Moss - What genes cant do - 2003 (522929), страница 46
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Again, theexample of colorectal cancer provides a model for what is at least equallythe case for breast cancer. The identification of the heritable germ-linemutations associated with no more than 15 percent of colorectal cancerprovides clinicians (and drug companies) a place to look, because just asfor the proverbial drunk who’s lost his keys and looks for them beneaththe lamppost, it is where the light is.
Cognitively speaking, the movefrom somatic mutation to genomic susceptibility represents a retreattoward a new burst of instrumental preformationism in the face of realadvances in the understanding of the complex epigenetics of carcinogenesis. In the larger sociocultural context it reflects an unprecedentedinfluence of the marketplace on the biomedical research agenda as wellas on the correlative state of public understanding.5After the GeneBased upon their fundamental roles in genome transmission and in determiningpatterns of gene expression, it can be proposed that repetitive DNA elementsset the “system architecture” of each species. .
. . From the system architectureperspective, what makes each species unique is not the nature of its proteinsbut rather a distinct “specific” organization of the repetitive DNA elements thatmust be recognized by nuclear replication, segregation, and transcription functions. In other words, resetting the genome system architecture through reorganization of the repetitive DNA content is a fundamental aspect of evolutionarychange.—James Shapiro, 1999• There appear to be about 30,000–40,000 protein-coding genes in the humangenome—only about twice as many as in worm or fly. However, the genesare more complex, with more alternative splicing generating a larger number ofprotein products.• The full set of proteins (the “proteosome”) encoded by the human genome ismore complex than those of invertebrates.
This is due in part to the presenceof vertebrate-specific protein domains and motifs (an estimated 7 percent ofthe total), but more to the fact that vertebrates appear to have arranged preexisting components into a richer collection of domain architectures.—International Human Genome Sequencing Consortium, 2001 (Lander et al.2001)Although we still lack the analytical tools, there is a growing appreciation thatorganisms constitute complex, self-organizing systems whose properties can beunderstood through the study of interactions within and between networks ofmutually interacting components, be they DNA sequences, proteins, or cells.Organisms must also be appreciated as historic entites.
. . . Whereas a high levelof internal redundancy is appreciated as one of the most distinctive features ofthe complex genomes of higher eukaryotes, the theoretic and practical difficulties associated the with origin and maintenance of redundancy, in my view, havegone largely unrecognized and may be central to understanding contemporary184Chapter 5genome structure. .
. . A rapidly growing body of data from genome characterization, cloning, and sequencing in a variety of organisms is making it increasingly evident that transposable elements have been instrumental in sculpting thecontemporary genomes of all organisms.—Nina V. Federoff, 1999The science of life gyrates to a centennial beat.
In 1800 it was first christened with the name “biology.”1 In 1900 it “rediscovered Mendel”(Carlson 1966) and took its “phylogenetic turn” (see chapter 1). In 2001,the preliminary findings of the Human Genome Project were reported(Lander 2001, Venter 2001), constituting certainly the culminationand, I would suggest, conclusion of the “century of the gene.”2 Comparative analyses of the human genome with that of the previouslysequenced fly (Drosophilia) and worm (C. elegans) genomes, brings intostriking relief realizations that have been bursting forth for some timeand provide the grist for some concluding comments on behalf of thenext gyration.I suggested earlier that the gene-centered perspective was built of aconflation of two individually warranted but mutually incompatibleconceptions of the gene (Gene-P and Gene-D) and that these were heldtogether by the rhetorical glue of the gene-as-text metaphor. And centralto the gene-as-text metaphor is the understanding that the biologicalfunction of DNA is that of “coding.” Much of the debate between contemporary preformationists (gene-centrists) and advocates of a new epigenesis can be construed as a debate about the scope of coding.My Gene-D is not denied a special template (coding if we must)function, but the scope of this function is limited to within an alwaysphenotypically indeterminate molecular level.
