Genetic Information

Figure 5.4 Possible representations of the multidimensional space controlling gene regulation in eukaryotic cells. A, Individual genetic elements (black circles) interact with many other elements through positive and negative interactions (activation and repression arrows, respectively); quantitative aspects of these interactions are represented by variable thicknesses (strength of the interaction) and lengths (duration of the interaction) of the interaction arrows. B, As a concept diagram, interaction network motifs as in A have been plotted on successive planes representing the dogma of molecular biology. C, A holistic view of gene expression in eukaryotic cells. The diagram illustrates a specific 'gene expression circuit' followed by a given gene and its products through the different regulatory planes. The functional output of a given gene will be determined by the efficiency with which each one of the gene's products (e.g. primary mRNA, spliced mRNA, exported mRNA, etc.) moves through the series of gene regulatory planes that compose the multidimensional space of the gene expression path.

genes, rather than the product of sequence changes affecting protein composition. This beautiful and powerful study grasped the attention of all of those interested in the genetic underpinnings of developmental evolution, taking them to the dilemma between structural (protein-coding) versus regulatory mutations; King and Wilson's study left, however, little margin for doubts about the power of regulatory changes.

Now, returning to our previous discussions on the prevalent molecular thinking in the mid 1970s that gene regulation was almost exclusively controlled at the level of transcription, and regardless of King and Wilson's (1975) careful writing, their article ended up being largely interpreted as supporting the view that transcriptional regulation was the key molecular level of regulation for organismal evolution.

Not surprisingly, the field searched, and searched again, and after three decades of intense work managed to find a handful of clean examples in which enhancer variation is indeed involved in morphological differences between species (Belting et al. 1998, Wang and Chamber-lin 2004, Wang et al. 2004, Gompel et al. 2005, Jeong et al. 2006, Prud'homme et al. 2006). Do these examples prove that enhancers are the principal nodes for change in developmental evolution? As we have seen above, given that the complexity of gene regulation exceeds transcriptional control, the answer is, probably, no: to distinguish the relative contribution of genetic variation at one regulatory level or other, we must look equally thoroughly at all regulatory levels, and this has not been done until now.

Yet another relevant piece of work needs to be mentioned to close this discussion: one that was to come two years after King and Wilson's article was published. This is Fran├žois Jacob's 'Evolution and Tinkering' paper (Jacob 1977). Here, Jacob put forward his views about how evolution proceeds, contrasting the process of evolution with the jobs of an engineer and that of a tinkerer. In his own words:

Natural selection has no analogy with any aspect of human behaviour. However, if one wanted to play with a comparison, one would have to say that natural selection does not work like an engineer. It works like a tin-kerer who does not know exactly what he is going to produce but uses whatever he finds around him whether it be pieces of string, fragments of wood, or old cardboards; in short it works as a tinkerer who uses everything at his disposal to produce some kind of workable object.

The experiments of King and Wilson, together with the ideas of Jacob, nicely complement each other telling us that the business of the evolutionary tinkerer is likely to be a regulatory one, and thus, chances are that he is going to use everything at hand, be it alternative splicing, RNA localisation, protein degradation or enhancer modules in order to manipulate developmental programs over time. The fact that we have found a few cases of variation at enhancer modules must not be confused with evidence in support of the idea that enhancers are the only elements involved in developmental evolution.

Although the history of ideas can itself be fascinating, the prime goal of this text is scientific utility. The exploration of the molecular elements used for the generation of developmental diversity during evolution is a venture of paramount importance in modern biology; to tackle this problem, the comparative study of variation at all levels of gene regulation emerges as the only unbiased strategy to establish the principal avenues of molecular change used during developmental evolution. This is, in my view, the only impartial path to follow for the true understanding of the arrival of the fittest.

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