Quantifying position-dependent codon usage bias.
Although the mapping of codon to amino acid is conserved across nearly all species, the frequency at which synonymous codons are used varies both between organisms and between genes from the same organism. This variation affects diverse cellular processes including protein expression, regulation, and folding. Here, we mathematically model an additional layer of complexity and show that individual codon usage biases follow a position-dependent exponential decay model with unique parameter fits for each codon. We use this methodology to perform an in-depth analysis on codon usage bias in the model organism Escherichia coli. Our methodology shows that lowly and highly expressed genes are more similar in their codon usage patterns in the 5'-gene regions, but that these preferences diverge at distal sites resulting in greater positional dependency (pD, which we mathematically define later) for highly expressed genes. We show that position-dependent codon usage bias is partially explained by the structural requirements of mRNAs that results in increased usage of A/T rich codons shortly after the gene start. However, we also show that the pD of 4- and 6-fold degenerate codons is partially related to the gene copy number of cognate-tRNAs supporting existing hypotheses that posit benefits to a region of slow translation in the beginning of coding sequences. Lastly, we demonstrate that viewing codon usage bias through a position-dependent framework has practical utility by improving accuracy of gene expression prediction when incorporating positional dependencies into the Codon Adaptation Index model.
Department of Chemical and Biological Engineering, Northwestern UniversityInterdepartmental Program in Biological Sciences, Northwestern University.
Adam J
AJ
Hockenberry
Department of Chemical and Biological Engineering, Northwestern University.
M Irmak
MI
Sirer
Department of Chemical and Biological Engineering, Northwestern UniversityNorthwestern Institute on Complex Systems, Northwestern UniversityHoward Hughes Medical Institute, Northwestern University.
Luís A Nunes
LA
Amaral
Department of Chemical and Biological Engineering, Northwestern UniversityInterdepartmental Program in Biological Sciences, Northwestern UniversityNorthwestern Institute on Complex Systems, Northwestern UniversityChemistry of Life Processes Institute, Northwestern UniversityInstitute for BioNanotechnology and Medicine, Northwestern University m-jewett@northwestern.edu.
Michael C
MC
Jewett
D003062:Codon; D004269:DNA, Bacterial; D004926:Escherichia coli / Q000235:genetics*; D029968:Escherichia coli Proteins / Q000235:genetics*; D019143:Evolution, Molecular; D014644:Genetic Variation; D016013:Likelihood Functions; D008957:Models, Genetic; D010802:Phylogeny
D003062:Codon; D004269:DNA, Bacterial; D029968:Escherichia coli Proteins
coding sequence evolution; codon adaptation; codon usage bias; gene expression