Gene Clustering in Eukaryotes


Recent advances in genomics have provided us with better understanding of genomes from many different species, their architectures and evolutionary relationships. Genome architecture (a nonrandom arrangement of functional elements in the genome, such as genes and regulatory regions) is different in eukaryotes than in prokaryotes. Although in prokaryotes, many genes are organised into linearly positioned cotranscribed groups (operons), eukaryotic genomes possess very small number of genes organised into operons. The acquisition of the nuclear membrane, decoupling of transcription and translation and adoption of the ribosome‐scanning mechanism for translation initiation (necessitating monocistronic messenger ribonucleic acids (mRNAs)) are possible reasons for the loss of operon structure in eukaryotes. Despite the general trend of low level of gene clustering within operon structures in eukaryotes, there is an evidence for nonrandom linear and spatial organisation of eukaryotic genomes, as a result of multiple mechanisms that can lead to the proximity of coexpressed genes.

Key Concepts:

  • Albeit not as common as the gene clustering within operons observed in bacteria, linear gene clustering does occur in eukaryotes.

  • In eukaryotes, linear gene clusters form predominantly by partially adaptive, but largely neutral processes, such as genome rearrangements.

  • In natal clusters, genes occupy adjacent positions on chromosomes as a result of a tandem duplication and consequent divergence.

  • In embedded clusters, coding sequence of one gene may be entirely positioned within an intron of another gene, or one gene may have exons that interweave with the exons of other genes.

  • In coregulated clusters, genes could be either linearly clustered on chromosomes to share regulatory sequences, or genes could be spatially colocalised within the nucleus forming transcription factories.

  • Linearly coregulated clusters in eukaryotes include: alternatively spliced transcripts, polycistronic messages, uORFs and genes regulated by bidirectional promoters.

  • Spatial sequestration of genes positioned distantly on the same chromosome or even on different chromosomes can modulate coregulated gene expression.

Keywords: linear gene clustering; spatial gene clustering; gene duplication; operons; polycistronic messages; trans‐splicing

Figure 1.

Examples of possible mechanisms that lead to gene clustering in eukaryotes. (a) Tandem duplication due to an unequal crossingover results in duplication of gene B and formation of gene B' that may aquire a new function. (b) Genome reduction may result in removal of large segment of , which may position genes A and B proximaly and under the control of the same promoter and regulatory elements. (c) An example of a selectively advanatageous cluster in prokaryotes. (d) An example of a spatial cluster; genes A and B are positioned distantly on the chromosome I, while genes C and D are positioned on chromosomes II and III. All of these genes are specially clustered in the nucleus.

Figure 2.

Examples of gene clustering in eukaryotes. (a) Organisation of the α‐ and β‐globin gene clusters on human chromosomes 16 and 11. Boxes represent gene locations. (b) Organisation of the Drosophila gene sina within the intron of Rh4; boxes represent exons, and introns are depicted as angled segments between exons. (c) Organisation of the cha‐1 and unc‐17 loci in Caenorhabditis elegans. Here, the first exon (SL1) is shared between the two transcripts; exon map after Alfonso et al. © Elsevier. (d) Organisation of the LASS1 and GDF1 loci in humans; transcript map after Lee © National Academy of Sciences, USA. (e) Organisation of CPA1 and its uORF controller in Saccharomyces cerevisiae. (f) Organisation of RanBP1 and Htf9‐c bidirectional genes located on murine chromosome 16. Reproduced from Guarguaglini et al. . © Portland Press Limited. (g) A generalised model for trans‐splicing in nematodes. The leader exon SL1, containing a CAP (5′ mRNA cap), is trans‐spliced onto the 5′ end of a polycistronic message, whereas the CAP‐containing SL2 leader is trans‐spliced into internal sites to generate multiple, mature mRNAs.



Alfonso A, Grundahl K, McManus JR, Asbury JM and Rand JB (1994) Alternative splicing leads to two cholinergic proteins in Caenorhabditis elegans. Journal of Molecular Biology 241: 627–630.

