Quantifying shifts in natural selection on codon usage between protein regions: a population genetics approach
Abstract
Codon usage bias (CUB), the non-uniform usage of synonymous codons, occurs across all domains of life. Adaptive CUB is hypothesized to result from various selective pressures, including selection for efficient ribosome elongation, accurate translation, mRNA secondary structure, and/or protein folding. Given the critical link between protein folding and protein function, numerous studies have analyzed the relationship between codon usage and protein structure. The results from these studies have often been contradictory, likely reflecting the differing methods used for measuring codon usage and the failure to appropriately control for confounding factors, such as differences in amino acid usage between protein structures and changes in the frequency of different structures with gene expression. Here we take an explicit population genetics approach to quantify codon-specific shifts in natural selection related to protein structure in S. cerevisiae and E. coli. Unlike other metrics of codon usage, our approach explicitly separates the effects of natural selection, scaled by gene expression, and mutation bias while naturally accounting for a region’s amino acid usage. Bayesian model comparisons suggest selection on codon usage varies only slightly between helix, sheet, and coil secondary structures and, similarly, between structured and intrinsically-disordered regions. Similarly, in contrast to previous findings, we findmore »
- Authors:
-
- Univ. of Tennessee, Knoxville, TN (United States); Rutgers Univ., Piscataway, NJ (United States)
- Univ. of Tennessee, Knoxville, TN (United States); National Institute for Mathematical and Biological Synthesis, Knoxville, TN (United States)
- Publication Date:
- Research Org.:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Center for Bioenergy Innovation (CBI)
- Sponsoring Org.:
- USDOE; National Science Foundation (NSF)
- OSTI Identifier:
- 1983037
- Grant/Contract Number:
- AC05-00OR22725; MCB-1546402; DBI-1936046; DBI-1300426
- Resource Type:
- Accepted Manuscript
- Journal Name:
- BMC Genomics
- Additional Journal Information:
- Journal Volume: 23; Journal Issue: 1; Journal ID: ISSN 1471-2164
- Publisher:
- Springer
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; codon usage bias; protein folding; protein secondary structure; population genetics
Citation Formats
Cope, Alexander L., and Gilchrist, Michael A. Quantifying shifts in natural selection on codon usage between protein regions: a population genetics approach. United States: N. p., 2022.
Web. doi:10.1186/s12864-022-08635-0.
Cope, Alexander L., & Gilchrist, Michael A. Quantifying shifts in natural selection on codon usage between protein regions: a population genetics approach. United States. https://doi.org/10.1186/s12864-022-08635-0
Cope, Alexander L., and Gilchrist, Michael A. Mon .
"Quantifying shifts in natural selection on codon usage between protein regions: a population genetics approach". United States. https://doi.org/10.1186/s12864-022-08635-0. https://www.osti.gov/servlets/purl/1983037.
