Moss - What genes cant do - 2003 (522929), страница 47
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The modular architecture ofa Gene-D allows for expanding the array of Genes-D through shufflingthe modules into new configurations. But more importantly the modulararchitecture of a Gene-D provides for great flexibility and variablity inhow the Gene-D, as a resource for making a protein, is put to use. Consider the example of the Gene-D called NCAM. NCAM contains 19modular exon units (figure 5.1) but there are no NCAM proteins thatare composed of the protein domains coded for by all 19 exons.
AnyNCAM protein is the result of some subset of these potential domains,After the Gene187FIVE lg DOMAINS110 KDaSEC15120 KDa161919140 KDa17181617180 KDa13,1412,11 101Cell membraneFigure 5.1A schematic diagram of the four main classes of NCAM protein; see text fordetails.and many different subsets are possible. The process by which a particular configuration of modules is assembled is called “splicing.” It is notthe DNA but rather a messenger RNA transcript that includes the complementary RNA version of all of the exons that become subject to splicing.
The ensemble of possible NCAM forms is classified into four maingroups depending upon size (110 KDa, 120 KDa, 140 KDa, 180 KDa)and plasma membrane attachment (see figure 5.1). Where the 140 KDaand 180 KDa classes traverse through the plasma membrane, the120 KDa class is linked to the membrane only superficially through anauxiliary connector.No N-CAM does both. And the basis for this difference is the either/or inclusion of one of two different exon modules into the final RNAtranscript. The 140 KDa and 180 KDa must be derived from a transcriptwhich includes exon no.
16 in order to be able traverse the plasma membrane, but must lack exon no. 15, as where the 120 KDa NCAM classis derived from a transcript which must include exon no. 15 in order tobe able to associate by auxiliary connector, but must lack exons nos. 16to 19.The human genome has twice the number of Genes-D as that of fly orworm, but the human proteosome (the full set of all expressed proteins)188Chapter 5is thought to be at least 5 times as complex as invertebrates. This isbecause of an enhanced variability produced through transcript splicing.For just the case of a single Gene-D such as NCAM—and prior to evenquestions of post-translational compartmentalization (see chapter 3),there are two regulatory nodal points that determine its fate: transcription initiation and splicing. Both of these are adjudicated by the complexproceedings of “ad hoc committees.”Whether a given Gene-D becomes transcribed into RNA to begin withis determined by two categories of proteins: the transcriptional factors,including the polymerase enzyme, which have been highly conservedfrom yeast to humans, and the transcriptional effectors whose ranks haveexpanded over evolutionary distance.
Back in Chapter 3, the example ofan artificially simple, hormone-sensitive proliferin transcription systemwas used to show how complex the effects of even just three transcriptional effectors can be. The regulation (yes or no and how much) ofGene-D transcription is determined by an ad hoc committee—which isto say it is a function of the complex relations of all of those transcriptional effector constituents present in the nucleus at that time.Human Genome Project findings suggest that the human genome possesses 2000 transcriptional effector genes (over 5 percent of the entiregene number), a major increase over the number found in the othersequenced species (Tupler et al.
2001). Inasmuch as the role of eachtranscriptional effector depends on the identity of as many as 2000 othereffectors, the complexity of the transcriptional initiation event and itspotential sensitivity to ancillary events that influence the composition ofthe “ad hoc committee” is enormous.What is true of transcriptional initiation is also true of transcript splicing. The ad hoc committee that determines how an RNA transcript willbe spliced (and thus just what biological significance the resulting proteinmight have) is called a spliceosome. Its effects are a complex functionof composition and assembly, and again the human genome reveals asignificant expansion in the number of potential committee members(Tupler et al.
2001).The evolution of complex, internally differentiated, and yet globallycoordinated life forms, including Homo sapiens, was achieved notby the elaboration of a master code or script but by the fragmentationAfter the Gene189of the functional resources of the cell into many modular units whoselinkages to one another have become contingent (Gerhart & Kirshner1997).The more contingently uncoupled the molecular and multimolecularconstituents of a cell become, the greater becomes the subset of potential specializations that can be achieved.
The decision as to when tocouple or not is made, as we’ve seen, by ad hoc committees. And theroster of potential committee members has decisively expanded inconcert with the increasing complexity of an organism.Why might this be? Might it be the case that what has underwrittenevolutionary complexification is not the expansion of the number ofenyzmatic craftsmen but rather the number of molecular “regulatorylawyers and politicians” who adjudicate at the coupling-uncouplingnodal points.
The character of a cell, its differentiated cellular identity,is generally correlated with the particular set of proteins of which it iscomposed. Transcriptional initiation and splicing are the first two nodaldecision points that determine the composition and, to a large extent,identity of a cell. The committees that adjudicate these processes can bethought of as constituent assemblies. Each constitiuent in turn reflectssome set of enabling conditions.