Andrews J, Smith M, Merakovsky J et al. (1996) The stoned locus of Drosophila melanogaster produces a dicistronic transcript and encodes two distinct polypeptides. Genetics 143: 1699–1711.

Ben‐Elazar S, Yakhini Z and Yanai I (2013) Spatial localization of co‐regulated genes exceeds genomic gene clustering in the Saccharomyces cerevisiae genome. Nucleic Acids Research 41: 2191–2201.

Ben‐Shahar Y, Nannapaneni K, Casavant TL, Scheetz TE and Welsh MJ (2007) Eukaryotic operon‐like transcription of functionally related genes in Drosophila. Proceedings of the National Academy of Sciences of the USA 104: 222–227.

Blumenthal T, Evans D, Link CD et al. (2002) A global analysis of Caenorhabditis elegans operons. Nature 417: 851–854.

Blumenthal T and Gleason KS (2003) Caenorhabditis elegans operons: form and function. Nature Reviews Genetics 4: 110–118.

Brogna S and Ashburner M (1997) The Adh‐related gene of Drosophila melanogaster is expressed as a functional dicistronic messenger RNA: multigenic transcription in higher organisms. EMBO Journal 16: 2023–2031.

Chen N and Stein L (2006) Conservation and functional significance of gene topology in the genome of Caenorhabditis elegans. Genome Research 16: 606–617.

Coenye T and Vandamme P (2005) Organisation of the S10, spc and alpha ribosomal protein gene clusters in prokaryotic genomes. FEMS Microbiology Letters 242: 117–126.

Ferrier DE and Holland PW (2001) Ancient origin of the Hox gene cluster. Nature Reviews Genetics 2: 33–38.

Guarguaglini G, Battistoni A, Pittoggi C et al. (1997) Expression of the murine RanBP1 and Htf9‐c genes is regulated from a shared bidirectional promoter during cell cycle progression. Biochemical Journal 325: 277–286.

Hermsen R, ten Wolde PR and Teichmann S (2008) Chance and necessity in chromosomal gene distributions. Trends in Genetics 24: 216–219.

Hill JR and Morris DR (1993) Cell‐specific translational regulation of S‐adenosylmethionine decarboxylase mRNA. Dependence on translation and coding capacity of the cis‐acting upstream open reading frame. Journal of Biological Chemistry 268: 726–731.

Huynen MA, Snel B and Bork P (2001) Inversions and the dynamics of eukaryotic gene order. Trends in Genetics 17: 304–306.

Itoh T, Takemoto K, Mori H and Gojobori T (1999) Evolutionary instability of operon structures disclosed by sequence comparisons of complete microbial genomes. Molecular Biology and Evolution 16: 332–346.

Jacob F, Perrin D, Sanchez C and Mond J (1960) L'operon: groupe de genes a l'expression coordonne par un operateur. Comptes Rendus de l'Académie des Sciences 245: 1727–1729.

Komonyi O, Schauer T, Papai G, Deak P and Boros IM (2009) A product of the bicistronic Drosophila melanogaster gene CG31241, which also encodes a trimethylguanosine synthase, plays a role in telomere protection. Journal of Cell Science 122: 769–774.

Lawrence JG (1997) Selfish operons and speciation by gene transfer. Trends in Microbiology 5: 355–359.

Lawrence JG and Roth JR (1996) Selfish operons: horizontal transfer may drive the evolution of gene clusters. Genetics 143: 1843–1860.

Lee S‐J (1991) Expression of growth/differentiation factor 1 in the nervous system: conservation of a bicistronic structure. Proceedings of the National Academy of Sciences of the USA 88: 4250–4254.

Lipinski KJ, Farslow JC, Fitzpatrick KA et al. (2011) High spontaneous rate of gene duplication in Caenorhabditis elegans. Current Biology 21: 3016–3310.

Lovett PS and Rogers EJ (1996) Ribosome regulation by the nascent peptide. Microbiological Reviews 60: 366–385.

Mekhail K and Moazed D (2010) The nuclear envelope in genome organization, expression and stability. Nature Reviews Molecular cell Biology 11: 317–328.

