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MBE Advance Access originally published online on November 22, 2006
Molecular Biology and Evolution 2007 24(2):522-531; doi:10.1093/molbev/msl179
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© The Author 2006. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Research Articles

Estimating the Neutral Rate of Nucleotide Substitution Using Introns

Michael M. Hoffman*,{dagger} and Ewan Birney*

* European Molecular Biology Laboratory–European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, England
{dagger} Graduate School of Biological, Medical and Veterinary Sciences, University of Cambridge, Cambridge, England

E-mail: birney{at}ebi.ac.uk.

Accepted for publication November 15, 2006.

Evolutionary biologists frequently rely on estimates of the neutral rate of evolution when characterizing the selective pressure on protein-coding genes. We introduce a new method to estimate this value based on intron nucleotide substitutions. The new method uses a metascript model that considers alternative splicing forms and an algorithm to pair orthologous introns, which we call Introndeuce. We compare the intron method with a widely used method that uses observed substitutions in synonymous coding nucleotides, by using both methods to estimate the neutral rate for human–dog and mouse–rat comparisons. The estimates of the 2 methods correlate strongly (rS = 0.75), but cannot be considered directly equivalent. We also investigate the effect of alignment error and G + C content on the variance in the intron method: in both cases there is an effect, and it is species-pair specific. Although the intron method may be more useful for shorter evolutionary distances, it is less useful at longer distances due to the poor alignment of less-conserved positions.

Key Words: introns • neutral rate • synonymous substitution • mammals

Lauren McIntyre, Associate Editor


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