@article{osti_1983037,
title = {Quantifying shifts in natural selection on codon usage between protein regions: a population genetics approach},
author = {Cope, Alexander L. and Gilchrist, Michael A.},
abstractNote = {Codon usage bias (CUB), the non-uniform usage of synonymous codons, occurs across all domains of life. Adaptive CUB is hypothesized to result from various selective pressures, including selection for efficient ribosome elongation, accurate translation, mRNA secondary structure, and/or protein folding. Given the critical link between protein folding and protein function, numerous studies have analyzed the relationship between codon usage and protein structure. The results from these studies have often been contradictory, likely reflecting the differing methods used for measuring codon usage and the failure to appropriately control for confounding factors, such as differences in amino acid usage between protein structures and changes in the frequency of different structures with gene expression. Here we take an explicit population genetics approach to quantify codon-specific shifts in natural selection related to protein structure in S. cerevisiae and E. coli. Unlike other metrics of codon usage, our approach explicitly separates the effects of natural selection, scaled by gene expression, and mutation bias while naturally accounting for a region’s amino acid usage. Bayesian model comparisons suggest selection on codon usage varies only slightly between helix, sheet, and coil secondary structures and, similarly, between structured and intrinsically-disordered regions. Similarly, in contrast to previous findings, we find selection on codon usage only varies slightly at the termini of helices in E. coli. Using simulated data, we show this previous work indicating “non-optimal” codons are enriched at the beginning of helices in S. cerevisiae was due to failure to control for various confounding factors (e.g. amino acid biases, gene expression, etc.), and rather than selection to modulate cotranslational folding. Our results reveal a weak relationship between codon usage and protein structure, indicating that differences in selection on codon usage between structures are slight. In addition to the magnitude of differences in selection between protein structures being slight, the observed shifts appear to be idiosyncratic and largely codon-specific rather than systematic reversals in the nature of selection. Overall, our work demonstrates the statistical power and benefits of studying selective shifts on codon usage or other genomic features from an explicitly evolutionary approach. Limitations of this approach and future potential research avenues are discussed.},
doi = {10.1186/s12864-022-08635-0},
journal = {BMC Genomics},
number = 1,
volume = 23,
place = {United States},
year = {Mon May 30 00:00:00 EDT 2022},
month = {Mon May 30 00:00:00 EDT 2022}
}
Works referenced in this record:
Codon usage affects the structure and function of the Drosophila circadian clock protein PERIOD
journal, August 2016
- Fu, Jingjing; Murphy, Katherine A.; Zhou, Mian
- Genes & Development, Vol. 30, Issue 15
Solving the riddle of codon usage preferences: a test for translational selection
journal, September 2004
- Reis, M. d.
- Nucleic Acids Research, Vol. 32, Issue 17
AnaCoDa: analyzing codon data with Bayesian mixture models
journal, March 2018
- Landerer, Cedric; Cope, Alexander; Zaretzki, Russell
- Bioinformatics, Vol. 34, Issue 14
Role of mRNA structure in the control of protein folding
journal, July 2016
- Faure, Guilhem; Ogurtsov, Aleksey Y.; Shabalina, Svetlana A.
- Nucleic Acids Research, Vol. 44, Issue 22
Does the Recombination Rate Affect the Efficiency of Purifying Selection? The Yeast Genome Provides a Partial Answer
journal, December 2001
- Pál, Csaba; Papp, Balázs; Hurst, Laurence D.
- Molecular Biology and Evolution, Vol. 18, Issue 12
Composite effects of gene determinants on the translation speed and density of ribosomes
journal, January 2011
- Tuller, Tamir; Veksler-Lublinsky, Isana; Gazit, Nir
- Genome Biology, Vol. 12, Issue 11
Synonymous codon substitutions perturb cotranslational protein folding in vivo and impair cell fitness
journal, February 2020
- Walsh, Ian M.; Bowman, Micayla A.; Soto Santarriaga, Iker F.
- Proceedings of the National Academy of Sciences, Vol. 117, Issue 7
Why do eukaryotic proteins contain more intrinsically disordered regions?
journal, July 2019
- Basile, Walter; Salvatore, Marco; Bassot, Claudio
- PLOS Computational Biology, Vol. 15, Issue 7
Quantifying codon usage in signal peptides: Gene expression and amino acid usage explain apparent selection for inefficient codons
journal, December 2018
- Cope, Alexander L.; Hettich, Robert L.; Gilchrist, Michael A.
- Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1860, Issue 12
Synonymous but not the same: the causes and consequences of codon bias
journal, November 2010
- Plotkin, Joshua B.; Kudla, Grzegorz
- Nature Reviews Genetics, Vol. 12, Issue 1
Correlation between the abundance of Escherichia coli transfer RNAs and the occurrence of the respective codons in its protein genes: A proposal for a synonymous codon choice that is optimal for the E. coli translational system
journal, September 1981
- Ikemura, Toshimichi
- Journal of Molecular Biology, Vol. 151, Issue 3
The evolutionary consequences of erroneous protein synthesis
journal, October 2009
- Allan Drummond, D.; Wilke, Claus O.
