J.B.S. Haldane wrote:The fact about science is that everyone who had made a serious contribution to it is aware, or very strongly suspects, that the world is not only queerer than anyone has imagined, but queerer than any one can imagine. This is a most disturbing thought, and one flees from it by stating the exact opposite. (Clark R. 1968, citing a letter from J.B.S. Haldane to Robert Gaves.)
-- Reid, Robert G. B. (1985) Evolutionary Theory: The Unfinished Synthesis. New York: Cornell Univesity Press. p. 117.
A little over 25 years later our "intimate knowledge" has grown significantly, providing insights which have yet to be fully intergrated into evolutionary theory:Reid wrote:The key to development, form, and function in multicellular organisms is differential gene expression, and the most intimate knowledge of the genetic code reveals nothing about the implementation of its information in space and time.
-- Reid, Robert G. B. (1985) Evolutionary Theory: The Unfinished Synthesis. New York: Cornell Univesity Press. p. 46.
Davidson wrote:Animal body plans, their structures and the functions with which their morphology endows them, are the integrals over time and space of their successive developmental processes.... At the outside, development is mediated by the spatial and temporal regulation of expression of thousands of genes that encode the diverse proteins of the organism, and that catalyze the creation of its nonprotein constituents. Deeper in is a dynamic progression of regulatory states, defined by the presence and state of activity in the cell nuclei of particular sets of DNA-recognizing regulatory proteins (transcription factors), which determine gene expression. At the core is the genomic apparatus that encodes the interpretation of these regulatory states. Physically, the core apparatus consists of the sum of the modular DNA sequence elements that interact with transcription factors. These regulatory sequences "read" the information conveyed by the regulatory state of the cell, "process" that information, and enable it to be transduced into instructions that can be utilized by the biochemical machines for expressing genes that all cells possess. The sequence content, arrangement, and other aspects of the organization of these modular control elements are the heritage of each species. They contain the sequence-specific code for development; and they determine the particular outcome of developmental processes, and thus the form of the animal produced by every embryo. In evolution, the alteration of body plans is caused by changes in the organization of this core genomic code for developmental gene regulation. (Davidson 2006: 1-2)
... [T]he system level organization of the core genomic regulatory apparatus, and how this is the locus of causality underlying the twin phenomena of animal development and animal evolution. Because the sequence of the DNA regulatory elements is the same in every cell of each organism, the regulatory genome can be thought of as hardwired, and genomic sequence may be the only thing in the cell that is. Indeed that is a required property of gene regulatory elements, for they must endow each gene with the information-receiving capacity that enables it to respond properly to every conditional regulatory state to which it might be exposed during all phases of the life cycle, and in all cell types. For development, and therefore for major aspects of evolution, the most important part of the core control system is that which determines the spatial and temporal expression of regulatory genes. As used here, "regulatory genes" are those encoding the transcription factors that interact with the specific DNA sequence elements of the genomic control apparatus. The reason that the regulation of genes encoding transcription factors is central to the whole core system is, of course that these genes generate the determinant regulatory states of development. (Davidson 2006: 2)
There follow several important and general principles of organization of the developmental regulatory apparatus, that is, of the control machinery directing expression of the regulatory genes themselves. First, signaling affects regulatory gene expression: The intercellular signals upon which spatial patterning of gene expression commonly depends in development must affect transcription of regulatory genes, or else they could not affect regulatory state. Therefore, the transcriptional termini of the intracellular signal transduction pathways required in development are located in the genomic regulatory elements that determine expression of genes encoding transcription factors. Second, developmental control systems have the form of gene regulatory networks: Since when they are expressed given transcription factors always affect multiple target genes, and since the control elements of each regulatory gene respond to multiple kinds of incident regulatory factor, the core system has the form of a gene regulatory network. That is, each regulatory gene has both multiple inputs (from other regulatory genes) and multiple outputs (to other regulatory genes), so each can be conceived as a node of the network. Third, the nodes of these genes regulatory networks are unique: Though it is not a priori obvious, each network node performs a unique job in contributing to overall regulatory state, in that its inputs are a distinct set, just as the factor it produces has a distinct set of target genes. Fourth, regulatory genes perform multiple roles in development: The repertoire of regulatory genes is evolutionarily limited, and all animals use more or less the same assemblage of DNA binding domains, which define the classes of transcription factor. However, given factors are frequently required for different processes in different forms of development, and they are often used for multiple unrelated purposes within the life cycle. Thus, both within and among animal species, many regulatory genes must be able to respond to diverse regulatory inputs that are presented in various space/time places in the developing organism. (Davidson 2006: 2-3)
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 nonenvironmentali.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)
-- Davidson, Eric H. (2006) The Regulatory Genome. Amsterdam: Academic Press.
