Moss - What genes cant do - 2003 (522929), страница 28
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The so-called spliced state ofan RNA molecule, for example, has been shown to be capable of selfsustaining, autoregulatory effects on subsequent RNA splicing (Bellet al. 1991). Proteolytic proteins—proteins which cut other proteins inspecific ways—are themselves regulated by their proteolytic state.
Theactivation of proteolyic protein, through its cleavage by another proteolytic enzyme, may initiate a cascade of proteolytic events that feed backon the proteolytic state of other tokens of that type. The inheritance ofeither RNA in a certain splice state or proteolytic enzymes in a certainproteolytic state will result in a daughter cell (including an egg cell) thatis already poised toward a certain “dynamic trajectory.”Most ubiquitous, and yet theoretically untouched, is the role of phosphorylation states in mediating what appears to be all of the decisionpoints in cellular life.
Phosphorylation of proteins is accomplished by aclass of proteins called “kinases” for which there are now thought to be2000 related genes in higher organisms (Hunter 1995). The reverse reaction, i.e., the removal of the highly charged phosphate groups, is accomplished by a class of enzymes known as “phophatases.” These are nowthought to number in the 1000 range (Hunter 1995).
Given the HumanGenome Project’s estimate of approximately 30,000 human genes(Lander et al. 2001), kinases and phosphates would account for nearly10 percent of the entire human genome.3 The activation state of bothkinases and phosphatases is regulated by their own phosphorylationstate.A Critique of Pure (Genetic) Information109The potential dynamic complexity of this subsystem alone is astronomical.
The phosphorylation state of one or more phosphorylationstate effector proteins may be the key regulatory determinant of acomplex autoregulatory system which is passed onto daughter cells. Theresponses of cells to all external and internal signals is mediated by cascades of phosphorylation and dephosphorylation reactions, which resultin everything from determining anabolic versus catabolic metabolicpatterns to “choosing” between paths of cell growth versus terminaldifferentiation. The vast complexity of the phosphorylation system mustbe a function of the stabilization needs of highly differentiated multicellular organisms. The challenge that lies ahead will be to determine howstabilization capacity is built into the dynamic architecture of the phosphorylation system itself.A bottom-up approach to conceptualizing the steady-state dynamicsof an organism would be one that manages to bring together the varioussubcellular systems into an integrated, dynamic whole.
The idea of a cellular state as a basic level of biological integration and identity wasalready considered by Sewall Wright (1945):Persistence may be based on interactions among constituents which make thecell in each of its states of differentiation a self-regulatory system as a whole, ina sense, a single gene, at a higher level of integration than the chromosomalgenes.
On this view the origin of a given differentiated state of the cell is to besought in special local conditions that favor certain chains of gene-controlledreactions which cause the array of cytoplasmic constituents to pass the threshold from the previous stable state to the given one.To what extent cellular states can be individuated from an empirical,bottom-up approach is an open question. Given the virtual infinityof potential cellular states based on theoretical combinatorics (Elsasser1987) it is likely that the number of effective possible cellular statesis in fact highly context-dependent (contra Kauffman).
If some finite setof even context-dependent individuated cellular states could be identifiedand their properties of transformation and stabilization characterized,then it would be possible for the “stories” of both ontogeny andevolution to be retold, using dynamic cellular states as basic units of variation and selection. The course of an ontogeny would then be understoodto be that of the reproduction of a long series of cell-state-inducing andcell-state-stabilizing interactions within multiple levels of constraining110Chapter 3context. The ability of each set of state-stabilizing couplings between cellsto become themselves part of the constraining context of subsequent cellstate decision points would have to be basic to the possibility of accounting for the macrostability necessary for producing whole lineages ofgenerically similar organisms. The theme of cell-state variation and selection will be revisited from another perspective in chapter 4.Chromatin Marking and the Fall of “Molecular Weismannism”The rhetoric of the hereditary code-script as discussed in chapter 2 hashelped itself to, among other things, the metaphorical resources associated with biblical religions.
