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This Concept Map, created with IHMC CmapTools, has information related to: n5. Ontogeny, A network consisting of even a modest number of genes can potentially explore a vast state space. But a handful of attractors pull it in a few directions. Depending on which state cycle the network is orbiting, different genes will be switched on or off. Different proteins will be produced. The genomic network will act as a different kind of cell. ???? The human genome encodes some 100,000 structural genes and an unknown number of operators, repressors, promoters (which switch genes on instead of off) and so forth. These genes, together with their RNA and protein products, are connected into a tangled web of regulatory interactions, the genomic network, whose joint behavior coordinates development from zygote to adult., Networks with as many as 100,000 nodes and state spaces of 2100,000 , hence 1030,000 will settle down and cycle through a tiny, tiny state cycle with a mere 317 states on it. The network squeezes itself into fraction of its state space. ???? A network consisting of even a modest number of genes can potentially explore a vast state space. But a handful of attractors pull it in a few directions. Depending on which state cycle the network is orbiting, different genes will be switched on or off. Different proteins will be produced. The genomic network will act as a different kind of cell., Networks with as many as 100,000 nodes and state spaces of 2100,000 , hence 1030,000 will settle down and cycle through a tiny, tiny state cycle with a mere 317 states on it. The network squeezes itself into fraction of its state space. ???? Tiny attractors, vast order., Monod used the phrase “Evolution is chance caught on the wing”. This phrase captures our sense, since Darwin, of untold freedom for the search of random mutation, of selection culling useful forms from the chaff of useless ones. ???? Kauffman – Selection, however, always had a partner in molding life; self-organization. If selection had to search too hard to find a genetic mechanism that allowed the zygote to unfold so beautifully, then the result would be too ad hoc, one of Jacob’s tinkered-together contraptions. Instead, large networks of genes spontaneously exhibit the order necessary for ontogeny. There is sacredness, a law – something natural and inevitable about us., If the genetic circuits of bacteria and higher organisms are examined, three features emerge. ???? 1. Any gene or other molecular variable is directly regulated by rather few molecular inputs. For example, the lactose operator is regulated by two molecular inputs; allalactase and the repressor protein., The importance of the apparent (but rare) simplicity of canalizing functions is that large networks of binary elements governed predominantly by canalizing functions spontaneously lie in the ordered regime. Vast order for free abounds for selection’s further sifting. If canalizing functions are abundant in cells because they are chemically simple, then that chemical simplicity itself suffices to engender massive large-scale spontaneous order. ???? The central dogma of developmental biology merely states that different cell types are different patterns of activity of the same genome. However, the possible number of trajectories in this large state space is astronomical. But because of the way they are constructed, genomic networks lie in the ordered regime. Instead of roaming all over the map, such networks are pulled by only a handful of attractors., Review: Large networks of binary elements, random Boolean networks, generically behave in three regimes; a chaotic regime, an ordered regime, and the edge-of-chaos regime. Two simple constraints suffice to guarantee that most members of the constrained ensembles lie in the ordered regime. ???? Another way to ensure orderly behavior is to construct networks using what are called “canalizing” Boolean functions. These Boolean rules have the easy property that at least one of the molecular inputs has one value, which might be 1,or 0,which by itself can completely determine the response of the regulated gene., The OR function is an example of a "canalizing" function. An element regulated by this function is active at the next moment if its first, or its second, or both inputs are active at the current moment. Thus if the first input is active, then the regulated element is guaranteed to be active at the next moment, regardless of the activity of the second input. ???? Almost all regulated genes in viruses, bacteria, and higher organisms (in this idealized framework) are governed by canalizing Boolean functions., Homeostasis, the tendency of cell types to remain the same following perturbations, is essential to life. Transiently “flip” the activity of a single gene in a Boolean network which has settled into a state-cycle attractor. For almost all of those perturbations, the system returns to the state cycle from which it was perturbed. That is homeostasis. And it comes for free in the ordered regime. ???? But homeostasis cannot be complete. If the zygote differentiates through branching pathways to intermediate cell types that themselves branch to the final cell types of the newborn adult, then occasionally a perturbation will have to push a cell into a new basin of attractions flowing to a new