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Codon-based tests of positive selection, branch lengths, and the evolution of mammalian immune system genes

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Abstract

Using basic probability theory, we show that there is a substantial likelihood that even in the presence of strong purifying selection, there will be a number of codons in which the number of synonymous nucleotide substitutions per site (d S) exceeds the number of non-synonymous nucleotide substitutions per site (d N). In an empirical study, we examined the numbers of synonymous (b S) and non-synonymous substitutions (b N) along branches of the phylogenies of 69 single-copy orthologous genes from seven species of mammals. A pattern of b N > b S was most commonly seen in the shortest branches of the tree and was associated with a high coefficient of variation in both b N and b S, suggesting that high stochastic error in b N and b S on short branches, rather than positive Darwinian selection, is the explanation of most cases where b N is greater than b S on a given branch. The branch-site method of Zhang et al. (Zhang, Nielsen, Yang, Mol Biol Evol, 22:2472–2479, 2005) identified 117 codons on 35 branches as “positively selected,” but a majority of these codons lacked synonymous substitutions, while in the others, synonymous and non-synonymous differences per site occurred in approximately equal frequencies. Thus, it was impossible to rule out the hypothesis that chance variation in the pattern of mutation across sites, rather than positive selection, accounted for the observed pattern. Our results showed that b N/b S was consistently elevated in immune system genes, but neither the search for branches with b N > b S nor the branch-site method revealed this trend.

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Acknowledgment

This research was supported by grant GM43940 from the National Institutes of Health.

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  1. Department of Biological Sciences, University of South Carolina, Coker Life Sciences Bldg., 700 Sumter St., Columbia, SC, 29208, USA

    Austin L. Hughes & Robert Friedman

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  1. Austin L. Hughes
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  2. Robert Friedman
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Correspondence to Austin L. Hughes.

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Hughes, A.L., Friedman, R. Codon-based tests of positive selection, branch lengths, and the evolution of mammalian immune system genes. Immunogenetics 60, 495–506 (2008). https://doi.org/10.1007/s00251-008-0304-4

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