Misra S, Crosby MA, Mungall CJ et al. (2002) Annotation of the Drosophila melanogaster euchromatic genome: a systematic review. Genome Biology 3: research0083.1–research0083.22.

Misteli T (2007) Beyond the sequence: cellular organization of genome function. Cell 128: 787–800.

Osbourn AE and Field B (2009) Operons. Cellular and Molecular Life Sciences 66: 3755–3775.

Pierard A and Schroter B (1978) Structure–function relationships in the arginine pathway carbomoylphosphate synthase of Saccharomyces cerevisiae. Journal of Bacteriology 134: 167–176.

Schneider R and Grosschedl R (2007) Dynamics and interplay of nuclear architecture, genome organization, and gene expression. Genes and Development 21: 3027–3043.

Semple C and Wolfe KH (1999) Gene duplication and gene conversion in the Caenorhabditis elegans genome. Journal of Molecular Evolution 48: 555–564.

Slot JC and Rokas A (2010) Multiple GAL pathway gene clusters evolved independently and by different mechanisms in fungi. Proceedings of the National Academy of Sciences of the USA 107: 10136–10141.

Takizawa T, Meaburn KJ and Misteli T (2008) The meaning of gene positioning. Cell 135: 9–13.

Trinklein ND, Aldred SF, Hartman SJ et al. (2004) An abundance of bidirectional promoters in the human genome. Genome Research 14: 62–66.

Uyar B, Chu JSC, Vergara IA et al. (2012) RNA‐seq analysis of the C. briggsae transcriptome. Genome Research 22: 1567–1580.

Wall AA, Phillips AM and Kelly LE (2005) Effective translation of the second cistron in two Drosophila dicistronic transcripts is determined by the absence of in‐frame AUG codons in the first cistron. Journal of Biological Chemistry 280: 27670–27678.

Wei W, Pelechano V, Järvelin AI and Steinmetz LM (2011) Functional consequences of bidirectional promoters. Trends in Genetics 27: 267–276.

Wolf YI, Rogozni IB, Kondrashov AS and Koonin EV (2001) Genome alignment, evolution of prokaryotic genome organization and prediction of gene function using genomic context. Genome Research 11: 356–372.

Further Reading

Batada NN and Hurst LD (2007) Evolution of chromosome organization driven by selection for reduced gene expression noise. Nature Genetics 39: 945–949.

Blumenthal T (1998) Gene clusters and polycistronic transcription in eukaryotes. BioEssays 20: 480–487.

Holland PW (2001) Beyond the Hox: how widespread is homeobox gene clustering? Journal of Anatomy 199: 13–23.

Lawrence JG (1999) Selfish operons: the evolutionary impact of gene clustering in prokaryotes and eukaryotes. Current Opinion in Genetics and Development 9: 642–648.

Mayor LR, Fleming KP, Müller A, Balding DJ and Sternberg MJ (2004) Clustering of protein domains in the human genome. Journal of Molecular Biology 340: 991–1004.

Mulley JF, Chiu CH and Holland PW (2006) Breakup of a homeobox cluster after genome duplication in teleosts. Proceedings of the National Academy of Sciences of the USA 103: 10369–10372.

Sémon M and Duret L (2006) Evolutionary origin and maintenance of coexpressed gene clusters in mammals. Molecular Biology and Evolution 23: 1715–1723.

Singer GA, Lloyd AT, Huminiecki LB and Wolfe KH (2005) Clusters of co‐expressed genes in mammalian genomes are conserved by natural selection. Molecular Biology and Evolution 22: 767–775.

Web Links

Growth differentiation factor 1 (GDF1); GeneID: 2657. GeneLink:

Growth differentiation factor 1 (GDF1); MIM number: 602880. OMIM:

LAG1 longevity assurance homolog 1 (LASS1); GeneID: 10715. GeneLink:

LAG1 longevity assurance homolog 1 (LASS1); MIM number: 606919. OMIM:

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Tarailo‐Graovac, Maja, and Chen, Nansheng(Oct 2013) Gene Clustering in Eukaryotes. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006117.pub3]