- Nature Reviews Genetics, Vol. 10, Issue 10
Rare Codons Cluster
journal, October 2008
- Clarke, Thomas F.; Clark, Patricia L.
- PLoS ONE, Vol. 3, Issue 10
Nonoptimal codon usage influences protein structure in intrinsically disordered regions: Codon usages regulates protein structures
journal, June 2015
- Zhou, Mian; Wang, Tao; Fu, Jingjing
- Molecular Microbiology, Vol. 97, Issue 5
Conflicting selection pressures on synonymous codon use in yeast suggest selection on mRNA secondary structures
journal, January 2008
- Stoletzki, Nina
- BMC Evolutionary Biology, Vol. 8, Issue 1
Selection on Codon Bias
journal, December 2008
- Hershberg, Ruth; Petrov, Dmitri A.
- Annual Review of Genetics, Vol. 42, Issue 1
High-resolution modeling of the selection on local mRNA folding strength in coding sequences across the tree of life
journal, March 2020
- Peeri, Michael; Tuller, Tamir
- Genome Biology, Vol. 21, Issue 1
Evidence of evolutionary selection for cotranslational folding
journal, October 2017
- Jacobs, William M.; Shakhnovich, Eugene I.
- Proceedings of the National Academy of Sciences, Vol. 114, Issue 43
Systematic Detection of Amino Acid Substitutions in Proteomes Reveals Mechanistic Basis of Ribosome Errors and Selection for Translation Fidelity
journal, August 2019
- Mordret, Ernest; Dahan, Orna; Asraf, Omer
- Molecular Cell, Vol. 75, Issue 3
Nature and Regulation of Protein Folding on the Ribosome
journal, November 2019
- Waudby, Christopher A.; Dobson, Christopher M.; Christodoulou, John
- Trends in Biochemical Sciences, Vol. 44, Issue 11
The PSIPRED Protein Analysis Workbench: 20 years on
journal, April 2019
- Buchan, Daniel W. A.; Jones, David T.
- Nucleic Acids Research, Vol. 47, Issue W1
Measuring and Detecting Molecular Adaptation in Codon Usage Against Nonsense Errors During Protein Translation
journal, December 2009
- Gilchrist, Michael A.; Shah, Premal; Zaretzki, Russell
- Genetics, Vol. 183, Issue 4
Coding-Sequence Determinants of Gene Expression in Escherichia coli
journal, April 2009
- Kudla, G.; Murray, A. W.; Tollervey, D.
- Science, Vol. 324, Issue 5924
Estimating Gene Expression and Codon-Specific Translational Efficiencies, Mutation Biases, and Selection Coefficients from Genomic Data Alone ‡
journal, May 2015
- Gilchrist, Michael A.; Chen, Wei-Chen; Shah, Premal
- Genome Biology and Evolution, Vol. 7, Issue 6
A switch from α‐helical to β‐strand conformation during co‐translational protein folding
journal, January 2022
- Agirrezabala, Xabier; Samatova, Ekaterina; Macher, Meline
- The EMBO Journal, Vol. 41, Issue 4
Explaining complex codon usage patterns with selection for translational efficiency, mutation bias, and genetic drift
journal, June 2011
- Shah, P.; Gilchrist, M. A.
- Proceedings of the National Academy of Sciences, Vol. 108, Issue 25
Synonymous codon usage influences the local protein structure observed
journal, June 2010
- Saunders, Rhodri; Deane, Charlotte M.
- Nucleic Acids Research, Vol. 38, Issue 19
Statistical correlation between protein secondary structure and messenger RNA stem-loop structure
journal, January 2003
- Jia, Mengwen; Luo, Liaofu; Liu, Ciquan
- Biopolymers, Vol. 73, Issue 1
Multimodel Inference: Understanding AIC and BIC in Model Selection
journal, November 2004
- Burnham, Kenneth P.; Anderson, David R.
