Limits...
Declining transition/transversion ratios through time reveal limitations to the accuracy of nucleotide substitution models.

Duchêne S, Ho SY, Holmes EC - BMC Evol. Biol. (2015)

Bottom Line: In the majority of cases our estimates of ti/tv decrease with time, even under sophisticated time-reversible models of nucleotide substitution.In contrast, we did not find any temporal patterns in selection pressures or CG-content over these short time-frames.Our study shows that commonly used substitution models can underestimate the number of substitutions among closely related sequences, such that the time-scale of viral evolution and emergence may be systematically underestimated.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, The University of Sydney, Sydney, NSW, 2006, Australia. sebastian.duchene@sydney.edu.au.

ABSTRACT

Background: Genetic analyses of DNA sequences make use of an increasingly complex set of nucleotide substitution models to estimate the divergence between gene sequences. However, there is currently no way to assess the validity of nucleotide substitution models over short time-scales and with limited mutational accumulation.

Results: We show that quantifying the decline in the ratio of transitions to transversions (ti/tv) over time provides an in-built measure of mutational saturation and hence of substitution model accuracy. We tested this through detailed phylogenetic analyses of 10 representative virus data sets comprising recently sampled and closely related sequences. In the majority of cases our estimates of ti/tv decrease with time, even under sophisticated time-reversible models of nucleotide substitution. This indicates that high levels of saturation are attained extremely rapidly in viruses, sometimes within decades. In contrast, we did not find any temporal patterns in selection pressures or CG-content over these short time-frames. To validate the temporal trend of ti/tv across a broader taxonomic range, we analyzed a set of 76 different viruses. Again, the estimate of ti/tv scaled negatively with evolutionary time, a trend that was more pronounced for rapidly-evolving RNA viruses than slowly-evolving DNA viruses.

Conclusions: Our study shows that commonly used substitution models can underestimate the number of substitutions among closely related sequences, such that the time-scale of viral evolution and emergence may be systematically underestimated. In turn, estimates of ti/tv provide an effective internal control of substitution model performance in viruses because of their high sensitivity to mutational saturation.

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Related in: MedlinePlus

Estimates ofti/tvplotted against root-node age in a broad-scale analyses of DNA (n = 52) (black) and RNA (red) (n = 24) viruses. The points represent individual virus data sets and the lines represent the regressions. Solid circles correspond to data sets that passed the date-randomization test, whereas empty circles are those that failed the test.
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Fig3: Estimates ofti/tvplotted against root-node age in a broad-scale analyses of DNA (n = 52) (black) and RNA (red) (n = 24) viruses. The points represent individual virus data sets and the lines represent the regressions. Solid circles correspond to data sets that passed the date-randomization test, whereas empty circles are those that failed the test.

Mentions: Importantly, our broad-scale analysis of substitution patterns across a diverse array of viruses also revealed a negative association between the estimate of ti/tv and the age of the root-node in the case of RNA viruses, again indicative of site saturation. Estimates for 32 data sets were found to be unreliable according to the date-randomization test [33], such that they were excluded from the linear regression. For the remaining viruses, the slope coefficients for ti/tv as a function of the root-node age on a log10 scale were -0.78 and -2.16 for DNA and RNA viruses, respectively (Figure 3). Notably, the slope term was significant for RNA viruses (p = 0.035), but not for DNA viruses (p = 0.14), suggesting that site saturation occurs on short time-scales for the more rapidly evolving RNA viruses.Figure 3


Declining transition/transversion ratios through time reveal limitations to the accuracy of nucleotide substitution models.

Duchêne S, Ho SY, Holmes EC - BMC Evol. Biol. (2015)

Estimates ofti/tvplotted against root-node age in a broad-scale analyses of DNA (n = 52) (black) and RNA (red) (n = 24) viruses. The points represent individual virus data sets and the lines represent the regressions. Solid circles correspond to data sets that passed the date-randomization test, whereas empty circles are those that failed the test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4358783&req=5

Fig3: Estimates ofti/tvplotted against root-node age in a broad-scale analyses of DNA (n = 52) (black) and RNA (red) (n = 24) viruses. The points represent individual virus data sets and the lines represent the regressions. Solid circles correspond to data sets that passed the date-randomization test, whereas empty circles are those that failed the test.
Mentions: Importantly, our broad-scale analysis of substitution patterns across a diverse array of viruses also revealed a negative association between the estimate of ti/tv and the age of the root-node in the case of RNA viruses, again indicative of site saturation. Estimates for 32 data sets were found to be unreliable according to the date-randomization test [33], such that they were excluded from the linear regression. For the remaining viruses, the slope coefficients for ti/tv as a function of the root-node age on a log10 scale were -0.78 and -2.16 for DNA and RNA viruses, respectively (Figure 3). Notably, the slope term was significant for RNA viruses (p = 0.035), but not for DNA viruses (p = 0.14), suggesting that site saturation occurs on short time-scales for the more rapidly evolving RNA viruses.Figure 3

Bottom Line: In the majority of cases our estimates of ti/tv decrease with time, even under sophisticated time-reversible models of nucleotide substitution.In contrast, we did not find any temporal patterns in selection pressures or CG-content over these short time-frames.Our study shows that commonly used substitution models can underestimate the number of substitutions among closely related sequences, such that the time-scale of viral evolution and emergence may be systematically underestimated.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, The University of Sydney, Sydney, NSW, 2006, Australia. sebastian.duchene@sydney.edu.au.

ABSTRACT

Background: Genetic analyses of DNA sequences make use of an increasingly complex set of nucleotide substitution models to estimate the divergence between gene sequences. However, there is currently no way to assess the validity of nucleotide substitution models over short time-scales and with limited mutational accumulation.

Results: We show that quantifying the decline in the ratio of transitions to transversions (ti/tv) over time provides an in-built measure of mutational saturation and hence of substitution model accuracy. We tested this through detailed phylogenetic analyses of 10 representative virus data sets comprising recently sampled and closely related sequences. In the majority of cases our estimates of ti/tv decrease with time, even under sophisticated time-reversible models of nucleotide substitution. This indicates that high levels of saturation are attained extremely rapidly in viruses, sometimes within decades. In contrast, we did not find any temporal patterns in selection pressures or CG-content over these short time-frames. To validate the temporal trend of ti/tv across a broader taxonomic range, we analyzed a set of 76 different viruses. Again, the estimate of ti/tv scaled negatively with evolutionary time, a trend that was more pronounced for rapidly-evolving RNA viruses than slowly-evolving DNA viruses.

Conclusions: Our study shows that commonly used substitution models can underestimate the number of substitutions among closely related sequences, such that the time-scale of viral evolution and emergence may be systematically underestimated. In turn, estimates of ti/tv provide an effective internal control of substitution model performance in viruses because of their high sensitivity to mutational saturation.

Show MeSH
Related in: MedlinePlus