Paul Higgs - Research Topics

Codon Usage, Translational Selection and the Dynamics of Ribosomes

  1. Ran W, Higgs PG (2012) Contributions of Speed and Accuracy to Translational Selection in Bacteria. PLoS ONE 7(12): e51652. doi:10.1371/journal.pone.0051652
  2. Ran W, Higgs PG (2010) The influence of anticodon-codon interactions and modified bases on codon usage in bacteria. Mol. Biol. Evol. 27: 2129-2140.
  3. Higgs PG, Ran W (2008) Coevolution of codon usage and tRNA genes leads to multiple stable states of biased codon usage. Mol. Biol. Evol. 25: 2279-2291.
  4. Jia WL, Higgs PG (2008) Codon usage in mitochondrial genomes: distinguishing context-dependent mutation from translational selection. Mol. Biol. Evol. 25: 339-351.
  5. Urbina D, Tang B, Higgs PG. (2006) The response of amino acid frequencies to directional mutational pressure in mitochondrial genome sequences is related to the physical properties of the amino acids and the structure of the genetic code. J. Mol. Evol. 62, 340-361.

Who is who?

WenqiHorse.JPG ArashAhmadi.jpg AamerSomani.jpg
Wenqi Ran
Now a Postdoc at NCBI
Arash Ahmadi
Current graduate student
Aamer Somani
Current undergraduate student

Codon Usage Bias and tRNA anticodons

StandardCode.png wobble.jpg

Most amino acids are encoded by more than one amino acid in the genetic code. Alternative codons for the same amino acid (synonymous codons) are not used with equal frequency. Codons that are more rapidly translated by the ribosome are used more frequently (particularly in highly expressed genes). This is known as selection for translational efficiency.

The choice of base at the synonymous third position of the codon is related to the base at the wobble position of the tRNA (the first anticodon base, or position 34 of the tRNA).

CodonUC.png CodonAG.png Codon4.png
In a two-codon U+C family, the wobble position is always a G and a single tRNA can translate both U and C codons. The C codon is preferred in almost all U+C families in almost all bacteria that we studied. Most likely, the ribosome recognizes the tRNA more rapidly when the third position base is a C than when it is a U. In a two-codon A+G family, there is always a tRNA with a U at the wobble position, and there is sometimes an additional tRNA with a wobble C. The direction of selection on the codon usage depends on the relative numbers of these two tRNAs. In a four-codon family, there is always a tRNA with a wobble U, and there can sometimes be tRNAs with wobble G and wobble C. The preferred codon is dependent on the relative numbers of these tRNAs.

The wobble base of tRNAs is often modified to a non-standard base, and the presence of these base modifications has important effects on the codon-anticodon interaction, and hence the direction of selection on codon usage. Our published papers condsider these effects in detail in a large number of bacterial genomes.

Measuring the Strength of Translational Selection in Bacteria

growthrate.png speedaccuracy.png
The minimum cell division time, T, for bacteria varies between ~15 minutes and several days, depending on the niche/lifestyle that the bacteria adopt. Protein synthesis is a limiting step determining the rate of cell growth and division. The maximum growth rate, 1/T, is strongly correlated with both the number of ribosomal RNAs in the genome and the number of tRNAs. Duplication of rRNA genes allows faster ribosome synthesis and increased number of ribosomes. Duplication of tRNA genes allows faster translation by each ribosome. Codon bias is strongest in organisms that have more tRNAs in the genome (i.e. the fast-growing organisms). δH measures the difference in codon frequencies between high-expression and low-expression genes. This is thought to be due to selection for speed/efficiency. δC measures the difference in codon frequencies between conserved and variable sites in genes. This is thought to arise from selection for translational accuracy. Our results show that selection for accuracy seems to be a weak effect and is not correlated with tRNA gene-number or growth rate, whereas selection for speed is a much stronger effect that is clearly correlated with both tRNA number and growth rate.

Ribosomal Dynamics and Traffic Jams


Often, more than one ribosome is translating a given mRNA at the same time, as shown in this image. If the density of ribosomes is high, they can potentially interfere with one another. The presence of slow codons within a sequence can cause a bottlenecks and a ribosomal traffic jam.


These figures show simulations of a model of particles moving along a one-dimensional track, representing the dynamics of ribosomes.

  1. Initiation is the limiting factor. Ribosomes are well spaced and do not interfere with each other. The current is slow, and equal to the initiation rate.
  2. Initiation is faster. The current rises to a maximum value controlled by the hopping rate within the sequence. This rate is uniform along the sequence. There is considerable interference between ribosomes. Ribosomes shown in red a blocked by the one in front.
  3. A bottleneck of slow codons in the middle of the sequence causes a traffic jam.
  4. A region of slow codons at the beginning causes an increase in the spacing of ribosomes in the remainder of the sequence.

Current Research Questions