- Sociological Methods & Research, Vol. 33, Issue 2
Misfolded proteins impose a dosage-dependent fitness cost and trigger a cytosolic unfolded protein response in yeast
journal, December 2010
- Geiler-Samerotte, K. A.; Dion, M. F.; Budnik, B. A.
- Proceedings of the National Academy of Sciences, Vol. 108, Issue 2
A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity
journal, January 2007
- Kimchi-Sarfaty, C.; Oh, J. M.; Kim, I.-W.
- Science, Vol. 315, Issue 5811, p. 525-528
Estimating Selection on Synonymous Codon Usage from Noisy Experimental Data
journal, March 2013
- Wallace, Edward W. J.; Airoldi, Edoardo M.; Drummond, D. Allan
- Molecular Biology and Evolution, Vol. 30, Issue 6
Transient helicity in intrinsically disordered Axin-1 studied by NMR spectroscopy and molecular dynamics simulations
journal, March 2017
- Bomblies, Rainer; Luitz, Manuel Patrick; Scanu, Sandra
- PLOS ONE, Vol. 12, Issue 3
Synonymous Codons Direct Cotranslational Folding toward Different Protein Conformations
journal, February 2016
- Buhr, Florian; Jha, Sujata; Thommen, Michael
- Molecular Cell, Vol. 61, Issue 3
GC-Biased Gene Conversion in Yeast Is Specifically Associated with Crossovers: Molecular Mechanisms and Evolutionary Significance
journal, March 2013
- Lesecque, Yann; Mouchiroud, Dominique; Duret, Laurent
- Molecular Biology and Evolution, Vol. 30, Issue 6
The relationship between synonymous codon usage and protein structure
journal, August 1998
- Tao, Xie; Dafu, Ding
- FEBS Letters, Vol. 434, Issue 1-2
Secondary Structure across the Bacterial Transcriptome Reveals Versatile Roles in mRNA Regulation and Function
journal, October 2015
- Del Campo, Cristian; Bartholomäus, Alexander; Fedyunin, Ivan
- PLOS Genetics, Vol. 11, Issue 10
A model of protein translation including codon bias, nonsense errors, and ribosome recycling
journal, April 2006
- Gilchrist, Michael A.; Wagner, Andreas
- Journal of Theoretical Biology, Vol. 239, Issue 4
Evolutionary conservation of codon optimality reveals hidden signatures of cotranslational folding
journal, December 2012
- Pechmann, Sebastian; Frydman, Judith
- Nature Structural & Molecular Biology, Vol. 20, Issue 2
The frailty of adaptive hypotheses for the origins of organismal complexity
journal, May 2007
- Lynch, M.
- Proceedings of the National Academy of Sciences, Vol. 104, Issue Supplement 1
Codon usage regulates protein structure and function by affecting translation elongation speed in Drosophila cells
journal, June 2017
- Zhao, Fangzhou; Yu, Chien-hung; Liu, Yi
- Nucleic Acids Research, Vol. 45, Issue 14
Codon usage is less optimized in eukaryotic gene segments encoding intrinsically disordered regions than in those encoding structural domains
journal, October 2016
- Homma, Keiichi; Noguchi, Tamotsu; Fukuchi, Satoshi
- Nucleic Acids Research
The codon adaptation index-a measure of directional synonymous codon usage bias, and its potential applications
journal, January 1987
- Sharp, Paul M.; Li, Wen-Hsiung
- Nucleic Acids Research, Vol. 15, Issue 3, p. 1281-1295
Accounting for Background Nucleotide Composition When Measuring Codon Usage Bias
journal, August 2002
- Novembre, John A.
- Molecular Biology and Evolution, Vol. 19, Issue 8
Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B
journal, December 2016
- Simhadri, Vijaya L.; Hamasaki-Katagiri, Nobuko; Lin, Brian C.
