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Causal signals between codon bias, mRNA structure, and the efficiency of translation and elongation.

Pop C, Rouskin S, Ingolia NT, Han L, Phizicky EM, Weissman JS, Koller D - Mol. Syst. Biol. (2014)

Bottom Line: We present a robust method to extract codon translation rates and protein synthesis rates from these data, and identify causal features associated with elongation and translation efficiency in physiological conditions in yeast.Deletion of three of the four copies of the heavily used ACA tRNA shows a modest efficiency decrease that could be explained by other rate-reducing signals at gene start.We also show a correlation between efficiency and RNA structure calculated both computationally and from recent structure probing data, as well as the Kozak initiation motif, which may comprise a mechanism to regulate initiation.

View Article: PubMed Central - PubMed

Affiliation: Computer Science Department, Stanford University, Stanford, CA, USA cpop@cs.stanford.edu.

No MeSH data available.


Related in: MedlinePlus

Estimated Kozak motif for efficient genesEstimated TE-driven Kozak motif based on a regression model (see Materials and Methods). The original Kozak consensus for yeast (Hamilton et al, 1987) is WAMAMAATGTCY.
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fig07: Estimated Kozak motif for efficient genesEstimated TE-driven Kozak motif based on a regression model (see Materials and Methods). The original Kozak consensus for yeast (Hamilton et al, 1987) is WAMAMAATGTCY.

Mentions: In addition to low structure at the start codon, initiation may be assisted by recognition of a 12-mer motif around the start codon called the Kozak sequence in eukaryotes (Kozak, 1981), derived in yeast based on a sequence consensus from highly expressed genes by Hamilton et al (1987). As expected, due to a tight correlation between mRNA abundance and TE (Supplementary Fig S7), similarity to the Kozak motif correlates strongly to TE (Spearman r = −0.21, P < 10−45) (measuring similarity by Kullback–Leibler divergence to the position weight matrix where 0 divergence means a closer match). The 3rd nucleotide preceding AUG is the most significant (Spearman r = −0.17, P < 10−29), consistent with experimental measures of initiation efficiency after modifying positions in the Kozak site (Looman & Kuivenhoven, 1993; Yun et al, 1996). Using a linear regression model for predicting TE based on a set of correlates suggested in the literature (see Materials and Methods), we learn a refined Kozak motif to reflect highly efficient genes (Fig7). Our learned Kozak motif reduces the error of our regression model predictions relative to an equivalent model using the original motif (from 0.84 to 0.75, averaged over 100 test sets selected randomly, compared to a model error of 0.97) (Supplementary Table S4). This indicates that our refined motif better corresponds to highly translated genes, likely because it was trained directly on translation efficiency measurements rather than on a proxy such as mRNA abundance.


Causal signals between codon bias, mRNA structure, and the efficiency of translation and elongation.

Pop C, Rouskin S, Ingolia NT, Han L, Phizicky EM, Weissman JS, Koller D - Mol. Syst. Biol. (2014)

Estimated Kozak motif for efficient genesEstimated TE-driven Kozak motif based on a regression model (see Materials and Methods). The original Kozak consensus for yeast (Hamilton et al, 1987) is WAMAMAATGTCY.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4300493&req=5

fig07: Estimated Kozak motif for efficient genesEstimated TE-driven Kozak motif based on a regression model (see Materials and Methods). The original Kozak consensus for yeast (Hamilton et al, 1987) is WAMAMAATGTCY.
Mentions: In addition to low structure at the start codon, initiation may be assisted by recognition of a 12-mer motif around the start codon called the Kozak sequence in eukaryotes (Kozak, 1981), derived in yeast based on a sequence consensus from highly expressed genes by Hamilton et al (1987). As expected, due to a tight correlation between mRNA abundance and TE (Supplementary Fig S7), similarity to the Kozak motif correlates strongly to TE (Spearman r = −0.21, P < 10−45) (measuring similarity by Kullback–Leibler divergence to the position weight matrix where 0 divergence means a closer match). The 3rd nucleotide preceding AUG is the most significant (Spearman r = −0.17, P < 10−29), consistent with experimental measures of initiation efficiency after modifying positions in the Kozak site (Looman & Kuivenhoven, 1993; Yun et al, 1996). Using a linear regression model for predicting TE based on a set of correlates suggested in the literature (see Materials and Methods), we learn a refined Kozak motif to reflect highly efficient genes (Fig7). Our learned Kozak motif reduces the error of our regression model predictions relative to an equivalent model using the original motif (from 0.84 to 0.75, averaged over 100 test sets selected randomly, compared to a model error of 0.97) (Supplementary Table S4). This indicates that our refined motif better corresponds to highly translated genes, likely because it was trained directly on translation efficiency measurements rather than on a proxy such as mRNA abundance.

Bottom Line: We present a robust method to extract codon translation rates and protein synthesis rates from these data, and identify causal features associated with elongation and translation efficiency in physiological conditions in yeast.Deletion of three of the four copies of the heavily used ACA tRNA shows a modest efficiency decrease that could be explained by other rate-reducing signals at gene start.We also show a correlation between efficiency and RNA structure calculated both computationally and from recent structure probing data, as well as the Kozak initiation motif, which may comprise a mechanism to regulate initiation.

View Article: PubMed Central - PubMed

Affiliation: Computer Science Department, Stanford University, Stanford, CA, USA cpop@cs.stanford.edu.

No MeSH data available.


Related in: MedlinePlus