The presence of a constitutent reflectsnot only the past history of the interior of the cell but also the recenthistory of interactions with other cells and extracellular environment.The more complex the constituent assembly the more facts about thepast and present history of the cell and its surround are being broughtto the decision making table.
The evolution of complexity is the evolution of increasingly sophisticated levels of horizontal and verticalcoordination.The evolutionary expansion of the ranks of representative intermediaries appears to be central to the means of achieving this. What each adhoc committee does in regulating transcription and splicing is to achievea kind of consensus about the “state of things.” A larger ensemble ofpotential constituents means a wider sampling of news from the hinterlands—a richer cellular Umwelt. The state of each cell then becomesbetter coordinated with that of the tissue, the organ, the organism as awhole, and so on. In addition, a larger more differentiated committeeallows for buffering.
The consensus of a complex committee can be such190Chapter 5that the absence (or mutation) of any one constituent need not be decisive. The ad hoc constituent committee simultaneously expands the reachof causal influence and yet dampens the effects of any one particularinfluence. Two phenomena discussed in the previous chapter can bebetter understood in the light of this analysis. The notion of an intercellular field and its influence on constituent cells becomes more palpable with the realization that many intracellular processes, mediated by“complex constituent committees,” serve as causal funnels for bringinga great variety of ambient influences to bear on intracellular events.Cell-cell contacts, cell-matrix contacts, ionic characteristics, receptormediated events, even steric constraints, can all influence the composition of the constituent assemblies with consequences that can reboundback to those regions of influence.
Second, and not unrelated, is thecontext sensitivity of somatic mutations and the loudly heralded discovery of redundancy. For 100 years somatic mutation theorists have wantedto affix the causal basis of malignancy to a purely internal condition ofthe cell. But if cells are not dictated by an internal script but rather byever so many ad hoc committees whose constituents reflect the dynamicstate of the cell and its larger milieu, then this inside-outside dichotomyis rendered bogus. Likewise, the sudden absence or aberrance of atranscription-initiation committee member, such as p53 (chapter 4), mayhave a grave impact on cellular behavior in the specific context of acertain tissue, intercellular field, and constituent assembly, while the samemolecule (p53) when missing from birth (as engineered in transgenicmice) may have negligible impact because its absence was accommodatedthrough “constituent buffering” from the get-go, resulting in a systematically modified developmental history.If the sum total of coding sequences in the genome be a script, then itis a script that has become wizened and perhaps banal.
It wouldn’t bethe script that continued to make life interesting but rather the ongoingand widespread conversations about it.What DNA Can DoIf it were the case that genes coded for all the information needed tobuild anything from a yeast to a fly to a human being, then the idea thatthe vast majority of the genome—all that isn’t involved in coding—isAfter the Gene191merely junk might be tenable.
But if indeed it is primarily the regulationof what boils down to the same old stuff that evolves, and if organismiccomplexity is built by pulling apart the pieces and expanding the rangeof choices to be made at the decision making nodal points, and if thesenodal points are fulcrums for wide ranges of influence, then the proponents of conflationary gene-speak have missed the forest for, well . . . onespecies of tree. Over half of the human genome consists of repetitivesequences and most, if not all, of these consist of parasitic transposableelements (Lander et al.
2001).Transposable elements come in four principle varieties, three of whichtranspose through RNA intermediates and one of which transposesdirectly as DNA. Transposable elements are referred to as parasiticbecause they come well equipped with their own promoters, reversetranscriptase and other enzyme templates, for advancing their own replication within the genome. But as such they also represent a source ofdynamism, of mobility, and of architectural innovation and reconstruction.
Transposable elements, it now appears, have been the motor-forceof genomic innovation from the one-celled stage onwards. It is theseengines of activity that have created new genes, but more importantlyhave created regulatory binding motifs that many of the regulatory committees become targeted to, and even more importantly it appears to betransposable units that have served to modularize genomes (Federoff1999; Lander 2001). Far from being biologically irrelevant, the spacing,the positioning, the separations and the proximities of different elementsin a complex system of distributed regulation appear to be of the essence(Shapiro 1999), and it is “transposable elements (that) have been instrumental in sculpting the contemporary genomes of all organisms”(Federoff 1999).
But how could this be? How can ostensibly parasiticDNA be essential to the evolution of higher, increasingly complex,multicellular life-forms?Symbiotic SymphoniesThe physicist Freeman Dyson (1999) has provided us with what isarguably our most interesting and plausible model for the origins of lifeand in so doing simultaneously solved our puzzle in advance. Dysonenvisaged the origin of living cells taking place not in one but in two192Chapter 5steps. In the first step a boundary-maintaining, autocatalytic, metabolizing system consisting largely of proteins becomes established.
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