo: finding regions of excess synonymous constraint in diverse viruses.

Sealfon RS, Lin MF, Jungreis I, Wolf MY, Kellis M, Sabeti PC - Genome Biol. (2015)

Identifying putative novel overlapping elements in bluetongue virus. (A) FRESCo recovers a previously identified overlapping ORF in the VP6 gene as a pronounced region of excess synonymous constraint. (B) For each segment of the bluetongue virus genome, we show with red bars positions with SCEs at a 10-codon resolution. As in rotavirus, SCEs are concentrated near the 5’ and 3’ ends of genome segments. (C) A conserved ORF in NS3 corresponds to a strong signal of excess synonymous constraint. (D) The region also has a weak signal for a conserved RNA structure, suggesting an alternative possible function for the SCE.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4376164&req=5

Fig5: Identifying putative novel overlapping elements in bluetongue virus. (A) FRESCo recovers a previously identified overlapping ORF in the VP6 gene as a pronounced region of excess synonymous constraint. (B) For each segment of the bluetongue virus genome, we show with red bars positions with SCEs at a 10-codon resolution. As in rotavirus, SCEs are concentrated near the 5’ and 3’ ends of genome segments. (C) A conserved ORF in NS3 corresponds to a strong signal of excess synonymous constraint. (D) The region also has a weak signal for a conserved RNA structure, suggesting an alternative possible function for the SCE.
Mentions: We recover several expected signals of synonymous constraint in the bluetongue virus genome. Firstly, we recover the known overlapping gene as a strong region of internal synonymous constraint in VP6 (Figure 5A). In all bluetongue virus segments, we also identify signals of excess synonymous constraint near the 5’ or 3’ termini of the segment (Figure 5B). This is a similar pattern to that observed in rotavirus and may influence packaging, genome replication, or translation as has been hypothesized in rotavirus, also a member of the reovirus family [36].Figure 5

Bottom Line: Synonymous substitutions in these regions would be selectively disfavored and thus these regions are characterized by excess synonymous constraint.Codon choice can also modulate transcriptional efficiency, translational accuracy, and protein folding.We developed a phylogenetic codon model-based framework, FRESCo, designed to find regions of excess synonymous constraint in short, deep alignments, such as individual viral genes across many sequenced isolates.

View Article: PubMed Central - PubMed

ABSTRACT

Background: The increasing availability of sequence data for many viruses provides power to detect regions under unusual evolutionary constraint at a high resolution. One approach leverages the synonymous substitution rate as a signature to pinpoint genic regions encoding overlapping or embedded functional elements. Protein-coding regions in viral genomes often contain overlapping RNA structural elements, reading frames, regulatory elements, microRNAs, and packaging signals. Synonymous substitutions in these regions would be selectively disfavored and thus these regions are characterized by excess synonymous constraint. Codon choice can also modulate transcriptional efficiency, translational accuracy, and protein folding.

Results: We developed a phylogenetic codon model-based framework, FRESCo, designed to find regions of excess synonymous constraint in short, deep alignments, such as individual viral genes across many sequenced isolates. We demonstrated the high specificity of our approach on simulated data and applied our framework to the protein-coding regions of approximately 30 distinct species of viruses with diverse genome architectures.

Conclusions: FRESCo recovers known multifunctional regions in well-characterized viruses such as hepatitis B virus, poliovirus, and West Nile virus, often at a single-codon resolution, and predicts many novel functional elements overlapping viral genes, including in Lassa and Ebola viruses. In a number of viruses, the synonymously constrained regions that we identified also display conserved, stable predicted RNA structures, including putative novel elements in multiple viral species.

Show MeSH
Related in: MedlinePlus