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Why do more divergent sequences produce smaller nonsynonymous/synonymous rate ratios in pairwise sequence
1Department of Genetics, Evolution, and Environment, University College London, London, WC1E 6BT, United Kingdom.
Genetics
|June 25, 2013
Summary
Statistical properties of evolutionary rate ratio (dN/dS) estimates reveal biases and correlations with sequence distance. Model misspecification, particularly among-site heterogeneity, explains observed patterns better than statistical artifacts alone.
Area of Science:
- Evolutionary biology
- Molecular evolution
- Bioinformatics
Background:
- Pairwise gene comparisons often show a negative correlation between the nonsynonymous to synonymous rate ratio (ω = dN/dS) and sequence distance (d).
- Previous explanations include segregating polymorphisms and nonlinear ratio dynamics.
Purpose of the Study:
- To investigate the statistical properties of maximum-likelihood estimates of ω and d.
- To determine if these properties fully explain the observed negative correlation.
Main Methods:
- Analysis of statistical properties of ω and d estimates in pairwise alignments.
- Exploration of model misspecification, specifically among-site heterogeneity in selection pressures.
Main Results:
- ω estimates are positively biased for small sequence distances (d), with bias decreasing as d increases.
- Estimates of ω and d are negatively correlated when ω < 1 and positively correlated when ω > 1.
- Statistical biases alone do not fully account for the strong negative correlation seen in empirical data.
Conclusions:
- Model misspecification, particularly failing to account for among-site heterogeneity in protein evolution, is a significant factor.
- This heterogeneity leads to underestimation of evolutionary rates, especially for divergent sequences.
- Tests for positive selection based on the ω ratio remain robust despite these estimation biases.
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