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Extensive purifying selection acting on synonymous sites in HIV-1 Group M sequences.

Ngandu NK, Scheffler K, Moore P, Woodman Z, Martin D, Seoighe C - Virol. J. (2008)

Bottom Line: Synonymous substitution rates were found to vary significantly within and between genes.We found evidence of strong purifying selection pressure affecting synonymous mutations in fourteen regions with known functions.We also found four conserved regions located in env and vpu which have not been characterized previously.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Bioinformatics Network Node, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, 7925, South Africa. nobubelo@cbio.uct.ac.za

ABSTRACT

Background: Positive selection pressure acting on protein-coding sequences is usually inferred when the rate of nonsynonymous substitution is greater than the synonymous rate. However, purifying selection acting directly on the nucleotide sequence can lower the synonymous substitution rate. This could result in false inference of positive selection because when synonymous changes at some sites are under purifying selection, the average synonymous rate is an underestimate of the neutral rate of evolution. Even though HIV-1 coding sequences contain a number of regions that function at the nucleotide level, and are thus likely to be affected by purifying selection, studies of positive selection assume that synonymous substitutions can be used to estimate the neutral rate of evolution.

Results: We modelled site-to-site variation in the synonymous substitution rate across coding regions of the HIV-1 genome. Synonymous substitution rates were found to vary significantly within and between genes. Surprisingly, regions of the genome that encode proteins in more than one frame had significantly higher synonymous substitution rates than regions coding in a single frame. We found evidence of strong purifying selection pressure affecting synonymous mutations in fourteen regions with known functions. These included an exonic splicing enhancer, the rev-responsive element, the poly-purine tract and a transcription factor binding site. A further five highly conserved regions were located within known functional domains. We also found four conserved regions located in env and vpu which have not been characterized previously.

Conclusion: We provide the coordinates of genomic regions with markedly lower synonymous substitution rates, which are putatively under the influence of strong purifying selection pressure at the nucleotide level as well as regions encoding proteins in more than one frame. These regions should be excluded from studies of positive selection acting on HIV-1 coding regions.

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HIV-1 genome-wide plot of mean nonsynonymous substitution rates. A 30 codon sliding window was used. Regions coding for proteins in more than one frame are shaded in pink. The frames that were used in each region are shown in grey rectangles, with frame 1 at the top and frame 3 at the bottom.
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Figure 1: HIV-1 genome-wide plot of mean nonsynonymous substitution rates. A 30 codon sliding window was used. Regions coding for proteins in more than one frame are shaded in pink. The frames that were used in each region are shown in grey rectangles, with frame 1 at the top and frame 3 at the bottom.

Mentions: Consistent with previous reports [5,10], we found evidence of variation in synonymous substitution rates within and across HIV-1 genes (Figure 1). For all genes the Dual Model [10], which allows independent variation of dS and dN had a much better fit to the data than a model with constant dN and dS (referred to as the Constant model in Table 2) or than a model in which only dN varied across sites (the Nonsynonymous model in Table 2). The variance of dS gives an indication of the extent of site-to-site synonymous rate heterogeneity within the different genomic regions (Table 3). There was significant variation between genes (p-value = 2 × 10-7, from Levene's test) with the least site-to-site variation in dS observed in vpu and the most in vpr followed by nef and env (Figure 2).


Extensive purifying selection acting on synonymous sites in HIV-1 Group M sequences.

Ngandu NK, Scheffler K, Moore P, Woodman Z, Martin D, Seoighe C - Virol. J. (2008)

HIV-1 genome-wide plot of mean nonsynonymous substitution rates. A 30 codon sliding window was used. Regions coding for proteins in more than one frame are shaded in pink. The frames that were used in each region are shown in grey rectangles, with frame 1 at the top and frame 3 at the bottom.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2666660&req=5

Figure 1: HIV-1 genome-wide plot of mean nonsynonymous substitution rates. A 30 codon sliding window was used. Regions coding for proteins in more than one frame are shaded in pink. The frames that were used in each region are shown in grey rectangles, with frame 1 at the top and frame 3 at the bottom.
Mentions: Consistent with previous reports [5,10], we found evidence of variation in synonymous substitution rates within and across HIV-1 genes (Figure 1). For all genes the Dual Model [10], which allows independent variation of dS and dN had a much better fit to the data than a model with constant dN and dS (referred to as the Constant model in Table 2) or than a model in which only dN varied across sites (the Nonsynonymous model in Table 2). The variance of dS gives an indication of the extent of site-to-site synonymous rate heterogeneity within the different genomic regions (Table 3). There was significant variation between genes (p-value = 2 × 10-7, from Levene's test) with the least site-to-site variation in dS observed in vpu and the most in vpr followed by nef and env (Figure 2).

Bottom Line: Synonymous substitution rates were found to vary significantly within and between genes.We found evidence of strong purifying selection pressure affecting synonymous mutations in fourteen regions with known functions.We also found four conserved regions located in env and vpu which have not been characterized previously.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Bioinformatics Network Node, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, 7925, South Africa. nobubelo@cbio.uct.ac.za

ABSTRACT

Background: Positive selection pressure acting on protein-coding sequences is usually inferred when the rate of nonsynonymous substitution is greater than the synonymous rate. However, purifying selection acting directly on the nucleotide sequence can lower the synonymous substitution rate. This could result in false inference of positive selection because when synonymous changes at some sites are under purifying selection, the average synonymous rate is an underestimate of the neutral rate of evolution. Even though HIV-1 coding sequences contain a number of regions that function at the nucleotide level, and are thus likely to be affected by purifying selection, studies of positive selection assume that synonymous substitutions can be used to estimate the neutral rate of evolution.

Results: We modelled site-to-site variation in the synonymous substitution rate across coding regions of the HIV-1 genome. Synonymous substitution rates were found to vary significantly within and between genes. Surprisingly, regions of the genome that encode proteins in more than one frame had significantly higher synonymous substitution rates than regions coding in a single frame. We found evidence of strong purifying selection pressure affecting synonymous mutations in fourteen regions with known functions. These included an exonic splicing enhancer, the rev-responsive element, the poly-purine tract and a transcription factor binding site. A further five highly conserved regions were located within known functional domains. We also found four conserved regions located in env and vpu which have not been characterized previously.

Conclusion: We provide the coordinates of genomic regions with markedly lower synonymous substitution rates, which are putatively under the influence of strong purifying selection pressure at the nucleotide level as well as regions encoding proteins in more than one frame. These regions should be excluded from studies of positive selection acting on HIV-1 coding regions.

Show MeSH