Genome-Wide Analysis in Vivo of Translation with Nucleotide Resolution Using Ribosome Profiling
Open accessAbstract
Techniques for systematically monitoring protein translation have lagged far behind methods for measuring messenger RNA (mRNA) levels. Here, we present a ribosome-profiling strategy that is based on the deep sequencing of ribosome-protected mRNA fragments and enables genome-wide investigation of translation with subcodon resolution. We used this technique to monitor translation in budding yeast under both rich and starvation conditions. These studies defined the protein sequences being translated and found extensive translational control in both determining absolute protein abundance and responding to environmental stress. We also observed distinct phases during translation that involve a large decrease in ribosome density going from early to late peptide elongation as well as widespread regulated initiation at non–adenine-uracil-guanine (AUG) codons. Ribosome profiling is readily adaptable to other organisms, making high-precision investigation of protein translation experimentally accessible.
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A recent study on embryonic stem cells revealed that changes in protein levels are not accompanied by changes in corresponding mRNAs.
“A recent study on embryonic stem cells revealed that changes in protein levels are not accompanied by changes in corresponding mRNAs, although this study did not discern translational and post-translational control 38 .”
From Global quantification of mammalian gene expression control (2011) · cites this paper as [38]
The Abstract says mRNA levels are an imperfect proxy for protein production, and “Genome-wide measurements of translation” reports a weaker correlation of protein abundance with mRNA abundance than with measured translation rates. But the study examines yeast, not embryonic stem cells, and those passages do not establish that changes in protein levels occurred without changes in corresponding mRNAs. (LLM, conf=0.84)
Experimental — accuracy not yet measuredFor most analyses, ribosome footprint alignments were mapped to specific A-site nucleotides using alignment position and length, with calibration from footprints at coding sequence boundaries.
“For most analyses, footprint alignments were assigned to specific A site nucleotides by using the position and total length of each alignment, calibrated from footprints at the beginning and the end of CDSes (Figures S1A and S1B) as previously described (Ingolia et al., 2009).”
From Ribosome Profiling of Mouse Embryonic Stem Cells Reveals the Complexity and Dynamics of Mammalian Proteomes (2011) · cites this paper as Ingolia et al., 2009
Mammalian protein-coding genes show widespread upstream translation, which is more extensive than the upstream translation previously seen in yeast.
“We also observe widespread translation upstream of mammalian protein-coding genes, similar to but more extensive than upstream translation that we observed in yeast (Ingolia et al., 2009).”
From Ribosome Profiling of Mouse Embryonic Stem Cells Reveals the Complexity and Dynamics of Mammalian Proteomes (2011) · cites this paper as Ingolia et al., 2009
Ribosome profiling has reported similar variation (Ingolia et al., 2009).
“Similar variation has been reported based on ribosome profiling (Ingolia et al., 2009).”
From Absolute Quantification of Protein and mRNA Abundances Demonstrate Variability in Gene-Specific Translation Efficiency in Yeast (2017) · cites this paper as Ingolia et al., 2009
For highly translated proteins, the study found a conservation pattern similar to prior work, with lysine (AAA) and serine (TCT) most frequent just before and after the start codon, respectively.
“we found a similar conservation pattern for the highly translated proteins (Gingold and Pilpel, 2011; Ingolia et al., 2009; Robbins-Pianka et al., 2010), where lysine (encoded by AAA) and serine (encoded by TCT) were the most frequently observed amino acids just before and after the start codon, respectively.”
From Absolute Quantification of Protein and mRNA Abundances Demonstrate Variability in Gene-Specific Translation Efficiency in Yeast (2017) · cites this paper as Ingolia et al., 2009
At least one of five ribosome profiling studies detects ribosomes in the coding sequence of 637 of the 864 genes with detected mRNA but no protein, suggesting active translation.
“At least one of five studies under compatible experimental conditions detects ribosomes in the coding sequence of 637 of these 864 genes, suggesting active translation.”
Wide per-gene variation exists in measurements of translational efficiency.
“Indeed, wide per-gene variation exists in measurements of translational efficiency [18, 58, 59].”
The report that translational activity, estimated by ribosome profiling, explained more than twice the protein-level variation than did measured mRNA levels [18] prompted us to more closely examine these results.
“The report that translational activity, estimated by ribosome profiling, explained more than twice the protein-level variation than did measured mRNA levels [18] prompted us to more closely examine these results.”
Such an effect was noted in passing in the earliest ribosome-profiling study.
“Such an effect was noted in passing in the earliest ribosome-profiling study [18].”
Translational efficiency increases with SCM-estimated mRNA level (Spearman r = 0.65), with some evidence for a ceiling or saturation effect at high expression levels.
“As this result implies, translational efficiency (TE) (median ribosome density divided by median normalized mRNA levels within these same studies [18, 58]) increases with SCM-estimated mRNA level (Fig 6E, Spearman rank correlation r = 0.65), with some evidence for a ceiling or saturation effect at high expression levels.”
Ribosome profiling (riboseq) has been developed as a direct method to quantify and characterize translation.
“Ribosome profiling (riboseq) has been developed as a direct method to quantify and characterize translation (Ingolia et al., 2009).”
From Addressing global ruminant agricultural challenges through understanding the rumen microbiome: past, present, and future (2018) · cites this paper as Ingolia et al., 2009
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- Authors
- Ingolia, N. T., Ghaemmaghami, S., Newman, J. R. S., & Weissman, J. S.
- Affiliations
- QB3 (US)
- Corresponding author
- Ingolia, Nicholas T.
- Ghaemmaghami, Sina
- Venue
- Science
- Published
- 2009-04-10
- Volume
- 324
- Issue
- 5924
- Pages
- 218-223
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2746483
- OpenAlex
- W2079517684
- Cited by
- 3,853
- References
- 34
- Citations by year
- 2026: 187 · 2025: 245 · 2024: 268 · 2023: 276 · 2022: 225 · 2021: 326 · 2020: 316 · 2019: 257 · 2018: 279 · 2017: 258 · 2016: 251 · 2015: 219 · 2014: 224 · 2013: 171 · 2012: 150
- FWCI
- 46.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute on Aging (AG10770, P01AG010770)
- National Institute of General Medical Sciences (F32GM080853, GM080853)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- ribosome profiling, mRNA translation, translational regulation, protein abundance, environmental stress response, ribosome density, peptide elongation, translation initiation, Saccharomyces cerevisiae, starvation
- MeSH terms
- Codon, Introns, Peptide Chain Elongation, Translational, Peptide Chain Initiation, Translational, Ribosomes, RNA, Fungal, RNA, Messenger, Saccharomyces cerevisiae, Protein Biosynthesis, Gene Library, Genome, Fungal, Sequence Analysis, DNA, 5' Untranslated Regions, Saccharomyces cerevisiae Proteins
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