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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.


Model of protein synthesisRibosomes initiate translation with a protein synthesis rate or flow (J) of ribosomes. This is conserved across the strand, so that at each residue (m,k) the flow depends on the dwell time of the ribosome (μ) and the ribosome occupancy (proportional to footprint count d). Slower positions, for example, (m,2) compared to (m,1), can inflate the average footprint count per gene and must be accounted for when estimating flow. Dwell times and flow are correlated with local and global cis-features.
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fig01: Model of protein synthesisRibosomes initiate translation with a protein synthesis rate or flow (J) of ribosomes. This is conserved across the strand, so that at each residue (m,k) the flow depends on the dwell time of the ribosome (μ) and the ribosome occupancy (proportional to footprint count d). Slower positions, for example, (m,2) compared to (m,1), can inflate the average footprint count per gene and must be accounted for when estimating flow. Dwell times and flow are correlated with local and global cis-features.

Mentions: Our model inputs are the set of ribosome footprint counts d at each codon in the genome, sparsely sampled (due to sequencing depth) from an unobserved steady-state distribution π. In particular, dmk is the observed footprint count at position k in mRNA message m and πmk encodes the fraction of ribosomes at (m,k). Consequently, the distribution must satisfy flow conservation constraints: If ribosomes do not fall off the message, then due to conservation of matter, the protein synthesis rate Jm for message m (the ribosome flow out of the stop codon) must be the same as the flow Jmk from any position k on m. If we define μmk as the dwell time of the ribosome at (m,k), flow conservation also implies that rapidly translating positions (small μmk) are occupied for a smaller fraction of time (small πmk) than positions that are slow to translate. The dwell time μmk is the inverse of the rate at which the ribosome elongates off of position (m,k) and so intuitively depends on the amount of time the ribosome requires to perform one elongation step (recruit tRNA, form the peptide bond, and translocate). Thus, at steady-state, flow Jmk is proportional (up to a constant encoding the number of ribosomes in the system) to πmk/μmk, where we use dmk throughout as our observed proxy for πmk. Figure1 shows the relationship between the variables.


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)

Model of protein synthesisRibosomes initiate translation with a protein synthesis rate or flow (J) of ribosomes. This is conserved across the strand, so that at each residue (m,k) the flow depends on the dwell time of the ribosome (μ) and the ribosome occupancy (proportional to footprint count d). Slower positions, for example, (m,2) compared to (m,1), can inflate the average footprint count per gene and must be accounted for when estimating flow. Dwell times and flow are correlated with local and global cis-features.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: Model of protein synthesisRibosomes initiate translation with a protein synthesis rate or flow (J) of ribosomes. This is conserved across the strand, so that at each residue (m,k) the flow depends on the dwell time of the ribosome (μ) and the ribosome occupancy (proportional to footprint count d). Slower positions, for example, (m,2) compared to (m,1), can inflate the average footprint count per gene and must be accounted for when estimating flow. Dwell times and flow are correlated with local and global cis-features.
Mentions: Our model inputs are the set of ribosome footprint counts d at each codon in the genome, sparsely sampled (due to sequencing depth) from an unobserved steady-state distribution π. In particular, dmk is the observed footprint count at position k in mRNA message m and πmk encodes the fraction of ribosomes at (m,k). Consequently, the distribution must satisfy flow conservation constraints: If ribosomes do not fall off the message, then due to conservation of matter, the protein synthesis rate Jm for message m (the ribosome flow out of the stop codon) must be the same as the flow Jmk from any position k on m. If we define μmk as the dwell time of the ribosome at (m,k), flow conservation also implies that rapidly translating positions (small μmk) are occupied for a smaller fraction of time (small πmk) than positions that are slow to translate. The dwell time μmk is the inverse of the rate at which the ribosome elongates off of position (m,k) and so intuitively depends on the amount of time the ribosome requires to perform one elongation step (recruit tRNA, form the peptide bond, and translocate). Thus, at steady-state, flow Jmk is proportional (up to a constant encoding the number of ribosomes in the system) to πmk/μmk, where we use dmk throughout as our observed proxy for πmk. Figure1 shows the relationship between the variables.

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.