The increase in whole genome data allows the study of molecular evolution at the codon rather than the nucleotide or amino acid level. Our statistical analysis of coding sequences in yeast has led to the proposition of a new mechanism for regulating translation. This work is described in "A role for codon oder in translation dynamics".

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The "central dogma of molecular biology" (to which there are many exceptions) is that the information encoded in the DNA of an organism, is transcribed to mRNA and then translated into proteins. The proteins do the work in the cell and form the structure of many cellular components. The proteins are what the cell needs and comprise a large part of the end products of the information stored in the DNA. The DNA is translated into proteins in words of length 3 nucleotides or codons. This happens at ribosomes which could be thought of as protein assembly factories. Amino acids are the basic building blocks of proteins. Each three letter codon tells which amino acid should come next in the protein sequence. As there are three DNA bases, if the words are of length 3 there are 64 possible words. There are only 20 amino acids that need encoding, however, so many of the words code for the same amino acid. In the translation, there are what could be thought of as little trucks (tRNAs) that bring the amino acid to the protein factory, the ribosome. There are around 42 different kinds of tRNAs (trucks) in S. cerevisiae. For example, the amino acid serine has 6 different codons and 4 different tRNAs. This means some tRNAs have to read more than one amino acid.

The genetic code known since the 60's tells which codons (words) code for which amino acids, e.g. a GCT codes for the amino acid alanine. What we have found here is a new code which is encoded in the order of the codons. The new code was found by observing for a given amino acid in a protein sequence, how many times was each codon pair used. These are not necessarily consecutive codons in the sequence. They are consecutive codons that code for the same amino acid. The observation was made that when observing only codons that code for the same amino acid in a protein sequence, the consecutive pairs use the same tRNA (truck) more often than expected by random. When considering codons only from one amino acid, there is a natural selection for the codons to be in a certain order. The codons are ordered such that the tRNA that brings the amino acid changes as little as possible.

This data suggest that the tRNAs are being reused and that this reuse increases the speed of translation. We further suggest that there may be an association between the tRNA and the ribosome, that is to say that the tRNA stays in the vicinity of the ribosome. That we can suggest this kind of information about cellular details via analysis of coding sequences alone is remarkable. Of course, experiments were done to verify that there is an increase in the speed of translation when the codons are put into order.



Codon mutation matrices. Codon substitution probabilities are used in many types of molecular evolution studies such as determining Ka/Ks ratios, creating ancestral DNA sequences or aligning coding DNA. We presented the first empirical codon substitution matrix entirely built from alignments of coding sequences from vertebrate DNA which provides an alternative to parameterized models of codon evolution and are currently extending the models.

SynPAM. SynPAM, a new method to obtain estimations of synonymouse change between two coding DNA sequences, is based on synonymous codon substitutions using maximum-likelihood estimation. The direct way of estimating the amount synonymous change within a maximum-likelihood framework is a fundamentally different approach than those of existing methods most notably dS. SynPAM shows less variance and is able to capture weaker phylogenetic signals than exisiting methods of measuring synonymous distance.