“Natural restoration” can generate biological complexity
Authors: Zuckerkandl Emile 
Published: December 2005

Factor complexes engaged in transcriptional regulation of gene expression and their cognate DNA elements recurrently suffer mutational damage that can result in deadaptations in the mutual fit of interacting macromolecules. Such mutations can spread in populations by drift if their functional consequences are not severe. Mutational restorations of the damaged complexes may ensue and can take many forms. One of these forms would represent spontaneous increases in gene interaction complexity and correlated aspects of organismic complexity. In this particular mode of restoration, restabilization of a factor/factor/DNA complex occurs through the binding of an additional factor. Factors added under such circumstances to regulatory kits of individual genes are thought to be at the origin of a slow but persistent “complexity drive.” This drive seems to be resisted in many forms whose developmental outcome has reached a finish line difficult to pass, but imposes itself along other lines of phylogenetic descent. In the process of restoration by an additional factor, the chances are significant that the original regulatory control of a target gene is not recovered exactly and that the restored gene expression has novel spatial, temporal, or quantitative characteristics. These new characteristics, which represent a functional transfer of the gene to a new domain of activity, may be selectable, even when the physicochemical properties of the gene product have remained largely unchanged. As a consequence of such activity transfers under quasi‐constancy of the molecular properties of the protein encoded by the regulation's target gene, the activity domain originally covered by that target gene may be left at least in part functionally vacant. At that point, an unmodified duplicate of the target gene and of its original regulatory dependencies probably becomes in turn selectable. A causal link is therefore predicted between the regulatory specialization and selection of one of two duplicates and the regulatory maintenance and selection of the other. A conserved increase in gene number would result indirectly from the regulatory shift in paralogs, and the organism's complexity would be increased in this sense also— complexity as number of genes in addition to complexity as number of regulatory factors per gene. It is thus proposed that increased biological complexity, innovation in the gene regulatory network, and the development of a novel evolutionary potential can be the result, counterintuitively, of conservative forces that intervene when mutations play a survivable form of havoc with the system of gene regulation. Increasing complexity, then, could be seen as one of the side effects of “natural restoration.” This phrase designates the mutational re‐establishment in the gene whose regulation has been damaged of a functionally effective activity pattern, albeit, perhaps, with changes in its mode of expression in regard to location, time, and rate. The higher complexity, innovation in the gene regulatory network, of higher organisms—their very character of higher organisms—would to a significant extent be a side effect of episodes of natural selection aimed at functional restoration, not at complexity itself. Regulatory impairment, the point of departure of the process outlined, represents a controller gene disease. It thus may well be the case that molecular diseases, the effects on the individual of inheritable structural decay, are among the conditions of the evolution of higher organisms. © 2005 Wiley Periodicals, Inc. Complexity 11: 14–27, 2005