Selection on codons

OEB 192 11.10.03

Degenerate Code

Codon Usage BiasNon-random usage of codons

Rickettsia - Winkler 1988

Percent codon usage in family

Codons for each amino acid

Preferredargininecodon

Unpreferredargininecodon

Different GC content alters codon usage

Mutational Bias

232 Bacterial genomes - Guchte 2006

Species differ in codon usage biasWithout considering selection, why might different species have

different codon usage patterns?

Massey 2003

6 LeucineCodons

Unequal numbers of tRNAs

There are six leucine codons

So, there are six corresponding tRNAs

tRNA copy number differences

E. coli - Ikemura 1981

Is there selection on codon bias?

Three levels of evidence:1. Genome level2. Species level3. Gene level

Evidence:Non-random patterns of codon usage that are difficult to explain without selection

Selection on codons1. Throughout genomes

Same organism, so not explained by differences in tRNA abundance or mutational bias

2. Between speciesWhy does the pattern decrease from E. coli to Human?

Drummond and Wilke 2008

expressionoptim

al c

odon

s

High Expression level genes have high codon bias

Selection on codons3. Within genes

Conserved sites more likely to use preferred codons

Likely tofind Preferred

codon

Likely tofind Unpreferred

codon

Species in alignemnt: Os = Oryza sativa, Pp = Physcomitrella patens, Dd = Dictyostelium discoideum, Hs = Homo sapiens, Dr = Danio reiro, Dm = Drosophila melanogaster, Sc = Saccharomyces cerevisiae, Sp = Schizosaccharomyces pombe, Pf = Plasmodium falciparum Gene = ubiquitin/SUMO-1 like protein

Wang et. al. 2001

Why is there selection on codons?

Why is there selection on codons?

Target of

selection

Impact of codon identity (effect on

protein cost vs. benefit)

Effect of

% rare

codons

Importance of

codon position

Effect of high

expression on

fitness

mRNA

structure /

sequence

1. Inhibits translation initiation

(insufficient benefit)

No general

prediction

5’ end most

sensitive

+

2. Promotes rapid degradation

(insufficient benefit)

No general

prediction

No general

prediction

+

Ribosomal

pausing

during

translation

of rare

codons

(due to

tRNA

limitation)

3. Slows translation & decreases

protein (insufficient benefit) –

No general

prediction

+

4. Sequesters ribosomes

(excess cost) -

Rare codons

good at 5′ end –

5. Promotes accurate protein folding.

Lack of ribosome pause leads to:

(a) Low protein activity or stability

(insufficient benefit)

No general

prediction

Rare codons

preferred at

domain

boundaries

+

(b) Misfolding-induced toxicity

(excess cost) –

6.

Increases translation errors causing:

(a) Low protein activity or stability

(insufficient benefit)

–

Rare codons

bad at

conserved or

active residues

+

(b) Misfolding-induced toxicity

(excess cost) –

–

(Agashe et al., in prep)

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