Key Points
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Despite early assumptions, gene order in eukaryotes is not random. In all well-studied genomes, genes of similar and/or coordinated expression tend to be linked.
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Understanding the clustering of related genes is crucial to our understanding of chromosome function and evolution.
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Clusters are not only found for co-expressed genes, but are also found for genes with products that are involved in the same metabolic pathway or that are associated in protein–protein complexes.
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There seems to be a correlation between the physical size of co-expression clusters and organism complexity, ranging from a few kilobases in yeast to several megabases in mammals.
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Many small clusters might be the result of shared regulatory elements.
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Co-expression (or co-suppression) of genes in many larger clusters can result from histone modifications, which spread down a chromosome until they meet a boundary element.
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Positioning of genes within the three-dimensional chromatin structure might promote or repress expression. In addition, some clusters might promote the association of genes with nuclear structures (for example, the nucleolus or SC-35 domains).
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The initial formation of clusters might be unrelated to expression regulation; for example, genetic linkage might be favoured for interacting loci.
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A theory of the evolution of genome organization is needed. This must incorporate mechanisms of genome rearrangement, mechanisms of gene-expression control and the evolutionary forces that result from different interactions between loci.
Abstract
In eukaryotes, unlike in bacteria, gene order has typically been assumed to be random. However, the first statistically rigorous analyses of complete genomes, together with the availability of abundant gene-expression data, have forced a paradigm shift: in every complete eukaryotic genome that has been analysed so far, gene order is not random. It seems that genes that have similar and/or coordinated expression are often clustered. Here, we review this evidence and ask how such clusters evolve and how this relates to mechanisms that control gene expression.
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Acknowledgements
We wish to thank two anonymous reviewers and J. Lawrence for comments on an earlier version of the manuscript. We also thank F. Grosveld, A. Ward, R. Kelsh and L. Weinert for discussion. M.J.L. is funded by a Royal Society University Research Fellowship. L.D.H. and C.P. are funded by the Biotechnology and Biological Sciences Research Council.
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DATABASES
LocusLink
FURTHER INFORMATION
Glossary
- TRANSGENE
-
Foreign DNA that is inserted experimentally into totipotent embryonic cells or into unicellular organisms.
- POSITION EFFECT
-
In general terms, any effect of a gene's genomic location on its expression. A phenomenon that is often observed in transgenic organisms in which transcription of an inserted transgene is affected by the proximity to heterochromatin.
- IMPRINTED GENES
-
Genes that are expressed from only one of the two parental copies, the choice being dependent on the sex of the parent from which the gene was derived.
- CO-EXPRESSION
-
A property of genes that show similar spatial or temporal expression patterns.
- QUANTITATIVE TRAIT LOCI
-
(QTLs). Genes that segregate for a quantitative trait. QTL mapping allows the determination of the genomic location of QTL using genetic markers.
- SERIAL ANALYSIS OF GENE EXPRESSION
-
(SAGE). An experimental method for determining transcript abundances in a tissue on the basis of sequencing thousands of short gene-specific tags.
- TRANSCRIPTION-COUPLED REPAIR
-
A specialized repair pathway that counteracts the toxic effects of DNA damage in transcriptionally active genes.
- EXPRESSION BREADTH
-
The number of tissues in which a gene is expressed.
- EXPRESSION RATE
-
mRNA or protein abundances of a gene in a given tissue or under given cellular conditions.
- KYOTO ENCYCLOPAEDIA OF GENES AND GENOMES
-
(KEGG). An online database that integrates current knowledge on molecular interaction networks (for example, metabolic pathways and protein complexes).
- MUNICH INFORMATION CENTRE FOR PROTEIN SEQUENCES
-
(MIPS). An online database that provides protein sequence-related information on the basis of whole-genome analysis of Saccharomyces cerevisiae, Arabidopsis thaliana and Neurospora crassa.
- GENE ONTOLOGY [DATABASE]
-
(GO). A collaborative effort to address the need for consistent descriptions and functional classification of gene products in different databases.
- HISTONES
-
Positively charged DNA-binding proteins that mediate the folding of DNA.
- LOCUS CONTROL REGION
-
(LCR). Cis-acting sequence that organizes a gene cluster into an active chromatin block and enhances transcription.
- CHROMATIN
-
A highly condensed structure of DNA that is associated with histone proteins and other DNA-binding proteins.
- BOUNDARY ELEMENTS [OR INSULATORS]
-
Cis-acting DNA sequences that act as barriers to the effects of distal enhancers and silencers.
- BIDIRECTIONAL PROMOTERS
-
Promoter sequences between divergently transcribed neighbouring gene pairs that initiate transcription in both directions.
- POLYCISTRONIC TRANSCRIPT
-
mRNA that encodes several polypeptides; a common phenomenon in bacteria.
- DNA METHYLATION
-
Covalent modification of the DNA that inhibits transcription initiation.
- HISTONE ACETYLATION/DEACETYLATION
-
These processes regulate changes in chromatin structure by covalent modification of histone proteins, and therefore influence the ability of transcriptions factors to bind to promoters.
- CHROMATIN IMMUNOPRECIPITATION
-
An experimental method that is used for analysing the acetylation state of histones in a specific genomic region.
- ISOCHORIC [STRUCTURE]
-
Large-scale variation in the G+C content of vertebrate genomes.
- SC-35 DOMAINS
-
A set of 10–30 prominent domains of the eukaryotic nucleus that are concentrated in mRNA metabolic factors. They are probably important in organizing euchromatin domains.
- NUCLEOSOMAL FIBRE
-
Fibre of chromatin that is made up of nucleosomes.
- SPORULATION
-
A defence mechanism of microbes in response to unfavourable environmental conditions that results in spores that are highly resistant to physical and chemical abuse.
- LINKAGE DISEQUILIBRIUM
-
Non-random assortment of alleles at different, usually linked, loci. Low population size and selection can increase linkage disequilibrum whereas recombination reduces linkage.
- MEIOTIC DRIVE
-
A departure from Mendelian segregation of chromosomes.
- MAJOR HISTOCOMPATIBILITY COMPLEX
-
(MHC). MHC molecules bind peptide fragments that are derived from pathogens and display them on the cell surface for recognition by the appropriate T cells. The organizations of the MHC gene clusters are similar in many species.
- GENE CONVERSION
-
Non-reciprocal transfer between a pair of non-allelic or allelic DNA sequences during meiosis and mitosis.
- NEUTRALIST [MODEL]
-
Evolutionary model that assumes that the trait being investigated has no selective advantage. Changes in allele frequency are said to be the result of chance (drift) alone.
- EFFECTIVE POPULATION SIZE
-
The number of individuals in a population that contribute to the next generation. It never exceeds the actual population size.
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Hurst, L., Pál, C. & Lercher, M. The evolutionary dynamics of eukaryotic gene order. Nat Rev Genet 5, 299–310 (2004). https://doi.org/10.1038/nrg1319
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DOI: https://doi.org/10.1038/nrg1319
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Gene function prediction in five model eukaryotes exclusively based on gene relative location through machine learning
Scientific Reports (2022)
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Three chromosome-scale Papaver genomes reveal punctuated patchwork evolution of the morphinan and noscapine biosynthesis pathway
Nature Communications (2021)