The recent completion of the human DNA sequence provides a prime example. When the Human Genome Project was proposed in the mids, geneticists believed the sequenced DNA would act as the blueprint for a human being. Time has proved otherwise. Mendel bred pea plants and proposed that a pair of elements or units guiding heredity existed in each plant. Still, no one knew exactly what a gene might be.
This paradox puzzled scientists throughout the first part of the 20th century: The entity had to be static enough to create an organism that looked and functioned almost exactly like its parents, but at the same time, it had to provide the variability upon which evolution could act. Watson and Francis Crick in elegantly fit the job description.
Why the 'Gene' Concept Holds Back Evolutionary Thinking
A lesson in humility soon followed. In The Century of the Gene , Keller begins with the notion of the gene itself. Some prominent theorists even proposed that evolution could be defined simply as a change over time in the frequencies of different gene forms in a population.
The identification of DNA as the key molecule of heredity and Crick's Central Dogma of Molecule Biology initially seemed to confirm Beadle and Tatum's "one gene -- one enzyme" hypothesis. However, molecular genetics quickly introduced difficulties with the theory of atomistic genes aligned like beads on a string. A major challenge was Britten and Kohne's discovery of massive amounts of repetitive DNA in certain genomes. Today, we know our DNA contains over 30 times as many base-pairs in repeats as it does in protein coding sequences.
By the conventional view, if genes are the only important actors, then these surprisingly abundant "intergenic" repeats must constitute " junk DNA " and be " ultimate parasites " in the genome. The basic issue is that molecular genetics has made it impossible to provide a consistent, or even useful, definition of the term "gene.
The modern concept of the genome has no basic units. It has literally become "systems all the way down. Various combinations of coding sequences and signals operate dynamically to produce multiple RNA and protein molecules from a single stretch of DNA. Distant sites in the genome cooperate to control genome expression and replication. Every cellular and organism trait is "determined" by molecules encoded at numerous genome locations. A particularly important novelty highlighted by the Genome Biology paper is the unexpected and burgeoning role of so-called "non-coding" RNAs ncRNAs in all aspects of genome function.
Thus, when we read that the yeast genome has 6, genes, are we to understand this number as including regulator genes as well as structural genes? Or should these be considered parts of the structural or regulatory genes they regulate? If so, where would we locate such a gene?
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Often, these elements are scattered far from the coding sequences they regulate. What then should we count as the beginning and end of a gene? For genes that are fragmented in this way, there is no strict one-to-one correspondence between the sequence of a gene and that of the protein it gives rise to. Thus the original RNA transcript directly transcribed from the gene the messenger RNA, or mRNA must be processed to remove these junk sequences before protein synthesis can begin.
The remaining exons are then spliced together to form a continuously coding mature transcript. Alternative splicing is the term biologists use to refer to the construction of different mRNA transcripts from a single primary transcript; these different mature transcripts, in turn, lead to the synthesis of correspondingly different proteins. As many as one third of eukaryotic genes are routinely subjected to such variable readings, where the decision as to how the primary transcript is to be read is itself carefully regulated, depending on the state and type of the cell.
Ex am Co py be cut and pasted together to form a variety of new templates for the construction of a corresponding variety of proteins.
See a Problem?
The number varies greatly from one organism to another, and estimates seem to increase daily. Accordingly, the number of different proteins at least hypothetically associated with a particular gene has escalated sharply, and in some organisms that number now reaches into the hundreds. RNA transcripts are subject to a variety of other kinds of editing as well, equally systematic and equally well-regulated. For example, in some organisms, mature transcripts can be formed by splicing together exons from two different primary transcripts.
Different ways of generating variability from splicing. After G. Malacinski and D. The question that can no longer be deferred is obvious: Which of these different transcripts corresponds to what we should call the gene? But doing so means that we have to give up on the notion, even for structural genes, that one gene makes one enzyme or protein.
Which protein should a gene make, and under what circumstances? And how does it choose? Responsibility for this decision lies elsewhere, in the complex regulatory dynamics of the cell as a whole. But if we take this option as molecular biologists often do , a different problem arises, for such genes exist in the newly formed zygote only as possibilities, designated only after the fact. A musical analogy might be helpful here: the problem is not only that the music inscribed in the score does not exist until it is played, but that the players rewrite the score the mRNA transcript in their very execution of it.
