Model B is limited to the transcribed region.
Model C includes only the set of exons derived from a pre-mRNA. Finally, model D is limited to the coding exons of a primary transcript, excluding non-coding leader and trailer sequences. Model A is the most inclusive, incorporating all cis -acting sequences which influence transcription, such as promoters, enhancers, terminators, regulators, etc.
This model faces a host of problems, mostly related to the fact that there are many different types of regulatory elements, generally operating in complex and varied combinations. There are cis- -acting factors which influence transcription independently of their distance from the coding sequences, such as enhancers and silencers, making it difficult to empirically assign the boundaries of a gene. There are cis -acting factors which simultaneously affect the expression of different genes.
There are even cis -acting factors which are nonspecific, influencing any compatible promoter within their range. Therefore, model A will lead to substantial overlapping of genes which depend on the same regulating sequences, raising difficulties to the idea that a gene is a structural unit. Consider also that in order to justify the inclusion of a cis -acting sequence in a gene, it is only necessary to show that it modulates transcription. This leads to problems when we consider phenomena such as position effects.
If a rearrangement of genetic material ends up placing a gene near heterochromatin and the expression of the gene is significantly affected by this position, model A will demand that a huge part of a chromosome, i. These problems, among many others, suggest that we have to abandon a completely inclusive model for the structural gene.
We should move, then, to model B, in which the structural boundaries of the gene are defined by the process of transcription. This model is appealing, since it is grounded on the clear borders that transcription seems at first to establish, and supports an interesting relationship between a transcription unit and the sequences necessary to make a polypeptide. Nevertheless, it is challenged by two particularly troublesome phenomena, split genes and alternative splicing. In this case, the sequences transcribed into RNA are not the same as those later translated into proteins, posing a first problem to model B, which relies on the transcription unit to demarcate what is a gene.
A protein encoded by a spliced mRNA molecule exists as a chromosomal entity only in potential Keller, The situation becomes more perplexing, and less promising with regard to the prospect of delimiting genes as entities to which we can ascribe a single, well-defined transcript, when we consider the diversity of splicing patterns of the same primary transcript, i.
The vast majority of genes in multicellular eukaryotes contain multiple introns, and the presence of such introns allows the expression of multiple related proteins isoforms from a single stretch of DNA by means of alternative splicing see, for ex. This phenomenon makes model B and, generally speaking, the whole idea of genes as units no matter if structural or functional very clumsy. But the situation may not be that simple. Splicing patterns are subject to a complex regulatory dynamics which, after all, involves the cell as a whole Keller, On the one hand, the unit transcribed into a single RNA could count as a gene, i.
But to treat mature mRNA as the gene has in itself a number of counter-intuitive consequences. It would mean, for instance, that genes exist in the zygote only as possibilities and do not show the permanence and stability typically ascribed to the genetic material. Moreover, genes would not be found in chromosomes and, sometimes, not even in the nucleus Keller, A linear correspondence between a gene and a transcription unit, therefore, does not hold.
A putative solution, then, is to move from model B to model C, treating units in the genome as smaller in size. This model seems at first capable of assimilating alternative splicing, by treating exons as the structural units in the genome and, consequently, rescuing the idea that a gene is a unit by redefining genes as sets of exons sharing a common transcript. We find this definition of gene in the paper in which Venter and colleagues , p. They argue for this definition of gene precisely because of the challenges to model B discussed above.
Could this be a putative solution to the gene problem? Model C faces the problem that there are patterns of RNA splicing resulting in transcripts which differ from one another by the presence or absence of exons corresponding to trailer sequences Henikoff and Eghtedarzadeh  offers an example, discussed by Fogle, As this model includes the exons corresponding to trailer sequences, this feature is enough to falsify it. Nevertheless, model C can be easily saved, in principle, by a slight modification, which leads to model D, including only coding exons.
In this case, any difference in the length of trailer sequences becomes irrelevant. But alternative splicing can also affect the size and coding region of exons, as shown by Schulz et al. Therefore, alternative splicing also challenges model D, and the conclusion we reach is that none of the structural models discussed above holds.
