Genome-wide search for exonic variants affecting translational efficiency
Quan Li1, Angeliki Makri, Yang Lu
1Endocrine Genetics Laboratory, The McGill University Health Center, Montreal Children's Hospital, Montréal, Québec, Canada.
Nature Communications
|August 1, 2013
Summary
This study introduces a new method to measure how genetic variants affect gene translation efficiency. A key finding links a variant in RPS26 to type 1 diabetes risk by altering protein production.
Area of Science:
- Genomics
- Molecular Biology
- Translational Regulation
Background:
- Genetic variation primarily studied for transcriptional effects on gene expression.
- Translational regulation by genetic variants remains under-explored.
- Need for high-throughput methods to assess translational cis-regulation.
Purpose of the Study:
- To develop and apply a high-throughput method for measuring translational cis-regulation in the human genome.
- To identify genetic variants that influence messenger RNA (mRNA) translation efficiency.
- To investigate the link between translational regulation and disease susceptibility.
Main Methods:
- Utilized ribosomal association as a proxy for translational efficiency of polymorphic mRNAs.
- Assessed the ratio of polysomal/non-polysomal mRNA levels as a quantitative trait.
- Associated this quantitative trait with single nucleotide polymorphisms (SNPs) within the same mRNA transcript.
- Validated findings using quantitative western blots for protein level confirmation.
Main Results:
- Identified a significant ribosomal distribution effect from SNP rs1131017 in the 5'-untranslated region of RPS26.
- This variant is in high linkage disequilibrium with the 12q13 locus associated with type 1 diabetes susceptibility.
- Demonstrated that the identified translational effect is confirmed at the protein level.
- Established a proof-of-principle for transcriptome-wide detection of allelic effects on translation.
Conclusions:
- Developed a scalable method to detect translational cis-regulation across the human transcriptome.
- Allelic effects on translation can significantly impact disease susceptibility, as exemplified by the RPS26 variant and type 1 diabetes.
- This approach opens new avenues for understanding genetic contributions to disease through post-transcriptional mechanisms.
Related Concept Videos
02:28Leaky Scanning
During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA. Marilyn Kozak discovered that the sequence RCCAUGG (where R stands for...
02:24Ribosome Profiling
Ribosome profiling or ribo-sequencing is a deep sequencing technique that produces a snapshot of active translation in a cell. It selectively sequences the mRNAs protected by ribosomes to get an insight into a cell’s translation landscape at any given point in time.
Applications of ribosome profiling
Ribosome profiling has many applications, including in vivo monitoring of translation inside a particular organ or tissue type and quantifying new protein synthesis levels.
The technique helps...
Applications of ribosome profiling
Ribosome profiling has many applications, including in vivo monitoring of translation inside a particular organ or tissue type and quantifying new protein synthesis levels.
The technique helps...
01:31Translation
Lesson: Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
01:31Translation
Lesson: Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
01:29Translational Regulation
Translational regulation in prokaryotes ensures efficient protein synthesis by controlling ribosome access to mRNA. This regulation is mediated by secondary RNA structures, including translational riboswitches, RNA thermometers, and small RNAs (sRNAs), which respond to intracellular and environmental signals to modulate gene expression.Translational RiboswitchesRiboswitches in the leader region of mRNAs can regulate translation by altering the accessibility of the Shine-Dalgarno (SD) sequence,...
02:07Improving Translational Accuracy
Base complementarity between the three base pairs of mRNA codon and the tRNA anticodon is not a failsafe mechanism. Inaccuracies can range from a single mismatch to no correct base pairing at all. The free energy difference between the correct and nearly correct base pairs can be as small as 3 kcal/ mol. With complementarity being the only proofreading step, the estimated error frequency would be one wrong amino acid in every 100 amino acids incorporated. However, error frequencies observed in...