Thursday, 6 November 2014

How the BLAST rendered me speechless today. Molecule of the month November 2014 FOXP2

I started this Blog, intending to look at the properties of gunpowder, but remembered I had discussed dynamite in October, so two explosive molecules in the same number of months, seems a little excessive! Then I started writing about Cytochrome P450s, but although I was ready to go with the P450 story, I realised how nicely the FOXP2 protein structure, function and genetics fitted together in the BLAST sessions today. So, P450 for Christmas and FOXP2 for November. This is a story that might leave you speechless!

The human genome project has proved a treasure trove for evolutionary biologists, and a quick search of a well known gene encoding say haemoglobin or a histone protein, will inevitably identify a closely related sequence in chimpanzees, orang utans or another ape. So far not surprising. However, I then asked the question: what genes would you expect to point to differences between man and apes? I was delighted when someone gave the answer "communication" genes. So of course I suggested an analysis of the "language" gene, FOXP2. 

The FOXP2 protein is a transcription factor (here you can find a lovely summary with simple sketches of transcrition factors in higher organisms) found widely in the genomes of mammals, that is a regulator of neuronal plasticity, with a direct impact on speech and language development. The protein sequence that you all obtained, showed a dominant feature: a run of tens of Q (Glutamine) residues. These are located at the N terminal side of the protein sequence and are not uncommon in some DNA binding proteins. In addition FOXP2 contains a zinc finger and a leucine zipper, both of which are protein sequence motifs, often associated with DNA binding. From a bioinformatics perspective, the FOXP2 sequence is a dead give away! Transcription factors bind to DNA and RNA Polymerases and promote gene transcription (expression). In the case of FOXP2 it regulates the levels of expression of a set of genes involved in language development which are mapped to the brain. The FOXP2 gene, therefore encodes a "master regulator" and mutations to the sequence  of such genes can be disastrous, leading to negative effects on a significant range of "downstream " functions.

Full-size image (74 K)
The protein (shown left in complex with DNA from the work of an international collaboration published in the journal Structure) recognises a specific DNA sequence. There are two amino acid substitutions between the FOXP2 proteins between chimpanzees and man, which appear to interfere with the function of FOXP2 in such a way that the coordinated expression of a family of genes required for speech is not possible in apes. The story was made possible by pioneering work from communication scientists at McGill and London Universities, and geneticists at Oxford University and the UCL in London. From a family with a rare, inherited speech disorder, the region of the chromosome containing the mutation came the first clues. Shortly afterwards, the FOXP2 gene was isolated and, as with apes, the changes in function relate to subtle amino acid differences: you should attempt to rationalise these observations. You will find that FoxP2 from a number of species is highly conserved, but look closely at the features in the protein primary structure. Subtle differences can give rise to profound functional consequences, which makes a powerful case for understanding the details of chemistry, structure and reactivity of amino acid side chains in understanding biological phenomena: in this case language skills!

The FOXP2 gene expresses a protein that regulates the levels of expression of a subset of genes which in turn cascade down information that leads to coordination of brain function leading to controlled action of facial muscles and the larynx, thereby producing speech. It should also be remembered from your BLAST searching that by way of contrast some protein sequences can tolerate significant amino acid changes without loss of function. The critical evaluation of protein sequences is the key to a deep understanding of function, so always treat similarities with a healthy level of scepticism and try to validate ideas by experiment, where possible.

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