Niall Dillon

Rediscovered in 1900 from theresearch of Gregor Mendel, andnamed in 1909 by WilhelmJohanssen, the gene became one of the mostinfluential scientific concepts of the twenti-eth century. Yet despite its iconic power, itremains a curiously nebulous entity thatdefies easy definition. From the start, therewas a tension between the concept of thegene as a unit of inheritance which wasdefined in purely operational terms as anautonomous unit that transmits specifictraits through multiple generations andthe gene as a physical entity whose posi-tion could be mapped in relation to othergenes on the chromosome.

The difficulty in reconciling these twoviews of the gene was highlighted whenAlfred H. Sturtevant and Hermann Mullerseparately described a new type of mutationin Drosophila in the 1920s and early 1930s.These mutants were the result of transloca-tions that alter the positions of genes on thechromosome but not their physical struc-ture. For example, placing a gene close to acompacted, transcriptionally silent region(heterochromatin) often gives rise to flieswith variegated phenotypes (such as patches of red and white eye colour) wherethe affected gene is expressed in some cellsand silenced in others.

The discovery that genes could be affectedby their position on the chromosome raisedthe question of whether the autonomousgene proposed by classical genetics actuallyexisted. Leslie Dunn commented in 1937that the gene was showing signs of disap-pearing in a cloud of position effects, andRichard Goldschmidt adopted the highlycontroversial view that the particulate geneconcept should be abandoned altogether.The gene was and still is too useful to be discarded, but even now, 50 years after the discovery of the double-helical structureof DNA, the problem of the relationshipbetween Johannsens unit of inheritance andthe gene as a physical structure is still notfully resolved.

A gene gives rise to a phenotype throughits ability to generate an RNA or proteinproduct. Thus the functional genetic unitmust encompass not only the DNA that is transcribed into RNA, but all of the surrounding DNA sequences that regulateRNA transcription. If it is to satisfy the fulldefinition of the particulate gene, the func-tional unit should also be isolated fromneighbouring genes.

Transgenic assays have been used to try to determine the nature of the genetic

functional unit and to establish a physicalbasis for gene autonomy. Because mosttransgenes are subject to position effects,they can be used to search for sequences that allow them to function normally whenintegrated at any position on the chromo-some. Candidate sequences are introducedinto the transgene construct,and expression isanalysed to test for sensitivity to integrationposition. These studies have led to two quitedifferent perspectives on the problem.

The simplest explanation for gene auton-omy would be for each gene to be flanked by barriers or insulators that isolate it from surrounding sequences. But despite inten-sive searches, such barriers have proved to beelusive. Where they have been found, theyhave turned out to be extremely diverse instructure, and often coincide with sequencesthat have other functions (for example,gene promoters). This heterogeneity arguesagainst the idea that barrier effects evolved as specific and highly conserved functions.Instead, it suggests that sequences withother roles can sometimes acquire a barrierfunction by virtue of their location.

There is also a quite different way of look-ing at genetic functional units,which focuseson the interactions with transcription factors (sequence-specific DNA-bindingproteins) that make a gene competent totranscribe its RNA product. If these factorsare able to bind to their recognition sites andinitiate chromatin remodelling despite thepresence of inhibitory chromatin, then theywill be able to overcome position effects.Dominance of clustered transcription-factorbinding sites over negative position effectswas first described by Frank Grosveld andcolleagues for the human b-globin locuscontrol region, and has since been demon-strated to operate at a number of other genes.These results portray the functional unit primarily as a dynamic information processor,comprising the transcribed region and associated factor-binding sites, which mayextend over hundreds of kilobases of DNA.

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Crucially, this type of organization allowsfunctional units to overlap yet still remainisolated from one another if they bind to different sets of factors. As more genes arecharacterized in detail, it is becoming clearthat overlap of genetic functional units is awidespread phenomenon.

Recent studies have also providedintriguing evidence that autonomy might be an optional feature for many genes.Microarray analysis of large numbers ofgenes in Drosophila and Caenorhabditiselegans showed that genes with similar patterns of expression are often groupedtogether on the chromosome despitebeing functionally unrelated. The authors of one of these studies, Paul Spellman andGerald Rubin, have noted that leaky geneexpression is often phenotypically silent.They speculate that such expression could bea frequent consequence of being locatedclose to a highly expressed gene. If correct,this would indicate that complete isolationfrom neighbouring genes instead of beingan intrinsic property evolves when it isrequired to prevent harmful position effects.

The particulate gene has shaped thinkingin the biological sciences over the past century. But attempts to translate such acomplex operational concept into a discretephysical structure with clearly definedboundaries were always likely to be prob-lematic, and now seem doomed to failure.Instead, the gene has become a flexible entitywith borders that are defined by a combina-tion of spatial organization and location, theability to respond specifically to a particularset of cellular signals, and the relationshipbetween expression patterns and the finalphenotypic effect. nNiall Dillon is in the Gene Regulation andChromatin Group, MRC Clinical Sciences Centre,Faculty of Medicine, Imperial College,Hammersmith Campus, Du Cane Road,London W12 0NN, UK.

FURTHER READINGBeurton, P., Falk, R. & Rheinberger, H.-J. (eds) TheConcept of the Gene in Development and Evolution(Cambridge Univ. Press, Cambridge, 2000).Dillon, N. & Sabbattini, P. BioEssays 22,657665 (2000). Spellman, P, T. and Rubin, G. M. J. Biol. 1, 5 (2002).

Positions, please... Geneautonomy Position effects continue to raisequestions about the physicalstructure of the particulatemendelian gene.

Eye-opener: studies of Drosophila showed that agenes position can affect its function.

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2003 Nature Publishing Group