If we treat them as forming the whole set of possible structural models, as it seems plausible to do, we can see why the idea of the gene as a structural unit is in crisis. It is clear, however, that we can understand the situation in a different way, since alternative splicing affecting coding exons simply shows that model D is not absolutely general. But where in biology do we have entirely general models? Why should we demand such a generality from models of the structural gene? It seems clear that the most reasonable conclusion regarding this latter model is that it should not be simply discarded on the grounds of a particular kind of alternative splicing, since the model remains useful despite possible exceptions.
However, we must then face additional challenges to the classical molecular gene concept, including gene overlapping, trans -splicing, mRNA edition, alternative translation modes, genomic rearrangements, etc. When we take into account all these challenges, it becomes clear that even model D is not in a comfortable situation as a basis for understanding genes as structural units in the genome. Therefore, according to some definitions, the sequences coding for micro-RNAs would count as genes, according to others, not.
What is dramatic about the problem is its dimension: Symptomatically, these features give support to a picture of molecular complexity in which the crucial aspect is not the amount of genes, but rather the way DNA sequences are embedded within complex information networks, such as those mediated by transcription factors see, for ex. In view of the difficulties faced by the idea that genes are structural units, we should investigate the alternative of treating them as functional units.
If one wants to understand gene function, it is necessary to examine the nature of gene expression, since it is by being expressed that a gene can have significance to the cell. Nevertheless, gene expression shows that the idea of the gene as a functional unit also faces important difficulties. The classical model of the gene as a unit of function is grounded on the idea that a gene produces a single polypeptide, which, in turn, has a singular function. But the complexity of gene action in the cellular context makes it quite difficult to maintain the idea of a unitary relationship between a gene and its function.
The context-dependence of gene action clearly shows that it makes no sense to ascribe a single function directly to a DNA locus, without taking into account in which context that locus is expressed. One manner of emphasizing the context-dependence of gene function is to properly consider the role of regulation in living systems.
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Differences in animal designs and complexity, for instance, are mostly related to changes in the temporal and spatial regulation of patterns of gene expression Carroll et al. Regulation is a process that entails an influence of higher-level processes on molecular processes, such as transcription, RNA splicing, translation etc. The time and place in which a given set of genes is or is not activated depend crucially on downward regulation, and this regulation is something to which genes are subjected, and not something that genes do, command, control, program, etc.
Even if we consider a single protein encoded by a gene, it will be difficult to sustain the idea of a functional unit, since many proteins are multifunctional. Among many possible examples, I can mention the enzyme tryptophan synthetase, which has two catalytic functions: while its a subunit catalyzes the conversion of 1- indolyl glycerol 3-phosphate to indole and glyceraldehyde 3-phosphate, its b subunit catalyzes the condensation of indole and serine to form tryptophan.
Things become even more problematic when we consider alternative splicing, by means of which one DNA locus can code for multiple polypeptides. Alternative splicing and multifunctional proteins are particularly consequential in these regards, since they cannot be assimilated by a move which limits the idea of functional unit to the proximal function of a gene, while this is possible in the case of arguments grounded on the context-dependence of gene action. Our current knowledge about the physical organization and dynamics of genomes brings to collapse the delicate juxtaposition of the molecular and the Mendelian gene established in the classical molecular concept.
Historically, it became evident that genes are neither discrete there are overlapping and nested genes , nor continuous there are introns within genes ; they do not necessarily have a constant location there are transposons , and they are neither units of function there are alternatively spliced genes and genes coding for multifunctional proteins, and gene action is strongly dependent on cellular and supra-cellular contexts , nor units of structure there are many kinds of cis -acting sequences influencing transcription, split genes, etc.
MECHANISMS OF HORIZONTAL TRANSFER
When there are so many problems with the properties used to define a concept, it is natural to ask what, after all, is the entity which is being defined. Recent advances in molecular biology, genomics and proteomics made it more and more difficult to conceive of genes as units. It is now quite clear that biological information operates at multiple hierarchical levels, in which complex networks of interactions between components are the rule, and, consequently, the understanding of the dynamics and even the structure of genes demands that they be located within complex informational networks and pathways Ideker et al.
