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Originally published as Genetics Published Articles Ahead of Print on December 30, 2005.

Genetics, Vol. 172, 1411-1425, March 2006, Copyright © 2006
doi:10.1534/genetics.105.044917

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Estimating Diversifying Selection and Functional Constraint in the Presence of Recombination

Daniel J. Wilson1 and Gilean McVean

Department of Statistics, University of Oxford, Oxford OX1 3TG, United Kingdom

1 Corresponding author: Department of Statistics, 1 South Parks Rd., Oxford OX1 3TG, United Kingdom.
E-mail: daniel.wilson{at}sjc.ox.ac.uk

Models of molecular evolution that incorporate the ratio of nonsynonymous to synonymous polymorphism (dN/dS ratio) as a parameter can be used to identify sites that are under diversifying selection or functional constraint in a sample of gene sequences. However, when there has been recombination in the evolutionary history of the sequences, reconstructing a single phylogenetic tree is not appropriate, and inference based on a single tree can give misleading results. In the presence of high levels of recombination, the identification of sites experiencing diversifying selection can suffer from a false-positive rate as high as 90%. We present a model that uses a population genetics approximation to the coalescent with recombination and use reversible-jump MCMC to perform Bayesian inference on both the dN/dS ratio and the recombination rate, allowing each to vary along the sequence. We demonstrate that the method has the power to detect variation in the dN/dS ratio and the recombination rate and does not suffer from a high false-positive rate. We use the method to analyze the porB gene of Neisseria meningitidis and verify the inferences using prior sensitivity analysis and model criticism techniques.




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