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In some ways, the synthesis of a protein marks only the beginning of the story of gene function. The rest of the tale centers on the function of the protein and the ways in which that function is regulated. During this process, the primary mRNA is transformed by splicing and editing into a mature mRNA ready for translation into a sequence of amino acids.
The ribosome proceeds to the elongation phase of protein synthesis. During this stage, complexes, composed of an amino acid linked to tRNA, sequentially bind to the appropriate codon in mRNA by forming complementary base pairs with the tRNA anticodon.
The ribosome moves from codon to codon along the mRNA. At the end, a release factor binds to the stop codon, terminating translation and releasing the complete polypeptide from the ribosome. As a consequence, molecular biologists have become obliged to adjoin to their updated notion of one gene—many proteins an additional admonition: one protein—many functions. However, cells have had to develop sophisticated mechanisms for switching between the distinct functions of these proteins. Ex am Co py dous amount about the structure and function of genetic material, and much of what we have learned falls outside the frame of our original picture.
The complications brought by the new data are vast; those I have discussed in this chapter are merely the tip of the iceberg. It is arguable that the old term gene, essential at an earlier stage of the analysis, is no longer useful.
The Century of the Gene by Evelyn Fox Keller
Certainly, astonishing progress has been made in understanding the importance of genetic mutations in the incidence of many diseases including a number of behavioral disorders. Such examples remain rare, however, and even in these clear-cut cases much remains to be understood about the processes that link the defective gene to the onset of disease.
In conditions that are known to involve the participation of many genes such as certain kinds of heart disease, stroke, psychoses, diabetes , the limits of current understanding are far more conspicuous. What is a gene today? Yet there is, I suggest, one feature that clearly distinguishes the present from the past. What is distinctive today is that progress in molecular biology has now made it possible to break this historic silence.
And for this development, the newly available sequence information has been especially valuable. Clear and demonstrable gaps have now been exposed between the many different attributes that had historically been assumed to inhere in one single entity, the gene. To be sure, many different kinds of research have played their parts in the exposure of such gaps, but the role of the new sequence data has been of unmistakable importance. Yet the lesson comes hard. Today, it is precisely that self-identity which has been disrupted. Ex am Co py to be identical with the unit of transmission, that is, with the entity responsible for or at least associated with intergenerational memory.
There, we learned that the source of genetic stability was not to be found in the structure of a static entity but that stability is itself the product of a dynamic process. Here, we learn that gene function needs also to be understood in dynamical terms. Because biological function inheres in the activity of proteins rather than of genes, the breakdown of the one gene—one protein hypothesis critically undercuts the possibility of attributing function to the structural unit that has traditionally been taken as the gene.
Yet reconceived as a functional unit for example, the spliced and edited mRNA sequence , the gene can no longer be set above and apart from the processes that specify cellular and intercellular organization.
One reason is that the story itself has become so complicated; but another reason may be that the very use of the term gene has become an impediment to its exposition. Perhaps it is time we invented some new words. This process, which we know as development, has been described and thought about by biologists for as long as there has been a science of biology. Its nature has remained a mystery because we have not heretofore understood enough about the nature of life itself.
Today we do. This is the picture of life given to us by molecular biology and it is general, it applies to all cells of all creatures. It is a description of the manner in which all cells are similar. But higher creatures, such as people and pea plants, possess different kinds of cells. Indeed, the genetic program has come to be widely regarded as a fundamental explanatory concept for biological development—if not the fundamental concept. What exactly is a genetic program? And in what sense can it be said to explain development?
xclimbing.ru/cut_editor1/today/onlayn-numerologiya-imeni-i-otchestva.html Here, as in Chapter 2, my concern is with the question of function, only now my focus is on the function of the genome as a whole, rather than on the function of individual genes. The question before us is not about the making of an enzyme but about the making of an organism. For even were we able to hold to a simple correspondence between one gene and one protein, we would still have to bridge the gap between proteins and organism: How can an organism be built out of the mere accumulation of different proteins?
As we will see, once again the question hinges on our understanding of regulation, but this time around I want to focus more directly on the sense of agency that tends to inhere in the very notion of regulation that is, in the supposition of a supervisory body responsible for regulating. Where, I ask, might such agency be located?
Yet even to talk about regulation is to jump ahead of the story. To answer that question, we need to look at the terms and concepts with which earlier generations of geneticists were obliged to work, starting once again with the notion of gene action. Already in it was clear to him that some supplementary assumption was needed—for example, that genes act variably, being called into action at different times of development by other factors that might themselves be nongenetic.