We should move beyond the treatment of genes as units of structure and function which, secondarily, interact in complex networks. Indeed, within the community of geneticists and molecular biologists, there is a growing feeling that a change of paradigm is taking place e. Two recent examples of empirical papers which express doubts about the gene concept are Wang et al. Emphasis added. It is this concept that cannot be reconciled with our current knowledge about the structure and functioning of genomes. This opens a door for rescuing the gene concept by redefining it in such a manner that the unit concept is dispensed with.
This is a major change in our view about genes. After all, the main historical baggage of this concept lies precisely in the understanding of genes as basic units of life Keller, , which in fact predates the gene concept itself Fogle, Conceptual variation and ambiguities in the gene concept. A major problem faced by the gene concept is proliferation of meanings Fogle, , ; Moss, Conceptual variation and ambiguities have been a feature of the gene concept throughout its whole history see, for instance, Carlson, , and a number of authors consider that they even have been heuristically useful in the past Kitcher, ; Burian, ; Falk, ; Griffiths and Neumann-Held, ; Stotz et al.
The recognition of the heuristic role of conceptual variation does not preclude, however, a concern about the possibility that it can now lead to serious difficulties. Falk , p. Fogle , p. This conceptual variation arguably results from a change in our attitude towards the gene. Emphasis in the original. That is, the gene is currently seen once again as an instrumental, pragmatically flexible construct that can be adjusted to the diverse needs of researchers in different fields. Fogle offers a mostly negative appraisal of this view, considering that retreating to the view that the gene is an instrumental construct confounds meaning and hinders specification of gene properties.
One such attempt is found in Waters , p. By using a number of open clauses, he intends to accommodate the challenges to the gene concept.
Gene Action and Morphogenesis in Plants
If we focus on the process of transcription at the stage of pre-mRNA, introns should be included in genes. But, if we focus on the polypeptide chain, introns should not be included. There seems to be no good reason for defining genes in such a way that they are conflated with established terms in the field. Nevertheless, even those who think of conceptual variation as a desirable feature consider it is still the case that we should clearly distinguish between different gene concepts and their domains of application e.
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This concept faces a number of difficulties I will not address here. In this approach, the unit of development corresponding to each gene would become a disjunction of possible consequences under a variety of epigenetic conditions. They claim, however, that we should abandon the goal of identifying genes with particular segments on chromosomes in favor of the second aim, to understand genes as developmentally meaningful units. This alternative builds the different epigenetic conditions which can affect gene expression into the gene.
It takes a more process-oriented rather than substance-oriented view on genes, stressing how they are used, rather than what they are as physical entities. Some problems faced by the gene concept support this move. Consider, for instance, that the role of a particular DNA sequence in a developmental system influences whether the sequence is used as an intron or a coding region, or whether it acts as a promoter or as part of an open reading frame. A structural description of DNA is, at best, a necessary condition for the functional description to apply, but not a sufficient condition, given the context-dependence of the function a given DNA region performs.
Moreover, the process nature of the concept arguably makes it possible to accommodate anomalies which the classical molecular or, for that matter, the contemporary molecular gene concept has difficulty in facing, such as alternative splicing or mRNA editing.
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The key for dealing with these anomalies is the fact that the molecular process gene concept builds into the gene the particular processes involved both in alternative splicing and mRNA editing. The molecular process gene concept has, however, a number of potential troublesome consequences Moss, First, it substantially increases the number of genes in eukaryotes, due to the great number of polypeptide isoforms generated by alternative splicing.
Gene expression - Wikipedia
Second, it makes it necessary to include in genes the multimolecular systems associated with transcription and splicing. Thus, the process molecular gene would jump to a higher level in the biological hierarchy. Third, it is hard to individuate genes in accordance with this concept, given the extreme context-dependence of gene expression.
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These thinkers advocate a process philosophical approach, in which processes are treated as being more fundamental than entities, as ontological categories.
Related Gene Action: Historical Account
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