attractor – that is, into new developmental pathway flowing to a new cell type., Already at this most primitive stage, we witness two fundamental processes of ontogeny, or development. The first is cell differentiation, and the second is morphogenesis (coordination into organized tissues and organs). ???? This leads to the central dogma of developmental biology; cells differ because different genes are active in different cell types., We can extend the networks of genes and their products in enormous wave of regulatory circuitry. ???? Here, in this familiar case, the substrate and the competitive inhibitor necessarily have the same molecular features. But because allolactose acts at a second site than the repressor, rather than at the repressor’s DNA binding site, allolactose might just as well be used a signal to control the transcription of a gene to encode actin, myosin, or the enzyme involved in the synthesis of hydrochloric acid., The zygote is a single cell of a single type. Over the course of 50 or so sequential rounds of cell division between the zygote and the newborn infant, that single cell gives rise to a menagerie of different cell types. The human body contains 256 different cell types, all specialized for specific functions in the tissues and organs. Almost all of these cells contain the same compliment of genes and DNA. ???? This leads to the central dogma of developmental biology; cells differ because different genes are active in different cell types., At least for the past 700,000 years, or from the Cambrian explosion 550,000 years ago, multicelled organisms began life as a single cell, the zygote, the fruit of parental union. ???? Begin with the zygote. After fertilization of the egg by the sperm, the human zygote undergoes rapid cleavage; cell divisions that create a small mass of cells. These cells migrate down the fallopian tube to enter the uterus. While migrating, the mass of cells hollows out, and a small number of inner cells migrate inward and burrow into the uterine lining to form the placenta., Here, in this familiar case, the substrate and the competitive inhibitor necessarily have the same molecular features. But because allolactose acts at a second site than the repressor, rather than at the repressor’s DNA binding site, allolactose might just as well be used a signal to control the transcription of a gene to encode actin, myosin, or the enzyme involved in the synthesis of hydrochloric acid. ???? The shape of the molecular-controlled molecule need bear no relation to the ultimate product of the controlled process., A cell orbiting a particular attractor will express certain genes and proteins making it a certain kind of cell. The same cell orbiting a different attractor will express other genes and proteins. ???? So if the cell types correspond to state-cycle attractors, then a cell cycle can be thought of as the cell traversing the length of its state cycle. And the resulting time scale to traverse the attractor is the real time scale of the cell cycle. (50 or so hours in the human), n5. Ontogeny see also n4. Boolean Networks, If the genetic circuits of bacteria and higher organisms are examined, three features emerge. ???? Almost any genomic regulatory network harboring these three known properties will exhibit all the order for free we might hope for. These known properties already predict much of the order of the biological world., In contrast, a substrate must fit its enzyme, and a second molecule, a competitive inhibitor that is to inhibit the enzyme by binding to the same enzymatic site, must look like the real substrate. ???? • The structural gene for beta-galatosidase can be either on or off, either being transcribed or not; • And the repressor protein can be either bound to the operator site, or not, either on or off. • The operator site can be free or not, on or off. • The allolactose can bind or not bind to the second site on the repressor protein, on or off., So the allolactose, binding a second site on the repressor protein, “pulls” it off the operator, thereby allowing synthesis of the gene that metabolizes lactose, beta-glycosidase. ???? But since allolactose acts via a second site, called an allosteric site, on the repressor protein, which is different from the site on the repressor that binds the operator DNA sequences, this implies that the shape of the lactose molecule bears no obvious relation to the ultimate consequences of its action; its capacity to control gene activity., With K = 2inputs per gene, and more generally with canalizing networks, the median number of state-cycle attractors is only about the square root of the number of genes. The suggested Boolean network predicts 317 cell types, close to the actual number of 256 in humans. ???? Thus our framework hypothesis states that cell types are attractors in the repertoire of the genomic network. Within this framework, many known properties of ontogeny fall readily into place. First of all, each cell type must be confined to an infinitesimal fraction of the possible patterns of gene activity. Just this behavior arises spontaneously in the ordered regime. The patterns of gene expression settle into, and cycle around, state cycles with only 317 states, an infinitesimal fraction of the possible patterns of gene activity. The small number of attractors in the ordered regime constitutes order for free.