The Regulatory Genome

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

Under the influence of external/internal stimuli, the CNS may induce adaptive changes in morphological and life history characters without any changes in genes. Commonly, these changes are not heritable, i.e. they do not reappear in the offspring if the offspring is not exposed to the same stimuli. This is the case for the overwhelming majority of described examples of predatory-induced defenses, polyphenisms, and adaptive camouflage. But reproducible cases of transgenerational changes, without changes in genes, changes that are transmitted to the offspring for one or more generations, occur and are described. All the cases of non-genetic, inherited changes are determined by underlying neural mechanisms. Such changes may represent the “primed”, ready-made material of evolution. The evidence on the neurally induced transgenerational nongenetic changes cannot be overestimated in respect to possible evolutionary implications of the epigentic system of heredity. (Cabej 2004: 201)

— Nelson R. Cabej (2004, 201) Neural Control of Development: The Epigenetic Theory of Heredity

Indeed, epigenetic modifications of phenotypic expression are sometimes considered to be “Lamarckian” because they can be transmitted to subsequent generations after being acquired. Not surprisingly, then, it has taken decades for these molecular effects to be accepted as a part of mainstream genetics. Contemporary awareness of molecular epigenetics has expanded the neo-Darwinian view of DNA sequence as the fundamental mode of inherited developmental information (Jablonka and Lamb 2002; Mattick 2012), placing even the initial phase of gene expression squarely in a dynamic cellular, organismic, and environmental context. (Sultan 2015, 11)

At the mechanistic level, epigenetic modification shape gene expression by altering protein-gene interactions that determine the accessibility of DNA to the biochemical machinery of gene transcription. (….) Epigenetic mechanisms may also be a heretofore unrecognized source of selectively important phenotypic variation in natural populations.

It has become clear that heredity is mediated at the molecular level not purely by discrete, stably transmitted DNA sequence variants but also by multiple information-altering mechanisms that lend the process an unlooked-for flexibility. Qualitatively new modes of cross-generational gene regulation are continuing to be found, including several that show gene silencing and other epigenetic roles for noncoding RNA (Bernstein and Allis 2005; Mattick and Mehler 2008: Lenhard et. al. 2012; Ha and Kim 2014). (Sultan 2015, 12)

Many genomic sequences that were previously considered “junk” are now known to code for small or “micro” RNAs (and possibly long RNAs as well) that play a role, for instance by altering enzymatic access to the chromatin by binding to DNA (Koziol and Rinn 2010). … Interestingly, noncoding RNAs may carry environmentally induced effects on the phenotype form one generation to the next, including the neurobehavioral effects of social environment. In one recent study, traumatic, unpredictable, separation of newborn mice from their mothers altered several aspects of microRNA activity in the pups, including their hippocampi and other brain structures involved in stress responses. These epigenetic changes were associated with different behavioral responses to aversive conditions such as brightly illuminated maze compartments. When sperm RNA from traumatized males was injected into fertilized wild-type egg cells, these phenotypic effects were reproduced in the F2 generation; this result indicates that RNA can contribute to the transmission of stress-induced traits in mammals (Gapp et. al. 2014) (Sultan 2015, 12-13)

Sonia E. Sultan (2015) Organism & Environment: Ecological Development, Niche Construction, and Adaptation

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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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