Distinct responses to rare codons in select Drosophila tissues

Codon usage bias has long been appreciated to influence protein production. Yet, relatively few studies have analyzed the impacts of codon usage on tissue-specific mRNA and protein expression. Here, we use codon-modified reporters to perform an organism-wide screen in Drosophila melanogaster for distinct tissue responses to codon usage bias. These reporters reveal a cliff-like decline of protein expression near the limit of rare codon usage in endogenously expressed Drosophila genes. Near the edge of this limit, however, we find the testis and brain are uniquely capable of expressing rare codon-enriched reporters. We define a new metric of tissue-specific codon usage, the tissue-apparent Codon Adaptation Index, to reveal a conserved enrichment for rare codon usage in the endogenously expressed genes of both Drosophila and human testis. We further demonstrate a role for rare codons in restricting protein expression of an evolutionarily young gene, RpL10Aa, to the Drosophila testis. Rare codon-mediated restriction of this testis-specific protein is critical for female fertility. Our work highlights distinct responses to rarely used codons in select tissues, revealing a critical role for codon bias in tissue biology.

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Codon usage biases co-evolve with transcription termination machinery to suppress premature cleavage and polyadenylation

eLife ◽

10.7554/elife.33569 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 22

Author(s):

Zhipeng Zhou ◽

Yunkun Dang ◽

Mian Zhou ◽

Haiyan Yuan ◽

Yi Liu

Keyword(s):

Protein Expression ◽

Codon Usage ◽

Codon Usage Bias ◽

Transcription Termination ◽

Model Organism ◽

Open Reading Frames ◽

Strong Negative Correlation ◽

Rare Codons ◽

Cleavage And Polyadenylation ◽

Mouse Cells

Codon usage biases are found in all genomes and influence protein expression levels. The codon usage effect on protein expression was thought to be mainly due to its impact on translation. Here, we show that transcription termination is an important driving force for codon usage bias in eukaryotes. Using Neurospora crassa as a model organism, we demonstrated that introduction of rare codons results in premature transcription termination (PTT) within open reading frames and abolishment of full-length mRNA. PTT is a wide-spread phenomenon in Neurospora, and there is a strong negative correlation between codon usage bias and PTT events. Rare codons lead to the formation of putative poly(A) signals and PTT. A similar role for codon usage bias was also observed in mouse cells. Together, these results suggest that codon usage biases co-evolve with the transcription termination machinery to suppress premature termination of transcription and thus allow for optimal gene expression.

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Overcoming codon-usage bias in heterologous protein expression in Streptococcus gordonii

Microbiology ◽

10.1099/mic.0.030064-0 ◽

2009 ◽

Vol 155 (11) ◽

pp. 3581-3588 ◽

Cited By ~ 9

Author(s):

Song F. Lee ◽

Yi-Jing Li ◽

Scott A. Halperin

Keyword(s):

Protein Expression ◽

Codon Usage ◽

Codon Usage Bias ◽

Heterologous Protein ◽

Trna Gene ◽

Heterologous Protein Expression ◽

Streptococcus Gordonii ◽

Heterologous Proteins ◽

Single Chain ◽

Rare Codons

One of the limitations facing the development of Streptococcus gordonii into a successful vaccine vector is the inability of this bacterium to express high levels of heterologous proteins. In the present study, we have identified 12 codons deemed as rare codons in S. gordonii and seven other streptococcal species. tRNA genes encoding 10 of the 12 rare codons were cloned into a plasmid. The plasmid was transformed into strains of S. gordonii expressing the fusion protein SpaP/S1, the anti-complement receptor 1 (CR1) single-chain variable fragment (scFv) antibody, or the Toxoplasma gondii cyclophilin C18 protein. These three heterologous proteins contained high percentages of amino acids encoded by rare codons. The results showed that the production of SpaP/S1, anti-CR1 scFv and C18 increased by 2.7-, 120- and 10-fold, respectively, over the control strains. In contrast, the production of the streptococcal SpaP protein without the pertussis toxin S1 fragment was not affected by tRNA gene supplementation, indicating that the increased production of SpaP/S1 protein was due to the ability to overcome the limitation caused by rare codons required for the S1 fragment. The increase in anti-CR1 scFv production was also observed in Streptococcus mutans following tRNA gene supplementation. Collectively, the findings in the present study demonstrate for the first time, to the best of our knowledge, that codon-usage bias exists in Streptococcus spp. and the limitation of heterologous protein expression caused by codon-usage bias can be overcome by tRNA supplementation.

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Protein Expression from Measles (MV) L Protein Genes Optimized and Suboptimized to Human and Canine Codon Usage Bias Varies with Construct and Cell Type

The FASEB Journal ◽

10.1096/fasebj.2018.32.1_supplement.819.20 ◽

2018 ◽

Vol 32 (S1) ◽

Author(s):

Akash Shah ◽

Elizabeth W. Uhl ◽

Michelle L. Osborn ◽

Frank Michel ◽

Robert J. Hogan

Keyword(s):

Protein Expression ◽

Codon Usage ◽

Codon Usage Bias ◽

Cell Type ◽

L Protein

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Tissue-Specific Protein Expression in Plant Mitochondria.

The Plant Cell ◽

10.1105/tpc.6.1.85 ◽

1994 ◽

pp. 85-91 ◽

Cited By ~ 31

Author(s):

C. A. Conley ◽

M. R. Hanson

Keyword(s):

Protein Expression ◽

Plant Mitochondria ◽

Specific Protein ◽

Tissue Specific

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The Critical Role of Codon Composition on the Translation Efficiency Robustness of the Hepatitis A Virus Capsid

Genome Biology and Evolution ◽

10.1093/gbe/evz146 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2439-2456 ◽

Cited By ~ 2

Author(s):

Lucía D’Andrea ◽

Francisco-Javier Pérez-Rodríguez ◽

Montserrat de Castellarnau ◽

Susana Guix ◽

Enric Ribes ◽

...

Keyword(s):

Codon Usage ◽

Sequence Space ◽

Hepatitis A ◽

Hepatitis A Virus ◽

Critical Role ◽

Translation Efficiency ◽

Rare Codons ◽

Codon Composition ◽

Cellular Genome

AbstractHepatoviruses show an intriguing deviated codon usage, suggesting an evolutionary signature. Abundant and rare codons in the cellular genome are scarce in the human hepatitis A virus (HAV) genome, while intermediately abundant host codons are abundant in the virus. Genotype–phenotype maps, or fitness landscapes, are a means of representing a genotype position in sequence space and uncovering how genotype relates to phenotype and fitness. Using genotype–phenotype maps of the translation efficiency, we have shown the critical role of the HAV capsid codon composition in regulating translation and determining its robustness. Adaptation to an environmental perturbation such as the artificial induction of cellular shutoff—not naturally occurring in HAV infection—involved movements in the sequence space and dramatic changes of the translation efficiency. Capsid rare codons, including abundant and rare codons of the cellular genome, slowed down the translation efficiency in conditions of no cellular shutoff. In contrast, rare capsid codons that are abundant in the cellular genome were efficiently translated in conditions of shutoff. Capsid regions very rich in slowly translated codons adapt to shutoff through sequence space movements from positions with highly robust translation to others with diminished translation robustness. These movements paralleled decreases of the capsid physical and biological robustness, and resulted in the diversification of capsid phenotypes. The deviated codon usage of extant hepatoviruses compared with that of their hosts may suggest the occurrence of a virus ancestor with an optimized codon usage with respect to an unknown ancient host.

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