We agree with Scherrer and Jost that a meaningful definition of gene has to be based on a notion of function because a purely structural gene definition is altogether dispensable as we have seen above. In this section, we will briefly outline a research agenda that may eventually lead to a useful function-based gene concept—or to the realization that such an endeavor cannot succeed.
First, we reject the idea of a one-to-one correspondence of function and “gene-product”, which seems much more a vestige of the history of the gene concept than a property of a biological system. The appeal of the equivalence of function and product is that it makes function “measurable” by virtue of detecting the product. We have argued above, however, that the existence of a product does not imply that it has any function at all, and conversely, the same product may have multiple and mechanistically diverse biochemical functions, depending on its context.
Hence, we expand the notion of function and postulate that function must be measurable directly by some experimental setup in finite time, and that one must be able to do this in such a way that functional equivalence can be determined. What constitutes a function, and whether two functions are distinguishable from each other, therefore depends on an experimental (or computational) procedure, which we will for short call a “measurement” in the following. Different procedures may represent “biological importance” more or less well. Time-honored procedures such as the classical complementation test of molecular genetics or the observation of the developmental effects of gene knock-outs are procedures that have proven useful. The approach of the Genon Theory, namely to determine whether a stretch of DNA is eventually translated into a polypeptide is yet another possible way to measure. We view computational approaches as yet another procedure to assess information about function. Of course, as with any “functional test”, all these procedures come with inherent limitations and the possibility of false positive and negative results. Such results may eventually lead to erroneous conclusions about particular “genes”. This is, however, also true for seemingly straightforward procedures such as the assignment of ORFs (Brent 2005
), and does not affect the conceptual framework.
Entire cells, organs, and organisms certainly convey function. Thus we would not want to be forced to call everything that has a measurable function a “gene”. Just as Scherrer & Jost do, we consider a gene a unit
of function. The nature of units, modules and their mutual relationships is a field of lively debate in theoretical biology, see, e.g., (Kvasnicka and Pospıchal 2002
; Tanaka et al. 2006
; Schlosser 2002
; Wagner et al. 2007
), which we will not enter here. Instead, we use the term “unit” in a broad sense: a unit should show stronger cohesion to itself than to other components, thereby ensuring its integrity in isolation. Consequently, a unit of function should execute its function in isolation,
thereby representing a “building block” or “basis element” of the space of functions.
Novel functions may emerge from collections of functional sub-units. Within a given experimental protocol we may be able to distinguish the function of higher level units from those of their components, thus functional units can be nested within each other. Intuitively, we would like to correlate the gene with the elementary functional unit
, i.e., a unit that cannot be understood as a collection of functional units together with the emergent function(s) arising from their combination. Whereas single molecules and/or molecular complexes and their interactions play the central role in molecular biology, researchers in other biological disciplines might be more interested in higher order functional units. Such a coarse-grained level of functionality could be represented by chemical reactions, interaction networks, or phenotypic traits rather than products as functional units. We suggest that each of these is a valid starting point for a gene definition.
In contrast to the Genon Theory, we postulate that genes are heritable
and therefore need to be part of the inherited material. In 1952, Hershey and Chase found that the “instructions” for functional units are made of genetic material, nucleic acid in general, DNA if present. However, exceptions to this rule are well known, e.g., epigenes, protein-based inheritance (i.e., centriols and prions) and RNA-based inheritance (Lolle et al. 2005
) do instruct heritable functional units. Heritability is determined by the process of inheritance, a sequence of reproduction and segregation. We may or may not want to restrict the concept of genes to entities that are inherited in a particular way, namely by means of the genetic material that comprises the genome.
A formal mathematical investigation of this schema should eventually be able to relate elementary functional units to their source in the inherited material
. If a function-based gene concept is feasible at all, such a mapping is the indispensable pre-requisite for genes to become a useful notion for molecular biology. We suspect that such a mapping is not necessarily possible for all underlying definitions of “function”, “unit” and/or their combinations. It is even conceivable that such a mapping can never be constructed, in which case we will have to abandon the notion of “functional genes”. Even if we can construct the map, there is no guarantee that the genomic source
corresponding to a particular definition of functional unit will show properties that we would expect or desire from a gene. In particular, the genomic representation of our functionally defined genes may well be frustratingly complex and disparate from the physical entities that we deal with in the various flavors of “omics”.
In line with our arguments above we suggest that an appropriate definition of a functional unit should not make explicit reference to a particular class of molecules. While determining the chemical composition is within the scope of acceptable experimental protocols, a consequence of this type of protocol is the disparate classification of molecules with similar or identical functions, e.g., a protein enzyme versus a ribozyme that catalyzes the same chemical reaction. It is at least conceivable that the chemical implementation of a catalyst or regulator is irrelevant for a cell. Consequently, functional units may just as well be of DNA nature. Operators and other cis
-regulatory elements behave much like regulatory genes when assayed with many procedures typically used in genetics. In such a context, we may well be obliged to treat them as functional units and consequently as genes. On the other hand, Developmentally Regulated DNA Rearrangements (DRDR) are not uncommon as mechanisms of expression regulation throughout eukaryotes (Zufall et al. 2005
). Ciliate genome processing (which interestingly is regulated by small RNAs (Garnier et al. 2004
)), chromatin diminution (i.e., the selective elimination of portions of chromosomes), the vertebrate immune system, and the amplification of rDNA genes are the most prominent examples. DRDR is also involved in mating type switching in yeast and prokaryotic differentiation, see, e.g., (Carrasco et al. 1995
). Hence processes operating on the genomic material have to be included in the processing program.
The boundaries of our genes as Heritable Elementary Functional Units are eventually determined by the underlying notion of function. Depending on this choice, genes may or may not contain the information necessary to orchestrate the production of the corresponding functional units from the heritable material.