I don’t think anyone can fully appreciate molecular biology without a serious knowledge of organic chemistry. That said, I’m not sure just how much molecular biology chemists of any stripe actually know. So I’ve made a new category “Molecular Biology Survival Guide for Chemists” which will contain all the background required to understand this and future posts on the subject. Currently it contains 3 longish posts in it called I, II, III. I’ll indicate where background is to be found by the Roman numeral. Just go to the category subheading on the left side, click it, and you see all three.
Synonymous and nonsynonymous codons are discussed in III. Until recently, it was thought that one synonymous codon (for a given amino acid) acted pretty much the same as another. Certainly this is true for the amino acids they code for. But they code for more than that. Here are two examples.
Example #1. Our genes occur in pieces. Dystrophin is the protein mutated in the commonest form of muscular dystrophy. The gene for it is 2,220,233 nucleotides long but the dystrophin contains ‘only’ 3685 amino acids, not the 770,000+ amino acids the gene could specify. What happens? The whole gene is transcribed into an RNA of this enormous length, then 78 distinct segments of RNA (called introns) are removed by a gigantic multimegadalton machine called the spliceosome, and the 79 segments actually coding for amino acids (these are the exons) are linked together and the RNA sent on its way.
Alternate splicing is not rare. [ Proc. Natl. Acad. Sci. vol. 102 pp. 12813 – 12818 ’05 ] contains 7 references which variously estimate the amount of alternative splicing of mammalian genes from 22 to 74%. What controls alternate splicing? Sequences in the gene for the protein itself. These sequences can be in either a given intron or a given exon and they can either enhance splicing or inhibit it. They are called ESS (for exonic splicing suppressor) or ESE (for exonic splicing enhancer). ISS and ISE have similar meanings where I stands for intron.
Here is one particularly horrible example (again from the muscular dystrophy clinic). There is nothing worse than watching an infant waste away and die. That’s what Werdnig Hoffmann disease is like, and I saw one or two cases during my years at the clinic. It is also called infantile spinal muscular atrophy. We all have two genes for the same crucial protein (called unimaginatively SMN). Kids who have the disease have mutations in one of the two genes (called SMN1) Why isn’t the other gene protective? It codes for the same sequence of amino acids (but using different synonymous codons). What goes wrong?
Intellectually fascinating, but truly ghastly to (ineffectually) watch.
Head swimming yet? The example in the next post is even more subtle, and it leads to a philosophic discussion of how just far reductionism of cellular events to chemistry can take us.