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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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Regions of excess synonymous constraint in rotavirus genomes. (A) SCEs in VP6. (B) For each segment of the rotavirus genome, we show with red bars positions with SCEs at a 10-codon resolution. Segments for which regions of excess synonymous constraint were not previously reported by Li and colleagues [36] are indicated with asterisks.
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Fig4: Regions of excess synonymous constraint in rotavirus genomes. (A) SCEs in VP6. (B) For each segment of the rotavirus genome, we show with red bars positions with SCEs at a 10-codon resolution. Segments for which regions of excess synonymous constraint were not previously reported by Li and colleagues [36] are indicated with asterisks.

Mentions: Consistent with previous work by Li and colleagues [36], we identify significant regions of excess synonymous constraint in all rotavirus segments (FigureĀ 4). In all segments except for segment 11, the detected regions of excess constraint lie at the beginning or end of the gene. (We recover the overlapping NSP6 gene within the NSP5 ORF in segment 11 as a strong signal of excess synonymous constraint in the interior of the gene).Figure 4


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)

Regions of excess synonymous constraint in rotavirus genomes. (A) SCEs in VP6. (B) For each segment of the rotavirus genome, we show with red bars positions with SCEs at a 10-codon resolution. Segments for which regions of excess synonymous constraint were not previously reported by Li and colleagues [36] are indicated with asterisks.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Regions of excess synonymous constraint in rotavirus genomes. (A) SCEs in VP6. (B) For each segment of the rotavirus genome, we show with red bars positions with SCEs at a 10-codon resolution. Segments for which regions of excess synonymous constraint were not previously reported by Li and colleagues [36] are indicated with asterisks.
Mentions: Consistent with previous work by Li and colleagues [36], we identify significant regions of excess synonymous constraint in all rotavirus segments (FigureĀ 4). In all segments except for segment 11, the detected regions of excess constraint lie at the beginning or end of the gene. (We recover the overlapping NSP6 gene within the NSP5 ORF in segment 11 as a strong signal of excess synonymous constraint in the interior of the gene).Figure 4

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