TY  - JOUR
A1  - Kirchner, Sebastian
A1  - Cai, Zhiwei
A1  - Rauscher, Robert
A1  - Kastelic, Nicolai
A1  - Anding, Melanie
A1  - Czech, Andreas
A1  - Kleizen, Bertrand
A1  - Ostedgaard, Lynda S.
A1  - Braakman, Ineke
A1  - Sheppard, David N.
A1  - Ignatova, Zoya
T1  - Alteration of protein function by a silent polymorphism linked to tRNA abundance
JF  - PLoS biology
N2  - Synonymous single nucleotide polymorphisms (sSNPs) are considered neutral for protein function, as by definition they exchange only codons, not amino acids. We identified an sSNP that modifies the local translation speed of the cystic fibrosis transmembrane conductance regulator (CFTR), leading to detrimental changes to protein stability and function. This sSNP introduces a codon pairing to a low-abundance tRNA that is particularly rare in human bronchial epithelia, but not in other human tissues, suggesting tissue-specific effects of this sSNP. Up-regulation of the tRNA cognate to the mutated codon counteracts the effects of the sSNP and rescues protein conformation and function. Our results highlight the wide-ranging impact of sSNPs, which invert the programmed local speed of mRNA translation and provide direct evidence for the central role of cellular tRNA levels in mediating the actions of sSNPs in a tissue-specific manner.
Y1  - 2017
U6  - https://doi.org/10.1371/journal.pbio.2000779
SN  - 1545-7885
VL  - 15
PB  - PLoS
CY  - San Fransisco
ER  - 
TY  - JOUR
A1  - Bentele, Kajetan
A1  - Saffert, Paul
A1  - Rauscher, Robert
A1  - Ignatova, Zoya
A1  - Bluethgen, Nils
T1  - Efficient translation initiation dictates codon usage at gene start
JF  - Molecular systems biology
N2  - The genetic code is degenerate; thus, protein evolution does not uniquely determine the coding sequence. One of the puzzles in evolutionary genetics is therefore to uncover evolutionary driving forces that result in specific codon choice. In many bacteria, the first 5-10 codons of protein-coding genes are often codons that are less frequently used in the rest of the genome, an effect that has been argued to arise from selection for slowed early elongation to reduce ribosome traffic jams. However, genome analysis across many species has demonstrated that the region shows reduced mRNA folding consistent with pressure for efficient translation initiation. This raises the possibility that unusual codon usage is a side effect of selection for reduced mRNA structure. Here we discriminate between these two competing hypotheses, and show that in bacteria selection favours codons that reduce mRNA folding around the translation start, regardless of whether these codons are frequent or rare. Experiments confirm that primarily mRNA structure, and not codon usage, at the beginning of genes determines the translation rate.
KW  - codon usage
KW  - mRNA structure
KW  - translation
Y1  - 2013
U6  - https://doi.org/10.1038/msb.2013.32
SN  - 1744-4292
VL  - 9
IS  - 6
PB  - Nature Publ. Group
CY  - New York
ER  -