The “Book of Life” and other such textualtropes connote a deep sense of antiquity. A genetic code which is seento have stood the test of eons is a likely candidate for accruing a secularized (albeit, barely) sense of sanctity. But such quasibiblical veneration trades on an ambiguity over form versus content of the code.Granted, all terrestrial life appears to be relatively united due to commondescent as well as in terms of the form of the code, but it is only in termsof its form that the code can be said to be universal. The Ten Commandments, on the other hand, are esteemed for their antiquity and thepresumed authority of their content, not for what language—whetherHebrew, Greek, Aramaic, Latin, or English—they are written in. DNA,for all its formal antiquity, turns out to be subject to rapid changes:transpositions, amplifications, recombinations, and the like, as well asmodulation by direct chemical modification—all in ontogenetic as wellas evolutionary time frames.August Weismann held that the germ line of organisms is sequesteredand insulated against the possible effects from the life experience of thehost organism.
Subsequent investigations of developmental patterns havesince shown that the vast majority of organisms do not sequester theirgerm line early if ever in development (Buss 1987). Early sequestrationof germ tissue appears only in higher organisms (and some invertebrates)and so cannot be treated as a basic evolutionary mechanism. In its placeorthodox neo-Darwinian theory has substituted the idea that DNA isimpervious to the effects of organismic experience; this has been referredto as “molecular Weismannism.”A Critique of Pure (Genetic) Information111While it seems likely that a strong focus of twenty-first century biologywill attend to the mechanisms of spontaneous recombination, theremainder of this section will consider the process known as “chromatinmarking” (Jablonka & Lamb 1995, Jablonka & Lamb 2001), wherebygene activity is modulated by direct chemical modification.
Chromatinmarking, also known as hypermethylation, is not in principle separatefrom the organizational and dynamic dimensions of life already discussed, but it does represent the most immediate epigenetic link betweenthe historical, contextual life history of a cell-organism and the chemical structure of its genome.Chromatin marking refers to the enzyme-mediated addition of methylgroups (CH3) to the C (cytosine) bases in regions of DNA where Cis followed by G (guanine), i.e., CpG dinucleotides. While (followingJablonka & Lamb 1995) I have grouped chromatin marking as one ofthree general classes of epigenetic inheritance systems, DNA methylationis generally what is meant in current biomedical literature when the terms“epigenetic programming” or “epigenetic mechanisms” are invoked.This is perhaps because the direct chemical modification of DNA wouldappear to correspond most closely to an etymologically literal interpretation of the word “epigenetic.” (The semantic link between “epigenetic”and “epigenesis” is lost to most researchers and clinicians, who arewoefully unschooled in the history of biology.)The addition of the above methyl groups to the CpG dincleotideswithin DNA decreases the likelihood of transcriptional activation, probably by inhibiting the association of DNA with proteins that promotetranscriptional activity.
Recent literature has also indicated an association between the methylation of DNA and the chemical modification ofhistone proteins which form the structural matrix of chromatin particles.The full significance of this with respect to epigenetic stability, heritability, and transcriptional repression is yet to be fully revealed. In additionto influencing transcriptional activation, the methylation state is alsofound to affect the susceptibility of DNA toward mutation, translocation, and meiotic recombination.Chromatin marking results in context-dependent modulation ofgenome activity in two distinct ways.
During the gametogenesis ofmammalian eggs and sperm chromosomes are methylated according to112Chapter 3sex-specific patterns. The genes of the mammalian zygote are thus differentially predisposed to activation or inactivation depending on theparent of origin. This phenomenon has been referred to as “imprinting”and is understood to be responsible for the inability of mammals toreproduce parthenogenically. Imprinting seems to ensure that the availability of both male- and female-derived chromosomes are necessary forsuccessful development.
Because the same allele (gene) at the same locuson differentially marked chromosomes can have different phenotypicconsequences, the term “epialleles” has been introduced. Two epiallelescan be associated with different phenotypes—not because of differencesin their nucleic acid sequence but rather because of differences in theirpattern of CpG methylation. For example, Prader-Willi syndrome andAngelman syndrome represent two phenotypically different humangenetic diseases, which, as it turns out, are due to the same chromosome15 deletion.
In the case of the former it is associated with the paternalchromosome and in the case of the latter the maternal chromosome.Recent studies on Turner’s syndrome individuals, females who have onlyone X chromosome (instead of two), have shown that it makes a difference whether the one X was derived from the mother or from the father.Those who derived their X chromosome paternally were reported to havea tendency toward better social skills acquisition.
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