Advocates of geneticpreformationism, by contrast, argue (by conflationary sleight of hand, Iargue) for a large-scale scope of coding, described as a genetic program,book of life, and so forth, that determines the phenotype.3 In either casethis debate looks at DNA qua coding, which is to say DNA qua gene.At this latest biological fin de siecle, DNA has come to burst the boundsof the gene itself.
On the threshold of the “postgenomic” era it is hasbecome possible to glimpse ahead to the nature of molecularized biologyafter the gene.After the Gene185Modularity, Complexity, and EvolutionComparisons of the human and invertebrate (fly and worm) genomeshave come to reinforce certain growing realizations that are reflected inthe epigraphs above. These realizations have to do with biologicalmodularity and its relationship to organizational complexity; with thedynamism of the genome; and with the significance of repetitive noncoding “parasitic” DNA to both of the above. Once upon a time it wasbelieved that something called “genes” were integral units, that eachspecified a piece of a phenotype, that the phenotype as a whole was theresult of the sum of these units, and that evolutionary change was theresult of new genes created by random mutation and differential survival.
Once upon a time it was believed that the chromosomal locationof genes was irrelevant, that DNA was the citadel of stability, that DNAwhich didn’t code for proteins was biological “junk,” and that codingDNA included, as it were, its own instructions for use. Once upon a timeit would have stood to reason that the complexity of an organism wouldbe proportional to the number of its unique genetic units. Beginning withthe discovery that eukaryotic genes are assemblages of ancient modules(Gilbert 1978) and with recognition of the actual dynamism of DNA avery different picture has progressively emerged.The percentage of the human genome which is responsible for proteincoding is extremely small (less than 1.5 percent) (Baltimore 2001).
It isorganized into modules referred to as exons. The exons themselves tendto be highly conserved throughout phylogeny going back to the onecelled stage. Exons generally correspond to a domain of a protein, adomain being a piece of protein that has some structural or functionalintegrity. The ability of proteins to bring specificity to chemical reactions,whether in catalyzing a reaction, forming durable structural elements(filaments, muscle, etc.), transmitting signals, or binding an “antigen” islocalized to the specificity of its domains. Human genes (Gene-D) on theaverage consist of 7 exons but may vary from as few as one to as manyas 178 (Lander et al.
2001) and thus code for an average of 7 (but asmany as 178) possible domains. Typically the exon modules are dispersedwithin the transcriptional unit (i.e., the Gene-D), like islands within asea of much more extensive intervening sequences (introns).186Chapter 5Neither humans nor higher organisms in general are distinguished bytheir repertoire of exons. The sum total of all bacteria contain as many,and almost certainly far more, kinds of exons than the sum total of allmulticellular (and one-celled eukaryotic) organisms.
Accordingly, bacteria display a far greater range of metabolic versatility than the sum totalof all higher organisms. There is scant evidence for evolution being builtupon the expansion of the number of basic coding modules.4 Genes(Gene-D) are composed of assemblages of old modules, and the increasein the number of genes one sees in going from bacteria to one-celled yeastto invertebrate to humans is based on the greater number of ways inwhich modules have been sorted into different combinations.Humans have about twice the number of genes (Gene-D) as fly andworm but less than 7 percent of this difference is accounted for on thebasis of apparently novel domains. The remainder is due to the furtherregrouping of exon modules in the genome.
But the difference in GeneD number between humans and these invertebrates does not account forthe difference in the complexity of such organisms.The evolution of increasingly complex organisms, it turns out, is basedupon the evolution of increasingly modular architectures. The criticaldecisions made at the nodal points of organismic development andorganismic life are not made by a prewritten script, program, or masterplan but rather are made on the spot by an ad hoc committee. And thesecommittees consist of ensembles of modular parts, the compositionof which are contingent upon circumstance. And the more complexthe organism, the greater the number of different potentially modularconstituents and the more sensitive is the outcome to the nuancesof circumstance.Gene-D is built out of modules (exons).
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