de Duve wrote:SUPERGENES ARE IN COMMAND
We have just seen that the cells of a pluricellular organism all have the some genes. If they differentiate into distinct cell types, it is because they do not express the totality of their genes but practice a selection that varies according to cell type. Otherwise, all the cells of an organism would be identical. Cells thus contain "genetic switches," systems that switch on or off the expression of certain genes. This control is carried out by proteins, called transcription factors, that either stimulate or repress the transcription of the genes involved. These proteins being themselves the products of genes, which are subject in turn to a similar regulation, genomes house a whole complex and hierarchical network of regulatory genes--the term "supergene" is sometimes used--next to those that code for "housekeeping," that is, for enzymes, structural proteins, etc. (de Duve 2002: 155)
Regulatory genes are known in bacteria, in which they are involved, among other things, in the adaptation of metabolism to different nutrients. A historic example, which made the fame of the French investigators Fançois Jacob and Jacques Monod, concerns the manner in which bacteria transferred to a medium containing milk sugar (lactose) as sole food supply switch on the genes coding for enzymes specifically needed to use this sugar. Regulatory genes are, however, much more numerous in eukaryotes, and their number increases with the complexity of the body plan of the species. Such is not the case for housekeeping genes, for which there is hardly any difference among species. Or when there is a difference, impoverishments rather than enrichments most often go together with increasing complexity. Witness the many vitamins we are unable to make, whereas humble bacteria do so without difficulty.... In spite of the advances of biotechnologies, we are still far from mastering evolution. (de Duve 2002: 155-156)
The discovery of regulatory genes has allowed us to discern, at least in principle, the mechanisms that direct and control development. Once fertilized, the egg cell divides into two cells, which similarly divide to produce four, which divide into eight, and so forth. Soon, in the course of this process, the cells cease to be identical. Depending on their location in the ensemble, they start expressing or stifling certain regulatory genes, with the consequence that the proteins translated from those genes create concentration gradients between the areas where they are produced and those where they are not. These gradients influence in unequal fashion the expression of other genes, which in turn influence others, in a cascade whose complexity soon exceeds the limits of our imagination and even anything that can be simulated by the most powerful computer programs. At the end of the game, there is an oak plantule, a jellyfish larva, or a newborn baby, depending on the program written into the genome. (de Duve 2002: 156)
Such a mechanism has long been suspected. Already, in the early part of the twentieth century, the German embryologist Hans Spemann demonstrated, by means of remarkably skillful and ingenious experiments, the existence of what he called morphogenetic--shape creating--gradients in embryos. Modern biology is beginning to flesh out those gradients in terms of genes and their protein products. Particularly important has been the discovery of so-called homeogenes, whose control is so wide-ranging that a single mutation of such a gene may cause a fruitfly to grow an extra pair of wings or to sprout additional antennae on its head. Homeogenes have been recognized throughout the pluricellular world, from simple fungi to the most complex animals. (de Duve 2002: 156)
EVOLUTION OCCURS BY WAY OF DEVELOPMENTAL PROGRAMS
With these elementary notions we may now address the problem of evolution, which is conditioned, as we have seen, by changes in the developmental program of organisms. This fact implies almost necessarily that the underlying genetic changes have as targets regulatory genes. But all depends on the cell type to which the modified gene belongs. Thus, a mutation in a skin, stomach, or brain cell may start a new cell line, for example, a cancerous one. But the individuals concerned do not, if they reproduce, give birth to descendants afflicted with cancer of the skin, stomach, or brain. Only genetic modifications of a germ cell that will eventually be involved in the generation of a new individual can be of significance for evolution. [See Epigenetics] Such modifications are the only ones that can influence the development of the fertilized egg. They are also the only ones that can be hereditarily transmitted, as they affect all the cells of the organism, including those that will become germ cells in turn and will give rise to the next generation. (de Duve 2002: 156-157)
-- de Duve, Christian Nobel Laureate. Life Evolving: Molecules, Mind, and Meaning. Oxford: Oxford University Press; 2002: 155-157.
Levinton wrote:Chapter 4: Development and Evolution
Constraint and Saltation
Developmental biology has long been a focus for evolutionary theory (Bonner 1982; de Beer 1958; Garstang 1922; Goldschmidt 1938; Gould 1977; Haeckel 1866; Raff 1996; Raff and Kaufman 1983; Waddington 1940). Evolution can be seen as a change in developmental programs that elaborate the phenotype. The effects of genes and the range of genetic variation would best be investigated on a mechanistic basis, yet until the 1990s, we had only a very small window on this enormously important developmental landscape.
Once we can understand the nature of development and how it constructs the phenotype, we confront anew some of the age-old questions of evolutionary biology. Development is legendary for its organization, sometimes appearing to be remarkably automatic and even self-organizing. The strong integration of the developmental process might not easily be breached by a mutant, which would disrupt fundamental and tightly integrated cellular and molecular processes. This would suggest a force for conservatism in evolution. On the other hand, the tremendous organization of developmental processes suggest to many that simple genetic changes might beget enormous salutatory evolutionary change.
