Posted on behalf of Retread

A few chemists who were both literary and literal recently looked fairly silly on the pages of the New York Times and in the blogosphere. You can read all about it on Michelle’s Francl’s blog “”http://cultureofchemistry.blogspot.com/“>Culture of Chemistry”. See her post of 1 May ‘08 — “”http://cultureofchemistry.blogspot.com/2008/05/you-pronounce-unionized-as-un-ionized.html">How to tell if you’re really a chemist." To make a long story short, 3 chemically impossible organic molecules (5 bonds to carbon etc., etc…) spelled out the word SEX in a review of a book about (what else?) sex. The chemists missed the semantic forest while closely inspecting the chemical trees.

Is there anything inside the cell being read chemically two different ways? Yes there is, and it has implications for how we determine what in the genome is being worked on by natural selection and what is being left alone. If intron, exon, neutral selection and synonymous and nonsynonymous codons aren’t old friends, have a look at the first comment which will give you all the background you need (which is quite a bit).

People attempt to measure the rate of natural selection acting on proteins using synonymous and nonsynonymous codons in the same protein in different organisms (say hemoglobin for example). Positive selection is measured as the rate of nonsynonymous nucleotide substitution (Ka) per nonsynonymous site, relative to the underlying ‘neutral mutation rate’, which is given by the rate of synonymous substitution per synonymous site (Ks). Usually Ka is much less than Ks (as most new mutations aren’t helpful or are actually harmful — this is negative selection). Positive selection is implied by Ka/Ks greater than 1. However, strictly by chance, the ratio of nonsynonymous (Ka) to synonymous (Ks) amino acid substitutions is 2:1.

All very nice, but ESSs and ESEs are found in exons, and mutations of them will change alternate splicing (something a functioning cell has a great interest in). It’s easy to see how changing one nucleotide in an ESS or an ESE could render it more or less effective, while leaving the amino acid sequence of the underlying protein unchanged. In short, the ‘neutral mutation rate’ may in fact not be neutral at all (if it is in an ESE or an ESS). Or possibly switching one amino acid for another has nothing whatever to with the protein and everything to do with controlling alternate splicing.

Now, chemists are adept at doing all sorts of different things with the same structure. Think what organic chemists can do with a carbonyl group. But whatever they do is over and done with. In protein-coding genes, the same sequence can mean two different things without being chemically changed at all.

We are far from understanding all the things DNA can do in a cell. Less than 2% of our 3.2 gigabases of DNA codes for exons. Calling the 98% of the genome not doing so ‘junk’ is a vestige of the protein-centric era of molecular biology, just as calling changing one synonymous codon for another neutral. Both assume that the only thing that DNA does is code for protein.

The expressive power of language lies in its ambiguity not its precision. DNA may be similar as we uncover the languages it speaks. My guess is that there are more to be found.