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Synonymous site conservation in the HIV-1 genome.

Mayrose I, Stern A, Burdelova EO, Sabo Y, Laham-Karam N, Zamostiano R, Bacharach E, Pupko T - BMC Evol. Biol. (2013)

Bottom Line: In our assays aiming to quantify viral fitness in both early and late stages of the replication cycle, no differences were observed between the mutated and the wild type virus following the introduction of synonymous mutations.The contradiction between the inferred purifying selective forces and the lack of effect of these mutations on viral replication may be explained by the fact that the phenotype was measured in single-cycle infection assays in cell culture.Such a system does not account for the complexity of HIV-1 infections in vivo, which involves multiple infection cycles and interaction with the host immune system.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Biology and Ecology of Plants, Tel Aviv University, Tel-Aviv 69978, Israel. itaymay@post.tau.ac.il

ABSTRACT

Background: Synonymous or silent mutations are usually thought to evolve neutrally. However, accumulating recent evidence has demonstrated that silent mutations may destabilize RNA structures or disrupt cis regulatory motifs superimposed on coding sequences. Such observations suggest the existence of stretches of codon sites that are evolutionary conserved at both DNA-RNA and protein levels. Such stretches may point to functionally important regions within protein coding sequences not necessarily reflecting functional constraints on the amino-acid sequence. The HIV-1 genome is highly compact, and often harbors overlapping functional elements at the protein, RNA, and DNA levels. This superimposition of functions leads to complex selective forces acting on all levels of the genome and proteome. Considering the constraints on HIV-1 to maintain such a highly compact genome, we hypothesized that stretches of synonymous conservation would be common within its genome.

Results: We used a combined computational-experimental approach to detect and characterize regions exhibiting strong purifying selection against synonymous substitutions along the HIV-1 genome. Our methodology is based on advanced probabilistic evolutionary models that explicitly account for synonymous rate variation among sites and rate dependencies among adjacent sites. These models are combined with a randomization procedure to automatically identify the most statistically significant regions of conserved synonymous sites along the genome. Using this procedure we identified 21 conserved regions. Twelve of these are mapped to regions within overlapping genes, seven correlate with known functional elements, while the functions of the remaining four are yet unknown. Among these four regions, we chose the one that deviates most from synonymous rate homogeneity for in-depth computational and experimental characterization. In our assays aiming to quantify viral fitness in both early and late stages of the replication cycle, no differences were observed between the mutated and the wild type virus following the introduction of synonymous mutations.

Conclusions: The contradiction between the inferred purifying selective forces and the lack of effect of these mutations on viral replication may be explained by the fact that the phenotype was measured in single-cycle infection assays in cell culture. Such a system does not account for the complexity of HIV-1 infections in vivo, which involves multiple infection cycles and interaction with the host immune system.

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A histogram portraying the HIV-1 proteome-wide distribution of inferred (A) Ka and (B) Ks values.
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Figure 1: A histogram portraying the HIV-1 proteome-wide distribution of inferred (A) Ka and (B) Ks values.

Mentions: Having established that KaD-KsD is the best fitting model, it was next used to infer site-specific Ka and Ks scores for each site in each of the ORFs. The posterior distributions of inferred Ka and Ks values were then examined (FigureĀ 1). There is a large difference between the two distributions: On the one hand, most of the Ka distribution surrounds very low values, with an average of 0.56, supporting the notion that extensive purifying selection is acting on the coding sequences. On the other hand, the mass of the Ks distribution is centered around 1 (average 1.39), suggesting that most synonymous sites are under neutral selection. Indeed, the coefficient of variation (CV) of the Ka distribution is much higher than that of the Ks distribution (1.18 versus 0.71) suggesting higher level of variation of Ka compared to Ks values.


Synonymous site conservation in the HIV-1 genome.

Mayrose I, Stern A, Burdelova EO, Sabo Y, Laham-Karam N, Zamostiano R, Bacharach E, Pupko T - BMC Evol. Biol. (2013)

A histogram portraying the HIV-1 proteome-wide distribution of inferred (A) Ka and (B) Ks values.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750384&req=5

Figure 1: A histogram portraying the HIV-1 proteome-wide distribution of inferred (A) Ka and (B) Ks values.
Mentions: Having established that KaD-KsD is the best fitting model, it was next used to infer site-specific Ka and Ks scores for each site in each of the ORFs. The posterior distributions of inferred Ka and Ks values were then examined (FigureĀ 1). There is a large difference between the two distributions: On the one hand, most of the Ka distribution surrounds very low values, with an average of 0.56, supporting the notion that extensive purifying selection is acting on the coding sequences. On the other hand, the mass of the Ks distribution is centered around 1 (average 1.39), suggesting that most synonymous sites are under neutral selection. Indeed, the coefficient of variation (CV) of the Ka distribution is much higher than that of the Ks distribution (1.18 versus 0.71) suggesting higher level of variation of Ka compared to Ks values.

Bottom Line: In our assays aiming to quantify viral fitness in both early and late stages of the replication cycle, no differences were observed between the mutated and the wild type virus following the introduction of synonymous mutations.The contradiction between the inferred purifying selective forces and the lack of effect of these mutations on viral replication may be explained by the fact that the phenotype was measured in single-cycle infection assays in cell culture.Such a system does not account for the complexity of HIV-1 infections in vivo, which involves multiple infection cycles and interaction with the host immune system.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Biology and Ecology of Plants, Tel Aviv University, Tel-Aviv 69978, Israel. itaymay@post.tau.ac.il

ABSTRACT

Background: Synonymous or silent mutations are usually thought to evolve neutrally. However, accumulating recent evidence has demonstrated that silent mutations may destabilize RNA structures or disrupt cis regulatory motifs superimposed on coding sequences. Such observations suggest the existence of stretches of codon sites that are evolutionary conserved at both DNA-RNA and protein levels. Such stretches may point to functionally important regions within protein coding sequences not necessarily reflecting functional constraints on the amino-acid sequence. The HIV-1 genome is highly compact, and often harbors overlapping functional elements at the protein, RNA, and DNA levels. This superimposition of functions leads to complex selective forces acting on all levels of the genome and proteome. Considering the constraints on HIV-1 to maintain such a highly compact genome, we hypothesized that stretches of synonymous conservation would be common within its genome.

Results: We used a combined computational-experimental approach to detect and characterize regions exhibiting strong purifying selection against synonymous substitutions along the HIV-1 genome. Our methodology is based on advanced probabilistic evolutionary models that explicitly account for synonymous rate variation among sites and rate dependencies among adjacent sites. These models are combined with a randomization procedure to automatically identify the most statistically significant regions of conserved synonymous sites along the genome. Using this procedure we identified 21 conserved regions. Twelve of these are mapped to regions within overlapping genes, seven correlate with known functional elements, while the functions of the remaining four are yet unknown. Among these four regions, we chose the one that deviates most from synonymous rate homogeneity for in-depth computational and experimental characterization. In our assays aiming to quantify viral fitness in both early and late stages of the replication cycle, no differences were observed between the mutated and the wild type virus following the introduction of synonymous mutations.

Conclusions: The contradiction between the inferred purifying selective forces and the lack of effect of these mutations on viral replication may be explained by the fact that the phenotype was measured in single-cycle infection assays in cell culture. Such a system does not account for the complexity of HIV-1 infections in vivo, which involves multiple infection cycles and interaction with the host immune system.

Show MeSH
Related in: MedlinePlus