The Regulatory Genome

THE SYSTEM OF HEREDITY AS A CONTROL SYSTEM

In a world dominated by thermodynamical forces of disorder and disintegration, all living systems, sooner or later, fall in disarray and succumb to those forces. However, living systems on Earth have survived and evolved for ~3 billion years. They succeeded in surviving because a. during their lifetime they are able to maintain the normal structure by compensating for the lost or disintegrated elements of that structure, and b. they produce offspring. The ability to maintain the normal structure, despite its continual erosion, indicates that living systems have information for their normal structure, can detect deviations from the “normalcy” and restore the normal structure. This implies the presence and functioning of a control system in living organisms. In unicellulars the control system, represented by the genome, the apparatus for gene expression and cell metabolism, functions as a system of heredity during reproduction. Homeostasis and other facts on the development of some organs and phenotypic characters in metazoans prove that a hierarchical control system, involving the CNS [Central Nervous System] and the neuroendocrine system, is also operational in this group. It is hypothesized that, in analogy with unicellulars, the control system in metazoans, in the process of their reproduction, serves as an epigenetic system of heredity.

Nelson R. Cabej (2004, 11) Neural Control of Development: The Epigenetic Theory of Heredity

A general character of genomic programs for development is that they progressively regulate their own readout, in contrast, for example, to the way architects’ programs (blueprints) are used in constructing buildings. All of the structural characters of an edifice, from its overall form to local aspects such as placement of wiring and windows, are prespecified in an architectural blueprint. At first glance the blueprints for a complex building might seem to provide a good metaphoric image for the developmental regulatory program that is encoded in the DNA. Just as in considering organismal diversity, it can be said that all the specificity is in the blueprints: A railway station and a cathedral can be built of the same stone, and what makes the difference in form is the architectural plan. Furthermore, in bilaterian development, as in an architectural blueprint, the outcome is hardwired, as each kind of organism generates only its own exactly predictable, species-specific body plan. But the metaphor is basically misleading, in the way the regulatory program is used in development, compared to how the blueprint is used in construction. In development it is as if the wall, once erected, must turn around and talk to the ceiling in order to place the windows in the right positions, and the ceiling must use the joint with the wall to decide where its wires will go, etc. The acts of development cannot all be prespecified at once, because animals are multicellular, and different cells do different things with the same encoded program, that is, the DNA regulatory genome. In development, it is only the potentialities for cis-regulatory information processing that are hardwired in the DNA sequence. These are utilized, conditionally, to respond in different ways to the diverse regulatory states encountered (in our metaphor that is actually the role of the human contractor, who uses something outside of the blueprint, his brain, to select the relevant subprogram at each step). The key, very unusual feature of the genomic regulatory program for development is that the inputs it specifies in the cis-regulatory sequences of its own regulatory and signaling genes suffice to determine the creation of new regulatory states. Throughout, the process of development is animated by internally generated inputs. “Internal” here means not only nonenvironmental — i.e., from within the animal rather than external to it but also, that the input must operate in the intranuclear compartments as a component of regulatory state, or else it will be irrelevant to the process of development. (Davidson 2006: 16-17)

(….) The link between the informational transactions that underlie development and the observed phenomena of development is “specification.” Developmental specification is defined phenomenologically as the process by which cells acquire the identities or fates that they and their progeny will adopt. But in terms of mechanism, specification is neither more nor less than that which results in the institution of new transcriptional regulatory states. Thereby specification results from differential expression of genes, the readout of particular genetic subprograms. For specification to occur, genes have to make decisions, depending on the new inputs they receive, and this brings us back to the information processing capacities of the cis-regulatory modules of the gene regulatory networks that make regulatory state. The point cannot be overemphasized that were it not for the ability of cis-regulatory elements to integrate spatial signaling inputs together with multiple inputs of intracellular origin, then specification, and thus development, could not occur. (Davidson 2006: 17)

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