- Journal of Medical Genetics, Vol. 54, Issue 5
Selection Conflicts, Gene Expression, and Codon Usage Trends in Yeast
journal, July 2003
- Kliman, Richard M.; Irving, Naheelah; Santiago, Maria
- Journal of Molecular Evolution, Vol. 57, Issue 1
The ribosome as a platform for co-translational processing, folding and targeting of newly synthesized proteins
journal, June 2009
- Kramer, Günter; Boehringer, Daniel; Ban, Nenad
- Nature Structural & Molecular Biology, Vol. 16, Issue 6
Studies on the Relationships between the Synonymous Codon Usage and Protein Secondary Structural Units
journal, March 2000
- Gupta, S. K.; Majumdar, S.; Bhattacharya, T. K.
- Biochemical and Biophysical Research Communications, Vol. 269, Issue 3
Cotranslational protein folding on the ribosome monitored in real time
journal, November 2015
- Holtkamp, W.; Kokic, G.; Jager, M.
- Science, Vol. 350, Issue 6264
The Correlation between Recombination Rate and Codon Bias in Yeast Mainly Results from Mutational Bias Associated with Recombination Rather than Hill-Robertson Interference
conference, January 2005
- Zhou, T.; Lu, Z. H.; Sun, X.
- 2005 IEEE Engineering in Medicine and Biology 27th Annual Conference
Synonymous codon usage in Drosophila melanogaster: natural selection and translational accuracy.
journal, March 1994
- Akashi, H.
- Genetics, Vol. 136, Issue 3
Protein secondary structural types are differentially coded on messenger RNA
journal, October 1996
- Thanaraj, T. A.; Argos, Patrick
- Protein Science, Vol. 5, Issue 10
A Major Controversy in Codon-Anticodon Adaptation Resolved by a New Codon Usage Index
journal, December 2014
- Xia, Xuhua
- Genetics, Vol. 199, Issue 2
Biased Gene Conversion and the Evolution of Mammalian Genomic Landscapes
journal, September 2009
- Duret, Laurent; Galtier, Nicolas
- Annual Review of Genomics and Human Genetics, Vol. 10, Issue 1
Biased Gene Conversion Affects Patterns of Codon Usage and Amino Acid Usage in the Saccharomyces sensu stricto Group of Yeasts
journal, July 2010
- Harrison, R. J.; Charlesworth, B.
- Molecular Biology and Evolution, Vol. 28, Issue 1
Roles for Synonymous Codon Usage in Protein Biogenesis
journal, June 2015
- Chaney, Julie L.; Clark, Patricia L.
- Annual Review of Biophysics, Vol. 44, Issue 1
Mistranslation-Induced Protein Misfolding as a Dominant Constraint on Coding-Sequence Evolution
journal, July 2008
- Drummond, D. Allan; Wilke, Claus O.
- Cell, Vol. 134, Issue 2
Splendor and misery of adaptation, or the importance of neutral null for understanding evolution
journal, December 2016
- Koonin, Eugene V.
- BMC Biology, Vol. 14, Issue 1
The intrinsic disorder alphabet. III. Dual personality of serine
journal, January 2015
- Uversky, Vladimir N.
- Intrinsically Disordered Proteins, Vol. 3, Issue 1
The selection-mutation-drift theory of synonymous codon usage.
journal, November 1991
- Bulmer, M.
- Genetics, Vol. 129, Issue 3
Widespread position-specific conservation of synonymous rare codons within coding sequences
journal, May 2017
- Chaney, Julie L.; Steele, Aaron; Carmichael, Rory
- PLOS Computational Biology, Vol. 13, Issue 5
Intragenic Spatial Patterns of Codon Usage Bias in Prokaryotic and Eukaryotic Genomes
journal, December 2004
- Qin, Hong; Wu, Wei Biao; Comeron, Josep M.
