Optimal codon pair bias design (extended abstract)

Abstract Motivation Synthesizing proteins in heterologous hosts is an important tool in biotechnology. However, the genetic code is degenerate and the codon usage is biased in many organisms. Synonymous codon changes that are customized for each host organism may have a significant effect on the level of protein expression. This effect can be measured by using metrics, such as codon adaptation index, codon pair bias, relative codon bias and relative codon pair bias. Codon optimization is designing codons that improve one or more of these objectives. Currently available algorithms and software solutions either rely on heuristics without providing optimality guarantees or are very rigid in modeling different objective functions and restrictions. Results We develop an effective mixed integer linear programing (MILP) formulation, which considers multiple objectives. Our numerical study shows that this formulation can be effectively used to generate (Pareto) optimal codon designs even for very long amino acid sequences using a standard commercial solver. We also show that one can obtain designs in the efficient frontier in reasonable solution times and incorporate other complex objectives, such as mRNA secondary structures in codon design using MILP formulations. Availability and implementation http://alpersen.bilkent.edu.tr/codonoptimization/CodonOptimization.zip.

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Development of a rabies virus-based retrograde tracer with high trans-monosynaptic efficiency by reshuffling glycoprotein

Molecular Brain ◽

10.1186/s13041-021-00821-7 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Fan Jia ◽

Li Li ◽

Haizhou Liu ◽

Pei Lv ◽

Xiangwei Shi ◽

...

Keyword(s):

Experimental Data ◽

Rabies Virus ◽

Oncolytic Virus ◽

Neural Circuits ◽

Bioinformatic Analysis ◽

Cell Engineering ◽

Bias Score ◽

Codon Pair Bias ◽

Codon Pair

AbstractRabies virus (RV) is the most widely used vector for mapping neural circuits. Previous studies have shown that the RV glycoprotein can be a target to improve the retrograde transsynaptic tracing efficiency. However, the current versions still label only a small portion of all presynaptic neurons. Here, we reshuffled the oG sequence, a chimeric glycoprotein, with positive codon pair bias score (CPBS) based on bioinformatic analysis of mouse codon pair bias, generating ooG, a further optimized glycoprotein. Our experimental data reveal that the ooG has a higher expression level than the oG in vivo, which significantly increases the tracing efficiency by up to 12.6 and 62.1-fold compared to oG and B19G, respectively. The new tool can be used for labeling neural circuits Therefore, the approach reported here provides a convenient, efficient and universal strategy to improve protein expression for various application scenarios such as trans-synaptic tracing efficiency, cell engineering, and vaccine and oncolytic virus designs.

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Changes in codon-pair bias of human immunodeficiency virus type 1 have profound effects on virus replication in cell culture

Retrovirology ◽

10.1186/1742-4690-10-78 ◽

2013 ◽

Vol 10 (1) ◽

pp. 78 ◽

Cited By ~ 52

Author(s):

Gloria Martrus ◽

Maria Nevot ◽

Cristina Andres ◽

Bonaventura Clotet ◽

Miguel Martinez

Keyword(s):

Cell Culture ◽

Human Immunodeficiency Virus ◽

Virus Replication ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Codon Pair Bias ◽

Immunodeficiency Virus ◽

Codon Pair

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Extensive recoding of dengue virus type 2 specifically reduces replication in primate cells without gain-of-function in Aedes aegypti mosquitoes

10.1101/365189 ◽

2018 ◽

Author(s):

Charles B. Stauft ◽

Sam H. Shen ◽

Yutong Song ◽

Oleksandr Gorbatsevych ◽

Emmanuel Asare ◽

...

Keyword(s):

Aedes Aegypti ◽

Dengue Virus ◽

Dengue Shock Syndrome ◽

Great Promise ◽

Gain Of Function ◽

Codon Pair Bias ◽

Life Threatening ◽

Codon Pair ◽

Codon Pairs ◽

And Control

AbstractDengue virus (DENV), an arthropod-borne (“arbovirus”) virus causing a range of human maladies ranging from self-limiting dengue fever to the life-threatening dengue shock syndrome, proliferates well in two different taxa of the Animal Kingdom, mosquitoes and primates. Unexpectedly, mosquitoes and primates have distinct preferences when expressing their genes by translation, e.g. members of these taxa show taxonomic group-specific intolerance to certain codon pairs. This is called “codon pair bias”. By necessity, arboviruses evolved to delicately balance this fundamental difference in their ORFs. Using the mosquito-borne human pathogen DENV we have undone the evolutionarily conserved genomic balance in its ORF sequence and specifically shifted the encoding preference away from primates. However, this recoding of DENV raised concerns of ‘gain-of-function,’ namely whether recoding could inadvertently increase fitness for replication in the arthropod vector. Using mosquito cell cultures and two strains of Aedes aegypti we did not observe any increase in fitness in DENV2 variants codon pair deoptimized for humans. This ability to disrupt and control an arbovirus’s host preference has great promise towards developing the next generation of synthetic vaccines not only for DENV but for other emerging arboviral pathogens such as chikungunya virus and Zika virus.

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A Codon-Pair Bias Associated With Network Interactions in Influenza A, B, and C Genomes

Frontiers in Genetics ◽

10.3389/fgene.2021.699141 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ewan P. Plant ◽

Zhiping Ye

Keyword(s):

Influenza Virus ◽

Rna Structure ◽

Influenza A ◽

Protein Translation ◽

Virus Evolution ◽

Codon Pair Bias ◽

Different Types ◽

Codon Pair ◽

Codon Pairs ◽

Insight Into

A new codon-pair bias present in the genomes of different types of influenza virus is described. Codons with fewer network interactions are more frequency paired together than other codon-pairs in influenza A, B, and C genomes. A shared feature among three different influenza types suggests an evolutionary bias. Codon-pair preference can affect both speed of protein translation and RNA structure. This newly identified bias may provide insight into drivers of virus evolution.

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The Deoptimization of Rabies Virus Matrix Protein Impacts Viral Transcription and Replication

Viruses ◽

10.3390/v12010004 ◽

2019 ◽

Vol 12 (1) ◽

pp. 4 ◽

Cited By ~ 1

Author(s):

Jun Luo ◽

Yue Zhang ◽

Qiong Zhang ◽

Yuting Wu ◽

Boyue Zhang ◽

...

Keyword(s):

Rabies Virus ◽

Matrix Protein ◽

Early Stage ◽

Viral Proteins ◽

Codon Pair Bias ◽

Codon Pair ◽

Codon Deoptimization ◽

Cell Spread ◽

Transcription And Replication

Rabies virus (RABV) matrix (M) protein plays several important roles during RABV infection. Although previous studies have assessed the functions of M through gene rearrangements, this interferes with the position of other viral proteins. In this study, we attenuated M expression through deoptimizing its codon usage based on codon pair bias in RABV. This strategy more objectively clarifies the role of M during virus infection. Codon-deoptimized M inhibited RABV replication during the early stages of infection, but enhanced viral titers at later stages. Codon-deoptimized M also inhibited genome synthesis at early stage of infection and increased the RABV transcription rates. Attenuated M through codon deoptimization enhanced RABV glycoprotein expression following RABV infection in neuronal cells, but had no influence on the cell-to-cell spread of RABV. In addition, codon-deoptimized M virus induced higher levels of apoptosis compared to the parental RABV. These results indicate that codon-deoptimized M increases glycoprotein expression, providing a foundation for further investigation of the role of M during RABV infection.

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