The Janus-headed coin of development is illustrated well by the evolutionary change of the tail in ascidian tadpole larva, which has been lost in evolution several times independently (Jeffery 1997). (....) This major switch in morphology is associated with a mundane larval adaptation for reduced dispersal by the tail-less form. (Tadpole larvae are not brilliant dispersers, either.) Tail-less development results from the abbreviation of developmental programs owing to maternal message and gene regulation in the zygote. The zinc-finger gene Manx is expressed in tailed species but is downregulated in tail-less species, which suggests a simple mechanism for a momentous developmental reorganization, dropping some of the lynchpins of the chordate anatomical plan (Swalla and Jeffery 1996).
The message told by the Manx gene is not clear, despite teh elegant experimental results. On the one hand, it tells us that it is rather easy to lose the tail and a host of associated developmental trajectories (e.g., notochord, tail, otolith, and muscle cells). (....) If it is that easy, why is it so uncommon? Again, we face teh two faces of constraint and possibility for major change.
Time and again, the concepts of constraint and saltation have been formulated in terms of development. Developmental constraints are nonrandom channelizations of evolutionary direction due to limitations imposed by complex interactions of gene expression and epigentic interactions, such as tissue inductions, in the developing organism. The disruption of such interactions may strongly influence fitness and therefore restrict evolutionary change. In the context of development, saltations are rapid evolutionary fixations of phenotypic discontinuities guided by developmental controls, which do not permit continuity of form in polymorphic populations.
The Holy Grail: Connecting an Understanding of Genes and Development
(....) We are now at the threshold of a completely new period, in which development and genetics are being connected in great detail. At first, this became apparent from the emerging understanding of a widespread homeobox sequence that united all of the triploblastic animals at least. Now, modern methods of gene sequencing, manipulation of gene expression, and tracing of spatial patterns of gene expression have resulted in an explosion of information that is not leading, as yet, to many useful evolutionary rules. So far, we are seeing the same errors promulgated in lionizing past laws of ontongeny and phylogeny. Beliefs in major genetic revolutions, master switch genes, and other universals are beginning to form a modern version of the ontogentic laws of old, with little consideration for the possibilities of convergence in developmental gene function. Nevertheless, the new tools allow us to better peak through the curtains, and the early flush of enthusiasm will likely be followed by substantial advances in development evolution.
Phylogeneticists and Developmentalists
(….) The developmentalists claim that “the diversity of structures that have been formed through the process of evolution is constrained by the rules which govern pattern formation during development” (Stock and Bryant 1981, p. 432). As such, evolutionary change of necessity is the evolution of developmental sequences. The individual, therefore, is treated in terms of its entire ontogeny, and development is therefore both the constraint and target of selection. There is a developmental toolbox, and certain tools may be used in many contexts, but this does impose a possibly limited set of alternative developmental pathways.
(….) [M]orphological structures often come as complete structures or not at all. Of equal interest is the importance of localization in development. Embryos develop only as the result of a complex series of timing events that bring different cells into contact or place cells or molecules of restricted developmental potency in a proper environment for induction. The spatial position of cell groups seems crucial in the generation of morphological patterns, owing to
· Localized intercellular movement and regional movement of dissolved substances that often set gene expression in motion (Garcia-Bellido, Rippoil, and Morata 1973; Summerbell 1981; Turing 1952; Wolpert 1969)
· Transcellular electric fields (Jaffe and Stern 1979; Nuccitelli 1983)
· Mechanochemical interactions (e.g., Odell, Oster, Alberch, and Burnside 1981; Oster, Murray, and Harris 1983)
· Specialized cell adhesion molecules (Edelman 1986)
Must these not influence the direction of evolution? These two phenomena integrity of structure and topological restriction of development suggest that an embryo can be transformed in only limited number of directions during the process of development and evolution. That is the fundamental message about form that Richard Goldschmidt’s pioneering book Physiological Genetics (1938), derived from Spémann (1938), underscored so well.
Some examples of developmental mutants show the discontinuous and often spectacular nature of possible structural change. Consider the cyclops mutant (Bowen, Hanson, Dowling, and Poon 1966) of brine shrimp males. After the fourth instar, the lateral eyes move forward and fuse together, forming a single large compound eye by the ninth instar. During this fusion, the ganglia and nerves of the two optic stalks fuse; the resultant eye resembles the normal medial eye of the cladoceran Leptodora. Thus, a quirk of development has caused a structure to change from that characteristic of one taxonomic order to another! The development of the vertebrate limb shows similar quantum steps.
(….) A developmental notion of macromutation springs from the nature of development described above. If a simple transplant places toes on wings or replaces scales with feathers, why couldn’t evolution occur in major steps? Some have seen such discontinuities in development as a vehicle for major evolutionary jumps (Goldschmidt 1940; Gould 1980a; Lovtrup 1974; Maderson et al. 1982; Schinderwolf 1936, 1950), or at least see them as possible stuff of major saltations (Alberch, Gould, Oster, and Wake 1979; Frazzetta 1970)
-- Levinton, Jeffrey S. Genetics, Paleontology, and Macroevolution. Cambridge: Cambridge University Press; 2001; pp. 157-162.