- Genetics, Vol. 168, Issue 4
IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding
journal, June 2018
- Mészáros, Bálint; Erdős, Gábor; Dosztányi, Zsuzsanna
- Nucleic Acids Research, Vol. 46, Issue W1
Unexpected correlations between gene expression and codon usage bias from microarray data for the whole Escherichia coli K-12 genome
journal, December 2003
- dos Reis, M.
- Nucleic Acids Research, Vol. 31, Issue 23
Codon usage bias in 5′ terminal coding sequences reveals distinct enrichment of gene functions
journal, October 2017
- Liu, Huiling; Rahman, Siddiq Ur; Mao, Yuanhui
- Genomics, Vol. 109, Issue 5-6
Non-random usage of ‘degenerate’ codons is related to protein three-dimensional structure
journal, December 1996
- Adzhubei, Alexei A.; Adzhubeib, Ivan A.; Krasheninnikov, Igor A.
- FEBS Letters, Vol. 399, Issue 1-2
Association between intrinsic disorder and serine/threonine phosphorylation inMycobacterium tuberculosis
journal, January 2015
- Singh, Gajinder Pal
- PeerJ, Vol. 3
Translational Accuracy and the Fitness of Bacteria
journal, December 1992
- Kurland, C. G.
- Annual Review of Genetics, Vol. 26, Issue 1
Unlocking a signal of introgression from codons in Lachancea kluyveri using a mutation-selection model
journal, August 2020
- Landerer, Cedric; O’Meara, Brian C.; Zaretzki, Russell
- BMC Evolutionary Biology, Vol. 20, Issue 1
Bayesian measures of model complexity and fit
journal, October 2002
- Spiegelhalter, David J.; Best, Nicola G.; Carlin, Bradley P.
- Journal of the Royal Statistical Society: Series B (Statistical Methodology), Vol. 64, Issue 4
Quantifying Position-Dependent Codon Usage Bias
journal, April 2014
- Hockenberry, Adam J.; Sirer, M. Irmak; Amaral, Luís A. Nunes
- Molecular Biology and Evolution, Vol. 31, Issue 7
Transient α-helices in the disordered RPEL motifs of the serum response factor coactivator MKL1
journal, June 2014
- Mizuguchi, Mineyuki; Fuju, Takahiro; Obita, Takayuki
- Scientific Reports, Vol. 4, Issue 1
Combining Models of Protein Translation and Population Genetics to Predict Protein Production Rates from Codon Usage Patterns
journal, August 2007
- Gilchrist, M. A.
- Molecular Biology and Evolution, Vol. 24, Issue 11
Codon Usage Influences the Local Rate of Translation Elongation to Regulate Co-translational Protein Folding
journal, September 2015
- Yu, Chien-Hung; Dang, Yunkun; Zhou, Zhipeng
- Molecular Cell, Vol. 59, Issue 5
Translationally Optimal Codons Associate with Structurally Sensitive Sites in Proteins
journal, April 2009
- Zhou, T.; Weems, M.; Wilke, C. O.
- Molecular Biology and Evolution, Vol. 26, Issue 7
Destabilizing Protein Polymorphisms in the Genetic Background Direct Phenotypic Expression of Mutant SOD1 Toxicity
journal, March 2009
- Gidalevitz, Tali; Krupinski, Thomas; Garcia, Susana
- PLoS Genetics, Vol. 5, Issue 3
Understanding the Influence of Codon Translation Rates on Cotranslational Protein Folding
journal, April 2014
- O’Brien, Edward P.; Ciryam, Prajwal; Vendruscolo, Michele
- Accounts of Chemical Research, Vol. 47, Issue 5
Protein secondary structure prediction based on position-specific scoring matrices 1 1Edited by G. Von Heijne
journal, September 1999
- Jones, David T.
- Journal of Molecular Biology, Vol. 292, Issue 2
Protein structure and the sequential structure of mRNA: α-Helix and β-sheet signals at the nucleotide level
journal, June 1996
- Brunak, Søren; Engelbrecht, Jacob
- Proteins: Structure, Function, and Bioinformatics, Vol. 25, Issue 2