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Non-Silent Story on Synonymous Sites in Voltage-Gated Ion Channel Genes

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posted on 2013-11-22, 00:00 authored by Tong Zhou, Eun A. Ko, Wanjun Gu, Inja Lim, Hyoweon Bang, Jae-Hong Ko
Synonymous mutations are usually referred to as ‘‘silent’’, but increasing evidence shows that they are not neutral in a wide range of organisms. We looked into the relationship between synonymous codon usage bias and residue importance of voltage-gated ion channel proteins in mice, rats, and humans. We tested whether translationally optimal codons are associated with transmembrane or channel-forming regions, i.e., the sites that are particularly likely to be involved in the closing and opening of an ion channel. Our hypothesis is that translationally optimal codons are preferred at the sites within transmembrane domains or channel-forming regions in voltage-gated ion channel genes to avoid mistranslation-induced protein misfolding or loss-of-function. Using the Mantel-Haenszel procedure, which applies to categorical data, we found that translationally optimal codons are more likely to be used at transmembrane residues and the residues involved in channel-forming. We also found that the conservation level at synonymous sites in the transmembrane region is significantly higher than that in the non-transmembrane region. This study provides evidence that synonymous sites in voltage-gated ion channel genes are not neutral. Silent mutations at channel-related sites may lead to dysfunction of the ion channel.


This work was supported by the Korea Research Foundation ( Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2011-0016587).


Publisher Statement

© 2012 Zhou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Zhou T, Ko EA, Gu W, Lim I, Bang H, Ko JH.. (2012) Non-Silent Story on Synonymous Sites in Voltage-Gated Ion Channel Genes. PLoS ONE 7(10): e48541. doi:10.1371/journal.pone.0048541


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