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. Author manuscript; available in PMC: 2011 Apr 12.
Published in final edited form as: Nat Rev Genet. 2010 Nov 23;12(1):32–42. doi: 10.1038/nrg2899

Table 1.

Coding-sequence covariates of gene expression, and other sources of codon bias unrelated to gene expression

Parameter Species Relationship with
expression		 Type of
evidence
(0) 		Proposed mechanism Refs (computation)
(1) 		Refs
(function)
Codon adaptation
CAI or FOP or tAI All Complex (see text) c Translation elongation rate/accuracy CAI35, fop28, tAI128 2, 37, 55, 81, 94, 96
Rare codon stretches Bacteria − c Translation elongation rate/accuracy 90
Rare codons between protein
domains		 Bacteria Complex c Translation elongation/Protein folding 91, 132
Frequency of starvation-resistant
codons		 Bacteria + c Translation elongation rate/accuracy 79, 81 81
Frequency of abundant codons All Complex c Unclear (2) 133 134
mRNA folding
Weak mRNA folding at start codon Bacteria + d Translation initiation rate mfold135 53, 55, 97
mRNA stem-loop 15 nt downstream of
start codon		 Bacteria, mammals + c Translation initiation rate 130, 131 130, 131
mRNA stem-loops further downstream All Complex c Translation elongation 135 46, 84
Regulatory motifs
Transcription terminators Bacteria − b Transcription RNAMotif136
RNAse E sites Bacteria − b mRNA stability 137
miRNA target sites Eukaryotes − b Translation, mRNA stability TargetScan138
Various mRNA regulatory elements All Complex b Translation, mRNA stability TransTerm139
Nucleotide bias
High GC3 content, low A content Mammals + c Transcription, mRNA processing,
mRNA export		 140, 141 82, 83, 101
High CpG content Mammals + c Transcription 102
Others sources of codon bias
Codon pair bias Bacteria, mammals + c Translation elongation rate 85, 104 85, 104
Codon ramp All Complex (3) b Translation initiation rate 57
Codon correlation Eukaryotes + c Translation elongation rate 62 62
Unknown All Complex c Protein folding efficiency 107
Unknown Eukaryotes Complex b Splicing regulation 4, 142
Unknown All Complex c Protein posttranslational modification 44 44
Replication strand nucleotide bias Bacteria,
Mitochondria		 unknown a Unknown
CTAG avoidance Bacteria unknown a Restriction avoidance 143 143

NOTE: This table lists coding-sequence derived parameters that can be changed by synonymous mutations. Other parameters may be important for expression (eg the identity of the N-terminal amino acid or the length of the sequence) but they require nonsynonymous changes.

(0)

Type of evidence supporting the influence of the parameter on expression. a: none; b: theoretical; c: anecdotal; d: systematic.

(1)

Generic tools to calculate some of these parameters: codonW140 (http://codonw.sourceforge.net/), INCA141, GeneDesigner144.

(2)

The frequency of abundant codons is highly correlated with GC content in mammals.

(3)

The codon ramp is predicted to decrease the cost of translation, which may indirectly influence expression levels.