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  • Review Article
  • Published:

Genome-wide transcription and the implications for genomic organization

Nature Reviews Genetics volume 8, pages 413–423 (2007)Cite this article

Key Points

  • In-depth analyses of the transcriptional outputs of eukaryotic genomes suggest that the information content of a genome is complex, and that this complexity manifests itself at two levels: the fraction of the genome that is devoted to encoding functional elements is higher than expected, and multiple functional elements can exist in a single region.

  • The architecture of the eukaryotic transcriptome is clearly much more complex than could have been anticipated in terms of the number of nucleotides that are transcribed and the final arrangements of nucleotides that are present in mature processed RNA molecules.

  • The complexity of genomic organization suggests that the currently accepted model, by which each region of DNA carries a single discrete function, must be re-evaluated, and an interleaved model for the arrangement of functional elements is more likely to represent the informational content of eukaryotic genomes.

  • Despite the potential problems that are presented by use of the same genomic space for multiple purposes, the following advantages are brought by this complex genomic organization: an increase in protein-coding transcript diversity; a widespread adoption of RNA transcripts as regulatory agents; and a reliance on transcription as a regulatory process.

  • On a global level, an interleaved genomic organization of functional elements seems to be preserved in different kingdoms, and the arrangement of specific overlapping functional elements is preserved among different species. This suggests that such a model does indeed provide advantages throughout evolution.

  • Mutations at non-canonical sites, such as intronic regions that lie distal from splice sites, can affect fitness if they involve internal promoter regions, an exon of an overlapping transcript or a short RNA.

Abstract

Recent evidence of genome-wide transcription in several species indicates that the amount of transcription that occurs cannot be entirely accounted for by current sets of genome-wide annotations. Evidence indicates that most of both strands of the human genome might be transcribed, implying extensive overlap of transcriptional units and regulatory elements. These observations suggest that genomic architecture is not colinear, but is instead interleaved and modular, and that the same genomic sequences are multifunctional: that is, used for multiple independently regulated transcripts and as regulatory regions. What are the implications and consequences of such an interleaved genomic architecture in terms of increased information content, transcriptional complexity, evolution and disease states?

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Figure 1: Overlapping transcriptional architecture — the PISD example.
Figure 2: Fusion transcripts combining exons of different genes and unannotated regions.
Figure 3: RNA-based signalling pathways.
Figure 4: Conservation of an overlapping region of two genes on opposite strands.

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Acknowledgements

We apologize to the authors whose primary work has not been cited due to the space constraints. Some of the work described in this Review has been funded in part with Federal Funds from the US National Cancer Institute and from the US National Human Genome Research Institute, and by Affymetrix. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Service, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

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  1. Affymetrix, Inc., 3420 Central Expressway, Santa Clara, 95051, California, USA

    Philipp Kapranov, Aarron T. Willingham & Thomas R. Gingeras

Authors
  1. Philipp Kapranov
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  2. Aarron T. Willingham
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  3. Thomas R. Gingeras
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Corresponding author

Correspondence to Thomas R. Gingeras.

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The authors are employees of Affymetrix, Inc.

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FURTHER INFORMATION

Affymetrix Human Transcriptome web site

ENCODE

RNAdb database of non-coding RNAs

UCSC Genome Browser

Glossary

Tiling array

A microarray design in which the probes are selected to interrogate a genome with a consistent, pre-determined spacing between each probe.

SAGE

Serial analysis of gene expression; a technique for mapping the 3′ ends of transcripts.

PET

Paired-end ditag; a method that extracts 36-bp signatures with 18 bp from the 5′ end and another 18 bp from the 3′ end of each cDNA.

Pyrosequencing

A method for DNA sequencing in which the inorganic pyrophosphate (PPi) that is released from a nucleoside triphosphate on DNA chain elongation is detected by a bioluminometric assay.

Massively parallel signature sequencing

A sequencing procedure that allows the reading, in parallel, of short sequence segments of about 17 or 12 nucleotides long, from hundreds of thousands of microbead-attached cDNAs.

LongSAGE

Long serial analysis of of gene expression; a method that allows for the cloning of 20-nucleotide SAGE tags.

RACE/tiling arrays

An unbiased, high-throughput method to identify the extents of DNA products from rapid amplification of cDNA ends (RACE) reactions by hybridizing them to tiling arrays.

CAGE

Cap analysis of gene expression; a technique for mapping the 5′ ends of transcripts.

P element

A member of a family of transposable elements that are widely used as the basis of tools for mutating and manipulating the genome of Drosophila melanogaster.

ChIP–chip

A method that combines chromatin immunoprecipitation with microarray technology to identify in vivo sites of protein–DNA interactions.

MicroRNA

A form of ssRNA, typically 20–25 nucleotides long that is thought to regulate the expression of other genes, either through inhibiting protein translation or degrading a target mRNA transcript through a process that is similar to RNAi.

snoRNA

A type of small RNA, the functions of which include RNA cleavage and specification of sites of ribose methylation and pseudouridylation.

snRNA

A small RNA molecule that functions in the nucleus by guiding the assembly of macromolecular complexes on the target RNA to allow site-specific modifications or processing reactions to occur.

Locus control region

A cis-acting sequence that organizes a gene cluster into an active chromatin block and enhances transcription.

Evolutionary conservation scores

A quantitative measure of evolutionary relationships derived from comparative analysis of genomic DNA sequences from multiple species. Phastcons are one type of evolutionary conservation score.

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Kapranov, P., Willingham, A. & Gingeras, T. Genome-wide transcription and the implications for genomic organization. Nat Rev Genet 8, 413–423 (2007). https://doi.org/10.1038/nrg2083

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