Genes and the genetic code are central concepts in biology. The question of how genes actually work generates wide-spread interest, fascination, and (sometimes) controversy in the general public. Long after their initial discovery, this question also continues to interest scientists.
Genes work because of intricate and complex molecular machines (the ribosomes) which read the genetic code, and from it produce the proteins that are the workhorses of cellular biochemistry. The award of the 2009 Nobel Prize for the elucidation of the molecular shape of ribosomes demonstrates how critical detailed knowledge of these decoding machines is for our understanding of biology.
An aspect of the genetic code that scientists have long acknowledged, but the true importance of which is only just emerging, is that it can be interpreted as a traffic flow problem. A gene is essentially a long, linear assembly of molecular 'letters,' where each letter is a molecule with one of four possible shapes. Decoding the genetic code involves the directional movement of the ribosomes on the linear gene, which allows the ribosome to probe the shape of the genetic letters in their correct order. In order to keep this process efficient, nature allows multiple ribosomes to act on a gene at the same time. The resulting movement of ribosomes resembles a one-way, one-lane street: cars can enter it one at a time, drive through it, and exit it again, but this will only work if all cars drive at the same speed. Genes however are not decoded with uniform speed, and this creates interesting optimisation problems. For example, slowly decoded stretches of a gene can follow more rapidly decoded ones, and this inevitably creates molecular collisions between ribosomes if they are loaded onto the gene in too rapid succession.
The figure shows a diagrammatic representation of two ribosomes (in blue) in the process of decoding a messenger RNA molecule (an intermediate copy of a DNA gene, in black). This process relies on transfer RNA molecules (in green), which enter the ribosome and are used to determine the sequence of letters in the ribosomal decoding centre by the principle of base complementarity. If a transfer RNA that is complementary to the messenger RNA enters the ribosome, the growing protein (in shades of red) is transferred to the newly incoming tRNA, the entire ribosome:tRNA complex shifts forward by three letters on the messenger RNA, and the process is repeated until the end of the gene is reached.
Recent work from various labs, including our own, has shown that speed differences are used quite creatively by nature to control how often a gene is decoded. Some genes, such as cell cycle- and cell growth-controlling ones, must only be decoded rarely for their proper functioning. On such genes, nature frequently generates traffic jams, as part of a portfolio of measures that prevent them from being decoded too often. On the other hand, on the abundantly decoded genes for the central energy producing proteins of cells, traffic jams must be avoided at all costs, and this strongly determines how such genes are shaped during evolution.
We propose to follow up on the initial discovery of gene regulation via traffic jams by studying how widely, and under which conditions, this mechanism is actually used in nature. At the moment, we know of only a handful of examples where gene decoding is regulated via this mechanism, but initial examinations of large biological datasets have shown that it may be much more widespread. This would be significant because ribosome speed can be modelled comparatively accurately on computers, giving us potentially unprecedented predictive power over many genes of interest to basic biology, bioprocessing, and medicine. The Leverhulme Trust was an ideal funder for this project since this mode of gene regulation is novel and not yet widely accepted, and we saw a good fit between the Leverhulme Trust's track record in funding innovative research and the aims of our project.
Dr Tobias von der Haar
University of Kent