Effect of Recombination on the Accuracy of the Likelihood Method for Detecting Positive Selection at Amino Acid Sites

Effect of Recombination on the Accuracy of the Likelihood Method for Detecting Positive Selection... Maria Anisimova a,b , Rasmus Nielsen c , and Ziheng Yang a a Department of Biology, University College London, London WC1E 6BT, United Kingdom, b Center for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London WC1E 6BT, United Kingdom c Department of Biometrics, Cornell University, Ithaca, New York 14853-7801 Corresponding author: Maria Anisimova, University College London, Darwin Bldg., Gower St., London WC1E 6BT, United Kingdom., m.anisimova@ucl.ac.uk (E-mail) Communicating editor: J. H EIN Maximum-likelihood methods based on models of codon substitution accounting for heterogeneous selective pressures across sites have proved to be powerful in detecting positive selection in protein-coding DNA sequences. Those methods are phylogeny based and do not account for the effects of recombination. When recombination occurs, such as in population data, no unique tree topology can describe the evolutionary history of the whole sequence. This violation of assumptions raises serious concerns about the likelihood method for detecting positive selection. Here we use computer simulation to evaluate the reliability of the likelihood-ratio test (LRT) for positive selection in the presence of recombination. We examine three tests based on different models of variable selective pressures among sites. Sequences are simulated using a coalescent model with recombination and analyzed using codon-based likelihood models ignoring recombination. We find that the LRT is robust to low levels of recombination (with fewer than three recombination events in the history of a sample of 10 sequences). However, at higher levels of recombination, the type I error rate can be as high as 90%, especially when the null model in the LRT is unrealistic, and the test often mistakes recombination as evidence for positive selection. The test that compares the more realistic models M7 (ß) against M8 (ß and ω) is more robust to recombination, where the null model M7 allows the positive selection pressure to vary between 0 and 1 (and so does not account for positive selection), and the alternative model M8 allows an additional discrete class with ω = d N / d S that could be estimated to be >1 (and thus accounts for positive selection). Identification of sites under positive selection by the empirical Bayes method appears to be less affected than the LRT by recombination. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Genetics Genetics Society of America

Effect of Recombination on the Accuracy of the Likelihood Method for Detecting Positive Selection at Amino Acid Sites

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Publisher
Genetics Society of America
Copyright
Copyright © 2003 by the Genetics Society of America
ISSN
0016-6731
eISSN
1943-2631
Publisher site
See Article on Publisher Site

Abstract

Maria Anisimova a,b , Rasmus Nielsen c , and Ziheng Yang a a Department of Biology, University College London, London WC1E 6BT, United Kingdom, b Center for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London WC1E 6BT, United Kingdom c Department of Biometrics, Cornell University, Ithaca, New York 14853-7801 Corresponding author: Maria Anisimova, University College London, Darwin Bldg., Gower St., London WC1E 6BT, United Kingdom., m.anisimova@ucl.ac.uk (E-mail) Communicating editor: J. H EIN Maximum-likelihood methods based on models of codon substitution accounting for heterogeneous selective pressures across sites have proved to be powerful in detecting positive selection in protein-coding DNA sequences. Those methods are phylogeny based and do not account for the effects of recombination. When recombination occurs, such as in population data, no unique tree topology can describe the evolutionary history of the whole sequence. This violation of assumptions raises serious concerns about the likelihood method for detecting positive selection. Here we use computer simulation to evaluate the reliability of the likelihood-ratio test (LRT) for positive selection in the presence of recombination. We examine three tests based on different models of variable selective pressures among sites. Sequences are simulated using a coalescent model with recombination and analyzed using codon-based likelihood models ignoring recombination. We find that the LRT is robust to low levels of recombination (with fewer than three recombination events in the history of a sample of 10 sequences). However, at higher levels of recombination, the type I error rate can be as high as 90%, especially when the null model in the LRT is unrealistic, and the test often mistakes recombination as evidence for positive selection. The test that compares the more realistic models M7 (ß) against M8 (ß and ω) is more robust to recombination, where the null model M7 allows the positive selection pressure to vary between 0 and 1 (and so does not account for positive selection), and the alternative model M8 allows an additional discrete class with ω = d N / d S that could be estimated to be >1 (and thus accounts for positive selection). Identification of sites under positive selection by the empirical Bayes method appears to be less affected than the LRT by recombination.

Journal

GeneticsGenetics Society of America

Published: Jul 1, 2003

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